WO1995018136A1 - Backbone modified oligonucleotide analogs and solid phase synthesis thereof - Google Patents
Backbone modified oligonucleotide analogs and solid phase synthesis thereof Download PDFInfo
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- WO1995018136A1 WO1995018136A1 PCT/US1994/014883 US9414883W WO9518136A1 WO 1995018136 A1 WO1995018136 A1 WO 1995018136A1 US 9414883 W US9414883 W US 9414883W WO 9518136 A1 WO9518136 A1 WO 9518136A1
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- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
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- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
Definitions
- This invention relates to the synthesis of nuclease resistant oligonucleotide analogs which are useful for therapeutics, diagnostics and as research reagents.
- the invention relates to solid-phase synthetic methods wherein amine-terminated synthons are coupled with aldehyde-terminated synthons to produce hydroxylamino- containing and/or hydrazino-containing covalent linkages.
- Classical therapeutics generally has focused upon interactions with proteins in an effort to moderate their disease causing or disease potentiating functions. Recently, however, attempts have been made to moderate the production of proteins by interactions with the molecules (i.e., intracellular RNA) that direct their synthesis. These interactions have involved hybridization of complementary "antisense" oligonucleotides or certain analogs thereof to RNA. Hybridization is the sequence-specific hydrogen bonding of oligonucleotides or oligonucleotide analogs to RNA or to single stranded DNA. By interfering with the production of proteins, it has been hoped to effect therapeutic results with maximum effect and minimal side effects.
- oligonucleotides and oligonucleotide analogs like other therapeutics, depends on a number of factors that influence the effective concentration of these agents at specific intracellular targets.
- One important factor for oligonucleotides is the stability of the species in the presence of nucleases. It is unlikely that unmodified oligonucleotides will be useful therapeutic agents because they are rapidly degraded by nucleases. Modification of oligonucleotides to render them resistant to nucleases therefore is greatly desired.
- oligonucleotides Modification of oligonucleotides to enhance nuclease resistance generally has taken place on the phosphorus atom of the sugar-phosphate backbone. Phosphorothioates, methyl phosphonates, phosphoramidates and phosphorotriesters have been reported to confer various levels of nuclease resistance. Phosphate-modified oligonucleotides, however, generally have suffered from inferior hybridization properties. See, e . g. , Cohen, J.S., ed. Oligonucleotides : Antisense Inhibi tors of Gene Expression, (CRC Press, Inc., Boca Raton FL, 1989) .
- Another key factor is the ability of antisense compounds to traverse the plasma membrane of specific cells involved in the disease process.
- Cellular membranes consist of lipid-protein bilayers that are freely permeable to small, nonionic, lipophilic compounds and are inherently impermeable to most natural metabolites and therapeutic agents. See, e . g. , Wilson, Ann . Rev. Biochem . 1978, 47, 933.
- the biological and antiviral effects of natural and modified oligonucleotides in cultured mammalian cells have been well documented. It appears that these agents can penetrate membranes to reach their intracellular targets.
- modified oligonucleotides and oligonucleotide analogs are internalized less readily than their natural counterparts.
- the activity of many previously available antisense oligonucleotides has not been sufficient for practical therapeutic, research or diagnostic purposes.
- Two other serious deficiencies of prior art compounds designed for antisense therapeutics are inferior hybridization to intracellular RNA and the lack of a defined chemical or enzyme-mediated event to terminate essential RNA functions.
- Modifications to enhance the effectiveness of the antisense oligonucleotides and overcome these problems have taken many forms. These modifications include base ring modifications, sugar moiety modifications and sugar-phosphate backbone modifications. Prior sugar-phosphate backbone modifications, particularly on the phosphorus atom, have effected various levels of resistance to nucleases. However, while the ability of an antisense oligonucleotide to bind to specific DNA or RNA with fidelity is fundamental to antisense methodology, modified phosphorus oligonucleotides have generally suffered from inferior hybridization properties.
- the present invention provides novel compounds that mimic and/or modulate the activity of wild-type nucleic acids.
- the compounds contain a selected nucleoside sequence which is specifically hybridizable with a targeted nucleoside sequence of single stranded or double stranded DNA or RNA.
- At least a portion of the compounds of the invention has structure I :
- L 1 -L 2 -L 3 -L 4 is CHa-R A -NRi-CHa, CHa-NR ⁇ A -CHa, R A -NR ⁇
- each R x and R 2 are, independently, the same or different and are H; alkyl or substituted alkyl having 1 to about 10 carbon atoms; alkenyl or substituted alkenyl having 2 to about 10 carbon atoms; alkynyl or substituted alkynyl having 2 to about 10 carbon atoms; alkaryl, substituted alkaryl, aralkyl, or substituted aralkyl having 7 to about 14 carbon atoms; alicyclic; heterocyclic; a reporter molecule; an RNA cleaving group; a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacodynamic properties of an • ⁇ oligonucleotide;
- B x is a nucleosidic base; n is an integer greater than 0; Q is 0, S, CH 2 , CHF or CF 2 ; X is H; OH; alkyl or substituted alkyl having 1 to about 10 carbon atoms; alkaryl, substituted alkaryl, aralkyl, or substituted aralkyl having 7 to about 14 carbon atoms; F; Cl; Br; CN; CF 3 ; 0CF 3 ; OCN; 0-alkyl; S-alkyl; N-alkyl; O- alkenyl; S-alkenyl; N-alkenyl; S0CH 3 ; S0 2 CH 3 ; 0N0 2 ; N0 2 ; N 3 ; NH 2 ; heterocycloalkyl; heterocycloalkaryl; aminoalkylamino; polyalkylamino or substituted silyl; an RNA cleaving group; a group for improving the pharmacokinetic properties of an
- the compounds of the invention are prepared by coupling preselected 3' -functionalized and 4' -functionalized nucleosides and/or oligonucleotides under conditions effective to form the above-noted L 1 -L 2 -L 3 -L 4 linkages.
- a 3'-C-formyl nucleoside or oligonucleotide synthon is reacted with a support-bound 5'- hydroxylamino or 5'-hydrazino nucleoside or oligonucleotide synthon.
- a 4'-C-formyl synthon is reacted with a support-bound 3' -methylhydroxylamino or 3' - methylhydrazino synthon.
- Z- L and Y 2 are selected such that
- Figures 1 and 2 show exemplary compounds used in accordance with the invention.
- Figure 3 is a synthetic scheme depicting a preferred method for preparation of oxime-linked oligonucleotide analogs.
- nucleoside refers to a unit made up of a heterocyclic base and its sugar.
- nucleotide refers to a nucleoside having a phosphate group on its 3' or 5 ' sugar hydroxyl group. Thus nucleosides, unlike nucleotides, have no phosphate group.
- Oligonucleotide refers to a plurality of joined nucleotide units formed in a specific sequence from naturally occurring bases and pentofuranosyl groups joined through a sugar group by native phosphodiester bonds. This term refers to both naturally occurring and synthetic species formed from naturally occurring subunits.
- oligonucleotide analogs that is, compounds which function like oligonucleotides but which have non-naturally occurring portions. Oligonucleotide analogs can have altered sugar moieties, altered base moieties or altered inter-sugar linkages. For the purposes of this invention, an oligonucleotide analog having non-phosphodiester bonds, i.e., an altered inter-sugar linkage, is considered to be an "oligonucleoside. " The term "oligonucleoside” thus refers to a plurality of nucleoside units joined by linking groups other than native phosphodiester linking groups.
- oligomers is intended to encompass oligonucleotides, oligonucleotide analogs or oligonucleosides.
- reference is made to a series of nucleosides or nucleoside analogs that are joined via either natural phosphodiester bonds or other linkages, including the four atom linkers of this invention.
- linkage generally is from the 3' carbon of one nucleoside to the 5' carbon of a second nucleoside
- the term “oligomer” can also include other linkages such as 2' -5' linkages.
- Oligonucleotide analogs also can include other modifications consistent with the spirit of this invention, particularly modifications that increase nuclease resistance.
- modifications that increase nuclease resistance For example, when the sugar portion of a nucleoside or nucleotide is replaced by a carbocyclic moiety, it is no longer a sugar.
- other substitutions such a substitution for the inter-sugar phosphorodiester linkage are made, the resulting material is no longer a true nucleic acid species. All such compounds are considered to be analogs.
- reference to the sugar portion of a nucleic acid species shall be understood to refer to either a true sugar or to a species taking the structural place of the sugar of wild type nucleic acids.
- reference to inter-sugar linkages shall be taken to include moieties serving to join the sugar or sugar analog portions in the fashion of wild type nucleic acids.
- This invention concerns modified oligonucleotides, i.e., oligonucleotide analogs or oligonucleosides, and methods for effecting the modifications.
- modified oligonucleotides and oligonucleotide analogs exhibit increased chemical and/or enzymatic stability relative to their naturally occurring counterparts.
- Extracellular and intracellular nucleases generally do not recognize and therefore do not bind to the backbone-modified compounds of the invention.
- the neutral or positively charged backbones of the present invention can be taken into cells by simple passive transport rather than by complicated protein-mediated processes.
- Another advantage of the invention is that the lack of a negatively charged backbone facilitates sequence specific binding of the oligonucleotide analogs or oligonucleosides to targeted RNA, which has a negatively charged backbone and will repel similarly charged oligonucleotides. Still another advantage of the present invention is it presents sites for attaching functional groups that initiate cleavage of targeted RNA.
- the modified internucleoside linkages of this invention are intended to replace naturally-occurring phosphodiester-5' -methylene linkages with four atom linking groups to confer nuclease resistance and enhanced cellular uptake to the resulting compound.
- Preferred linkages have structure CHa-R A -NRi-CHa, CE 2 -NR 1 -R h -CU 2 , R A -NR ⁇ C ⁇ -C ⁇ , CH 2 -CH 2 - NR ⁇ R A , CHz-CHa-R A -NRi, or NR ⁇ A -CHa-CHa where R A is 0 or NR 2 .
- linkages are prepared by functionalizing the sugar moieties of two nucleosides which ultimately are to be adjacent to one another in the selected sequence.
- an "upstream” synthon such as structure III is modified at its terminal 3' site
- a “downstream” synthon such as structure II is modified at its terminal 4' site.
- the invention provides efficient syntheses of oligonucleosides via intermolecular reductive coupling on a solid support.
- B x can be nucleosidic bases selected from adenine, guanine, uracil, thymine, cytosine, 2-aminoadenosine or 5- methylcytosine, although other non-naturally occurring species can be employed to provide stable duplex or triplex formation with, for example, DNA.
- Representative bases are disclosed in U.S. Patent No. 3,687,808 (Merigan, et al . ) , which is incorporated herein by reference.
- Q can be S, CH 2 , CHF CF 2 or, preferably, 0. See, e . g. , Bellon, et al . , Nucleic Acids Res . 1993, 21 , 1587.
- X can be H, OH, alkyl, substituted alkyl, alkaryl or aralkyl, F, Cl, Br, CN, CF 3 , 0CF 3 , OCN, O-alkyl, S-alkyl, N-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, SOCH 3 , S0 2 CH 3 , ON0 2 , N0 2 , N 3 , NH 2 , heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino or substituted silyl, an RNA cleaving group, a group for improving the pharmacokinetic properties of an oligonucleotide, or a group for improving the pharmacodynamic properties of an oligonucleotide.
- alkyl denote branched and straight chain hydrocarbyl residues, including alkyl groups having one or more 3 H and/or 1 C atoms. It is preferred that X is H or OH, or, alternatively F, O-alkyl or O-alkenyl, especially where Q is 0. Preferred alkyl and alkenyl groups have from 1 to about 10 carbon atoms.
- Solid supports e . g. , (P) ) according to the invention include any of those known in the art for polynucleotide synthesis, including controlled pore glass
- CPG oxalyl-controlled pore glass
- TentaGel Support an aminopolyethyleneglycol derivatized support (see, e . g. , Wright, et al . , Tetrahedron Letters 1993, 34 , 3373) or Poros -- a copolymer of polystyrene/divinylbenzene. Attachment and cleavage of nucleosides and oligonucleosides can be effected via standard procedures. See, e . g. , Pon, R.T.
- solid support further includes any linkers (e . g. , long chain alkyl amines and succinyl residues) used to bind a growing oligonucleoside to a stationary phase such as CPG.
- linkers e . g. , long chain alkyl amines and succinyl residues
- Y can be OH, OR HP , CH 2 0H, or CH 2 0R HP where R HP is a hydroxyl protecting group.
- R HP is a hydroxyl protecting group.
- a wide variety of hydroxyl protecting groups can be employed in the methods of the invention. See, e . g. , Beaucage, et al . , Tetrahedron 1992, 12 , 2223. In general, protecting groups render chemical functionality inert to specific reaction conditions, and can be appended to and removed from such functionality in a molecule without substantially damaging the remainder of the molecule.
- hydroxyl protecting groups include phthalimido, t-butyldimethylsilyl (TBDMS) , t- butyldiphenylsilyl (TBDPS) , fluorenylmethoxycarbonyl (FMOC) , and other hydroxyl protecting groups.
- the invention is also directed to methods for the preparation of oligonucleosides with modified inter-sugar linkages. These modifications may be effected using solid supports which may be manually manipulated or used in conjunction with a DNA synthesizer using methodology commonly known to those skilled in DNA synthesizer arts . Generally, the procedure involves functionalizing the sugar moieties of two nucleosides which will be adjacent to one another in the selected sequence. In a 5' to 3' sense, an "upstream” synthon such as structure II is modified at its terminal 3' site, while a “downstream” synthon such as structure III is modified at its terminal 5' site.
- linkages can be formed by selecting a 3'-C-formyl derivatized compound as the upstream synthon and a 5' -aminohydroxy derivatized compound as the downstream synthon. Coupling then is effected to provide, for example, a dinucleoside having an oxime linkage.
- the oxime is present as E/Z isomers.
- the oxime nitrogen atom is adjacent to a carbon atom on the 3' end of the upstream nucleoside.
- Dinucleosides having the oxime nitrogen adjacent to a carbon atom on the 5' or downstream nucleoside are synthesized utilizing a 4'-C-formyl derivatized compound as the upstream synthon and a 3'-deoxy- 3' -aminohydroxymethyl derivatized compound as the downstream synthon, again providing E/Z isomers.
- the oxime linked compound can be incorporated directly into an oligomer and/or can be reduced to a corresponding hydroxylamino linked species.
- Reduction of oxime linked dinucleosides either as the dinucleoside or as a dinucleoside moiety in an oligomer with sodium cyanoborohydride yields the corresponding hydroxylamino linked compounds.
- Hydroxylamino linked compounds can be alkylated at the amino moiety of the hydroxylamino linkage to yield a corresponding N-alkylamino linkage.
- 3'-C-f ⁇ rmyl derivatized nucleosides can be formed via several synthetic pathways.
- the presently preferred method utilizes a stereoselective intermolecular radical C-C bond formation reaction, ( see, e . g. , U.S. Application Serial No. 08/040,903, filed March 31, 1993) .
- a 3'-0- phenylthiocarbonate ester derivative of thymidine reacted with j ⁇ -tri-n-butylstannylstyrene and AIBN to provide a 3'-C- styryl derivative, which on oxidative cleavage gave a 3'-C- formyl thymidine derivative.
- 3'-C-formyl nucleotide analog a radical carbonylation of the corresponding 3 ' -deoxy-3 ' -iodo nucleoside gives the 3'-C-formyl nucleotide analog.
- the iodo compound is treated with CO, 2,2' -azobisisobutrylonitrile (AIBN) , and tris (trimethylsilyl) silane (TTMS) .
- AIBN 2,2' -azobisisobutrylonitrile
- TTMS tris (trimethylsilyl) silane
- 3'-C-formyl derivatized compounds can be synthesized from either a 3' -deoxy-3' -cyano sugar or nucleoside.
- Both 4'-C- formyl (also identified as 5'-aldehydo) and 3'-C-formyl group can be blocked in a facile manner utilizing O- methylaminobenzenthiol as a blocking group.
- the 4'- and 3'- C-formyl groups can be deblocked with silver nitrate oxidation.
- An alternate method of 3'-C-formyl nucleoside synthesis employs l-O-methyl-3' -deoxy-3' -O-methylaminobenzene thiol-5' -O-trityl-S-D-erythro-pento furanoside, which serves as a precursor for any 3' -deoxy-3' -C-formyl nucleoside.
- the l-O-methyl-3 ' -deoxy-3' -O-methyl amino benzenethiol-5' -O- trityl- ⁇ -D-erythro-pentofuranoside is reacted with an appropriate base utilizing standard glycosylation conditions and then deblocked to yield the nucleoside.
- a 3' -deoxy-3' -cyano nucleoside is prepared from either the corresponding 3' -deoxy-3' -iodo nucleoside or by glycosylation with l-O-methyl-3' -deoxy-3' -O-cyano-5' -0- trityl- ⁇ -D-ervthro-pentofuranoside.
- Oligonucleosides according to the invention linked by hydrazines, hydroxylamines and other linking groups, can be protected by a dimethoxytrityl group at the 5' -hydroxyl and activated for coupling at the 3'-hydroxyl with cyanoethyldiisopropyl-phosphite moieties.
- oligonucleosides are linked with the units of a specified DNA sequence utilizing normal phosphodiester bonds.
- the resulting oligonucleotide analog or oligomer has a "mixed" backbone containing both phosphodiester linkages and four atom linkages of the inventions.
- a sequence-specific 15-mer oligonucleotide can be synthesized to have seven hydroxylamine, hydrazine or other type linked dinucleosides attached via alternating phosphodiester linkages.
- Such a structure will provide increased solubility in water compared to fully modified oligomers, which may contain linkages of the invention.
- Oligonucleosides containing a uniform backbone linkage can be synthesized by use of CPG-solid support and standard nucleic acid synthesizing machines such as Applied Biosystems Inc. 380B and 394 and Milligen/Biosearch 7500 and 8800s.
- the initial nucleoside (number 1 at the 3 '-terminus) is attached to a solid support such as controlled pore glass .
- each new nucleoside is attached either by manual manipulation or by the automated synthesizer system.
- One preferred method, shown in Figure 1 employs a solid support to which has been bound a downstream synthon having a protected 5' site.
- the 5' site preferably is protected with a phthalimido group.
- DHMO 1,2-dihydro-4- hydroxy-2-methyl-l-oxaphthalazine
- the 5' site of the downstream synthon can be liberated with any nucleophilic base having a pKa from about 7.7 to about 10.0.
- the selected base should not appreciably react with any linker used to bind a growing oligonucleoside to a stationary phase.
- Representative bases include hydrazine and methylhydrazine.
- the 5' site preferably is liberated with 3% methylhydrazine in methylene chloride and washed with methylene chloride:methanol.
- the aminohydroxyl group at the 5' position of the upstream synthon also is protected with a phthalimido group to yield a 5' -phthalimido protected 3'- deoxy-3' -C-formyl nucleoside, which is reacted with the downstream synthon in, for example, 2.5% acetic acid in methylene chloride.
- Deprotection at the 5' position and washing liberates the next 5' -aminohydroxy reaction site.
- the cycle is repeated with the further addition of upstream synthon until the desired sequence is constructed.
- Each nucleoside of this sequence is connected with oxime linkages.
- the terminal nucleoside of the desired oligonucleoside preferably is added to the sequence as a 5'-OTBDMS blocked 3' -deoxy-3' -C-formyl nucleoside.
- the oxime linked oligonucleoside can be removed from the support with, for example, ammonium hydroxide. If an aminohydroxyl linked oligonucleoside is desired, the oxime linkages are reduced with sodium cyanoborohydride in acetic acid. Alternately reduction can be accomplished while the oxime linked oligonucleoside is still attached to the support.
- Free amino groups produced upon reduction can be alkylated with, for example, acetone and sodium cyanoborohydride in acetic acid.
- the alkylation step can be used to introduce other, useful, functional molecules on the macromolecule.
- useful functional molecules include but are not limited to reporter molecules, RNA cleaving groups, groups for improving the pharmacokinetic properties of an oligonucleotide, and groups for improving the pharmacodynamic properties of an oligonucleotide.
- Such molecules can be attached to or conjugated to the macromolecule via attachment to the nitrogen atom in the backbone linkage. Alternatively, such molecules can be attached to pendent groups extending from the 2' position of the sugar moiety of one or more of the nucleosides of the macromolecules.
- pendent groups extending from the 2' position enhance binding or hybridization of the compound to a target nucleic acid.
- Dimeric pairs of compounds of the invention linked via MMI [methylene (methylimino) ] linkages were studies by NMR. While we do not wish to be bound by theory, the sugar moieties of RNA and DNA oligonucleotides normally are located in one of two major conformations, either the C2'-endo conformation (DNA like or southern conformation) or the C3'-endo conformation (RNA like or northern conformation) .
- RNA character imparted by the MMI linkage might contribute to the +0.2 °C increase in Tm per modification for MMI oligomers as compared to normal phosphodiester oligonucleotides.
- RNA like characteristic were imparted to the dimers.
- the compounds of this invention can be used in diagnostics, therapeutics, and as research reagents and kits.
- the oligonucleotide analog is administered to an animal suffering from a disease modulated by some protein. It is preferred to administer to patients suspected of suffering from such a disease an amount of oligonucleotide analog that is effective to reduce the symptomology of that disease.
- One skilled in the art can determine optimum dosages and treatment schedules for such treatment regimens .
- RNA or DNA portion which is to be modulated be preselected to comprise that portion of DNA or RNA which codes for the protein whose formation or activity is to be modulated.
- the targeting portion of the composition to be employed is, thus, selected to be complementary to the preselected portion of DNA or RNA, that is to be an antisense oligonucleotide for that portion.
- the compounds of the invention hybridize to HIV mRNA encoding the tat protein, or to the TAR region of HIV mRNA. In another preferred embodiment, the compounds mimic the secondary structure of the TAR region of HIV mRNA, and by doing so bind the tat protein.
- Other preferred compounds complementary sequences for herpes, papilloma and other viruses are also preferred.
- RNA for research and diagnostic purposes. Such selective, strong binding is accomplished by interacting such RNA or DNA with compositions of the invention which are resistant to degradative nucleases and which hybridize more strongly and with greater fidelity than known oligonucleotides or oligonucleotide analogs.
- CPG beads were washed thoroughly with dichloromethane methanol (3 x 50 ml, 1:1, v/v) and cloudy solution was decanted. Finally, CPG beads 2 were filtered off and washed with ethyl ether and dried under vacuum for 6 hours.
- the CPG beads were filtered off and washed thoroughly with pyridine (30 ml) , dichloromethane (30 ml) and ether (30 ml) . The CPG beads then were dried under vacuum for 2 hours . Then, the CPG beads were shaken with piperidine (10 ml) for 15 minutes, filtered off and washed with dichloromethane (30 ml) ether (30 ml) and dried under vacuum for 4 hours. The resulting beads were suspended in glacial acetic acid (10 ml) and sonicated for 30 minutes. The suspension was diluted with methanol dichloromethane (3 x 30 ml, 1:1 v/v) and cloudy solution was decanted.
- Example 2A The procedure of Example 2A was repeated except that 5' -O-phthalimido-2' -deoxyadenosine 4 . was used in place of 5' -O-phthalimidothymidine.
- the loading was 36 ⁇ mol of 4 . per gram of CPG.
- Example 2A The procedure of Example 2A was repeated except that 5' -O-phthalimido-N-2-isobutyryl-) -6-diphenylcarbamoyl- 2' -deoxyguanosine 5 was used in place of 5'-0- phthalimidothymidine.
- the loading was 38 ⁇ mol of 5 . per gram of CPG.
- Example 2A The procedure of Example 2A was repeated except that 5' -0-phthalimido-N-4-benzoyl-2' -deoxycytidine 6 . was used in place of 5' -O-phthalimidothymidine. The loading was 32 ⁇ mol of 6 . per gram of CPG.
- Example 2A The procedure of Example 2A is repeated except that 5' -0-phthalimido-5-methyl-N-4-benzoyl-2' -deoxycytidine 7 . is used in place of 5' -O-phthalimidothymidine.
- EXAMPLE 3 The procedure of Example 2A is repeated except that 5' -0-phthalimido-5-methyl-N-4-benzoyl-2' -deoxycytidine 7 . is used in place of 5' -O-phthalimidothymidine.
- 5' -O-Phthalimidothymidine-3' -O-succinyl-CPG (7 . , 28 mg, l ⁇ mol of nucleoside) was packed into a small column and connected on an ABI DNA synthesizer model 380B.
- Compound 7 . was treated with a solution 3% N-methyl hydrazine in dichloromethane: methanol (9:1 v/v) for 120 seconds with a 300 second wait step to give 5' -0-amino-thymidine-3' -0- succinyl-CPG.
- Step 2 The CPG was washed with dichloromethane for 240 seconds.
- the CPG was washed with dichloromethane for 150 seconds.
- Steps 1-4 were repeated ten times.
- the 5-terminal nucleotide e . g. , 5'-t- butyldiphenylsilyl-3' -aldehyde-3' -deoxy-thymidine 18 .
- the excess of 18 was removed by washing step 4.
- the resulting CPG beads (with oligomer) were transferred into a small flask and 1.0 ml of glacial acetic acid was added. NaCNBH 3 (15 mg) was added and the mixture was shaken and sonicated for .15 minutes. Formaldehyde (20% in water, lOO ⁇ l) was added, the mixture was sonicated for 15 minutes and NaCNBH 3 (2 x 15mg) was added with 15 minutes sonication between each addition. The resulting beads were washed with methanol dichloromethane (1:1, v/v, 15 ml) . H. Step 8.
- Oligomer was cleaved from the solid support by treatment with 30% ammonia for 2 hours at room temperature. The ammonia then was evaporated. I . Step 9 .
- T.T oxime dimer was prepared as described in Example 3. Thus, twice repeating the steps 1-4 provided T.T oxime dimer. This dimer was further extended by repeating steps 1-4 using a 5'0-FMOC (9- fluorenylmethoxycarbonyl) protected nucleoside 22_ instead of nucleoside 12 . during step 3. This modification provides a convenient way of switching to standard phosphoramidite chemistry without removing the CPG from automated DNA synthesizer. The resulting T.T.T oxime trimer, still attached to CPG, was treated with a solution of 5% piperidine in acetonitrile for two minutes with a flow rate of 1.6 ml/minute.
- a three minute waiting step and a three minute acetonitrile wash step following the piperidine treatment removed the 5'-0-FMOC group completely (see, e . g. , Ma et al . Biopolymers 1989, 28, 965-993) .
- T * T.T oxime trimer bearing a free 5' -OH group now was ready for a standard phosphoramidite cycle of DNA synthesis.
- Thymidine was incorporated as the last residue utilizing a procedure generally in accordance with Oligonucleotide Synthesis, M.J. Gait, ed., IRL Press, Oxford, 1984, to furnish a tetramer.
- the two oxime linkages of the tetramer were reduced and methylated following
- T.T.T oxime trimer was prepared as described in Example 4.
- the last thymidine nucleoside residue was incorporate utilizing standard phosphoramidite chemistry, followed sulfurization with Beaucage reagent (see, Beaucage et al . , Tetrahedron 1992, 48, 2223-2312) to provide a CPG attached tetramer.
- the CPG was taken off the DNA synthesizer and treated in a manner described in steps 7 and 8 of Example 3.
- the product was purified by reverse phase HPLC as described in step 10 of Example 3.
- the 5'-0-trityl off phosphorothioate oligonucleotide (T s C s G s C s T s G s G s T s G s A s G s TsT s T s C) was synthesized on a DNA synthesizer in l ⁇ M scale on a CPG support utilizing standard phosphoramidite chemistry, (see, Zon in Protocols For Oligonucleotides and Analogs, pages 165-189, S. Agrawal, Humana Press, Totowa, NJ, 1993) .
- coupling was performed with the 5' -O-phthalimido-3' -O-phosphoramidite derivative of thymidine 2$.
- the terminal TBDPS group was then removed by TBAF treatment as described in step 9 of Example 3.
- the crude, chimeric oligomer was then purified by HPLC in a manner described in step 10 of Example 3.
- the purified material had a retention time of 22 . 1 minutes .
- the chromatographic peak was broad due to a mixture of phosphorothioate diastereomers .
- Example 6 The synthesis of the phosphorothioate portion is accomplished by standard phosphoramidite chemistry protocol as described in Example 6. The resulting chimeric oligomer with a 3' -MMI tail/cap is then purified by HPLC. Alternatively, the procedure described in Example 5 can be employed to prepare chimeric oligomers of any desired length and base composition.
- Synthesis of 3' - and 5' -end capped chimeric oligomers is accomplished by combination of the methods described in Examples 3 and 5.
- 5'-0-DMT blocked oligomer T* ⁇ *T*C is synthesized by incorporating appropriate building blocks (compounds ⁇ , 2J3 and 13.) following the protocol described in Example 3 (steps 1-6) .
- the 5'-0-DMT group is removed from the CPG-attached oligomer utilizing standard acidic deprotection.
- a phosphorothioate chain of desired length is synthesized onto the oxime tetramer.
- the 5'-cap of the MMI tetramer is attached following the protocol of Example 6(A) to furnish the title compound.
- the process consists of two steps on an automated DNA synthesizer ( e . g. , ABI 380 B) and two steps off the synthesizer.
- the oligomers were cleaved from the solid support (CPG) by ammonia treatment (55°C, 5 hours) and the resulting solution was concentrated in vacuo . The residue was diluted with 300 ⁇ l of water and the samples were analyzed by HPLC. A reverse phase C18 column (5 ⁇ m, 5.0 X 0.46 cm) and a short (1 cm) guard column were used with a flow-rate of
- Each dimer bears a 5'-0-TBDPS group, which was left on the molecule to increase lipophilicity during HPLC analysis.
- EXAMPLE 8 Synthesis Of 5' -O-Phthalimido-2' -deoxynucleoside Derivatives. A. 5' -O-Phthalimidothymidine, 3 .
- the 5' -O-phthalimidothymidine was prepared by the procedure described in the Example 6 of Application Serial No. 08/040,903.
- 2' -Deoxyadenosine was conveniently transformed into 5' -0-tert-butyldiphenylsilyl-2' ,3' -dideoxy-3' -C- styryladenosine in 60% yield utilizing the radical reaction described in Example 82 of Application Serial No. 08/040,903.
- the 5'-0-TBDPS group of the latter compound was deblocked to provide 2', 3' -dideoxy-3' -C-styryladenosine in 91% yield, mp 215-217°C.
- Oxidative cleavage (0 s 0 4 /NaI0 4 ) of the styryl group of the latter compound furnished the title compound in 55% yield as a white powder.
- 3 '-C-styryl nucleoside derivatives of 2' -deoxycytidine, 2' -deoxyadenosine, and 2'- deoxyguanosine are transformed into 3' -C-formyl-5' -O-FMOC- derivatives of 2' -deoxycytidine 2JL, 2' -deoxyadenosine 2_4, and 2' -deoxyguanosine .25 . , respectively.
- Luminescence Spectrophotometer PERKIN ELMER LS50B
- N-Hydroxyphthalimide (10 g, 59.5 mmoles) was dissolved in anhydrous CH 2 C1 2 (300 ml) and N-methyl hydrazine (9.7 ml) was added to the stirred solution. The solution turned red and then yellow. When all the starting material had disappeared, the solvent was evaporated and the resulting oil was crystallized from anhydrous ethanol as fine needles.
- Analysis Protocol A Neutral conditions The spectrometer was turned on 0.5 hour prior to the measurement . A blank run was performed using spectrophotometer grade methanol.
- 1,2-Dihydro-4-hydroxy-2- methyl-1-oxophthalazine (0.234 mg) was then dissolved in methanol (100 ml) and the sample analyzed on the spectrophotometer. The excitation wavelength was chosen at 298 nm. and the corresponding emission was observed at 400 nm. The following concentrations ( ⁇ Mol) of 1,2-Dihydro-4- hydroxy-2-methyl-1-oxophthalazine were tested:
- Example 11 (A) The procedure of Example 11 (A) was repeated except that the oxophthalazine sample was basified by addition of N- methyl hydrazine (1% volume) . Basification results in the decay of emission intensity by 25 units and moves the excitation wavelength to 485 nm.
- Example 11 (A) The procedure of Example 11 (A) was repeated except that the oxophthalazine sample was acidified with glacial acetic acid (0.1 ml) . The intensities of the emission was enhanced considerably and the values are summarized below.
- MMI dimers in which one of the starting nucleosides bears an amide protecting group on the base for example i ⁇ -benzoyl-S- methylcytosine
- the oxime was stirred overnight with methanolic ammonia, and the resulting solution concentrated to provide the crude product.
- the so obtained intermediate, base unprotected oxime dimer was dissolved in glacial acetic acid (0.1 M) , placed in an ice bath, and sodium cyanoborohydride (3 x 2 eq) was added over 15 minutes. The mixture was allowed to warm to room temperature over 1 hour, placed in an ice bath, and aqueous formaldehyde (20 eq, 20%) was added in one portion.
- the silylated MMI dimer was dissolved in dry THF (0.1 M) and cooled in an ice bath. A solution of tetrabutylammonium fluoride in THF (1 M, 1.5 eq per silyl group) was added dropwise over 5 minutes. The solution was stirred at 0 °C until the reaction was complete as judged by TLC (1-2 hours) , at which point silica (5 g/mmol) was added, and the mixture carefully concentrated. The silica was applied to a column packed in 5% MeOH/CH 2 Cl 2 , and eluted with 5% to 10% MeOH/CH 2 Cl 2. The appropriate fractions were combined, concentrated, and the residue azeotroped with EtOAc to provide the silylated product .
- reaction mixture was then directly loaded onto a column packed with 25% EtOAc/hexane + 0.1% Et 3 N, and eluted with a stepwise gradient to EtOAc + 0.1% Et 3 N.
- Fractions containing only the product were pooled and concentrated to yield a hard foam, which was lyophilized from dry 1,4-dioxane to afford the phosphoramidite as a fine white powder.
- the crude oxime dimer was then evaporated and dissolved in (1/1 : v/v) mixture of water and 1,4-dioxane with NaI0 4 (0.503 mmole, 2.2 eq, ) osmium tetroxide (4% solution in water, 0.229 mmole, O.leq.), 4-methyl-morpholine-N-oxide (0.332 mmole, 1.45 eq.) before being stirred in the dark for 4 hours. After work-up (same as described in the example 9 above) , the residue was chromatographed on silica gel column with 5% MeOH/CH 2 Cl 2 to yield 36% (0.082 mmole) of a white foam.
- 5' -O-phthalimido-3' -deoxy-3' -C-formyl-5-methyl-i ⁇ -benzoyl- cytidine (0.150 mmole, leq.) and 5' -O-amino-3' -O-TBDPS- thymidine (0.15 mmole, leq.) in CH 2 C1 2 were coupled following the general procedure described above.
- the MMI tetramer was purified by silica gel column chromatography using 3% MeOH/CH 2 Cl 2 to yield 56% over four synthetic steps (oxime coupling, debenzoylation, reductive methylation and rebenzoylation) of the title compound.
- MMI tetramer (0.113 mmole, leq.) was dimethoxytritylated following the general procedure described above. MMI tetramer was purified by silica gel column chromatography. Elution with 5% MeOH/CH 2 Cl 2 , pooling and evaporation furnished 81% yield of the desired compound.
- Tetameric MMI containing oligonucleotides correspond to chimeric oligonucleotides where several phosphodiesters and/or phosphorothioates linkages have been replaced by at least three consecutive methylene (methyl) imino (MMI) internucleosidic link.
- MMI methylene (methyl) imino
- MMI tetramer (or longer chain) containing chimeric oligonucleotides can be - synthesized using standard phosphoramidite chemistry.
- the chimeric oligomers were synthesized attached to CPG (Controlled Pore Glass) solid support and the assembling was performed on an automated DNA synthesizer such as Millipore Expedite or Applied Biosystem 380B.
- the initial deoxynucleoside or MMI tetramer determining the 3'-end of the MMI containing chimeric oligonucleotide was loaded on to the CPG solid support via a succinyl linkage following the procedure described in Example 2 above (for example: 5' -0-DMTr-T*T*T*C-0- (succinyl-CPG-NMe 2 ) -3' MMI was loaded onto the CPG providing a loading of 22.67 mmole/g) .
- the chain elongation of chimeric oligomers was performed in a similar manner as described for the MMI phosphoramidite Dimers.
- Table 1 Chimeric Oligomers Containing T*T*T*C and ⁇ *T* M ⁇ C*T MMI Tetramers.
- the aqueous layer was slowly diluted to a total volume of 350 mL with cold water, at whic point solid began forming.
- the ether was decanted, an additional portion ether was added, stirred, and decanted, and the process repeated.
- the solution was now diluted to a total volume of 500 mL with water, and allowed to stand on ice for several hours.
- the reaction mixture was cooled to room temperature and diluted with CH 2 C1 2 (50 ml) .
- the CH 2 C1 2 suspension was transferred onto the top of a prepacked silica gel (CH 2 C1 2 ) column.
- Elution with CH 2 C1 2 /CH 2 C1 2 :MeOH (9:1, v/v) furnished the desired product as homogenous material .
- Appropriate fractions were pooled and concentrated to provide 0.6 g (29%) of the title compound (contaminated with 20% of the 3'-0-methyl isomer) and 0.61 g (31%) of the unreacted starting material.
- Triethylamine (25 mL) and water (25 mL) were added and the mixture was concentrated to a small volume, diluted with EtOAc (500 mL) and extracted with 5% aqueous sodium bicarbonate (2 x 200 mL) , water (100 mL) , brine (100 mL) , then dried over magnesium sulfate, filtered and concentrated to afford 10.7 g (106%) of a foam. This material was azeotroped with dry 1,4-dioxane, then dissolved in 160 mL of the same solvent .
- reaction mixture was then coevaporated with toluene (3 x 50 ml) under vacuum.
- the reaction was complete (by TLC) by the third coevaporation.
- NaCNBH 3 (3 x 250 mg, 12 mmol) was added to the stirred reaction mixture in small portions (fume-hood) .
- the stirring was continued for 30 minutes and additional amount of NaCNBH 3 (3 x 250 mg, 12 mmol) was added in a similar manner.
- reaction mixture was poured into ice-water (250 ml) and extracted with CH 2 C1 2 (2 x 250 ml) .
- CH 2 C1 2 layer was washed with water (2 x 250 ml) and dried MgS0 4 ) .
- the solvent was removed and the residue purified by silica gel column chromatography. Elution with a gradient of CH 2 Cl 2 -CH 2 Cl 2 :MeOH (95:5, v/v) provided the desired product as homogenous material. Appropriate fractions were pooled and concentrated to furnish 5.08 g (50%) of the 3', 5' -protected MMI dimer.
- DMT-0-T*T-OH (1.78 g, 2.19 mmol) was phosphitylated according to the general procedure, except that the organic layer was extracted with 5% aqueous sodium bicarbonate, dried, filtered, and concentrated prior to chromatography (1% MeOH/CH 2 Cl 2 + 0.1% Et 3 N) . This resulted in contamination with an impurity, and additional chromatography (1:1 CH 2 Cl 2 /EtOAc + 0.1% Et 3 N to 2% MeOH in 1:1 CH 2 Cl 2 /EtOAc + 0.1% Et 3 N) was necessary to completely purify the product.
- MMI methyl imino
- the chimeric oligonucleotides containing MMI dimers were synthesized utilizing standard phosphoramidite chemistry.
- the chimeric oligomers were synthesized attached to CPG (Controlled Pore Glass) solid support and the assembling was performed on an automated DNA synthesizer such as
- the initial deoxynucleoside or MMI dimer determining the 3'-end of the MMI containing chimeric oligonucleotide was loaded on to the CPG solid support via a succinyl linkage following the procedure described in Example 2 above.
- Step 4 Capping:
- Step 5- Isolation And Purification At the end of the automated synthesis, MMI containing oligonucleotides were concomitantly deprotected and cleaved from the solid support by treatment with concentrated aqueous ammonia solution (30%) at 55 °C for 10 hours. The ammonia solution was then evaporated and the full length oligonucleotides were separated from the failure sequences on reverse phase HPLC (column: RCM Waters 8 X 10 Bondapack HC18HA, flow rate 2 ml/minutes, gradient 5% to 25% CH,CN in TEAA 0.05 N pH 7.00 over 25 minutes) .
- the flask containing the mixture was then equipped with a magnetic stir bar, a rubber septum, and an argon inlet and dissolved in 7.5 mL CH 2 C1 2 and diluted with 7.5 mL MeOH.
- Bromocresol green indicator solution in MeOH was added dropwise to give a more notable yellow color to the solution and a catalytic amount of AcOH was also added at this time.
- the mixture was then equilibrated in an ice water bath. At ice bath temperature, NaCNBH 3 (0.850 g, 13.52 mmol) was added in four approximately equal portions over a period of 4 h. Over this time, HOAc was added dropwise upon the appearance of blue-green color to restore the original gold-yellow tint and maintain the pH of the mixture.
- the propypyreneyl T-T dimer of Example 17 was incorporated into a oligomer of the sequence Gp 0 G po Ap 0 T*Tp 0 Gp 0 Gp 0 Tp 0 C in a lO ⁇ mol synthesis using the standard protocols above.
- the oligomer was further shown by CGE to be full length material free of short mer sequences.
- PROCEDURE 1 Nuclease Resistance A. Evaluation of the resistance of oligonucleotide- mimicking macromolecules to serum and cytoplasmic nucleases.
- Oligonucleotide-mimicking macromolecules of the invention can be assessed for their resistance to serum nucleases by incubation of the oligonucleotide-mimicking macromolecules in media containing various concentrations of fetal calf serum or adult human serum. Labelled oligonucleotide-mimicking macromolecules are incubated for various times, treated with protease K and then analyzed by gel electrophoresis on 20% polyacrylamine-urea denaturing gels and subsequent autoradiography. Autoradiograms are quantitated by laser densitometry.
- cytoplasmic nucleases an HL 60 cell line can be used. A post-mitochondrial supernatant is prepared by differential centrifugation and the labelled macromolecules are incubated in this supernatant for various times. Following the incubation, macromolecules are assessed for degradation as outlined above for serum nucleolytic degradation. Autoradiography results are quantitated for evaluation of the macromolecules of the invention. It is expected that the macromolecules will be completely resistant to serum and cytoplasmic nucleases.
- oligonucleotide- mimicking macromolecules to specific endo- and exo-nucle- ases.
- Evaluation of the resistance of natural oligonucleotides and oligonucleotide-mimicking macromolecules of the invention to specific nucleases i.e., endonucleases, 3',5'-exo-, and 5' , 3' -exonucleases
- the oligonucleotide-mimicking macromolecules are incubated in defined reaction buffers specific for various selected nucleases.
- urea is added and analysis on 20% polyacrylamide gels containing urea is done. Gel products are visualized by staining with Stains All reagent (Sigma Chemical Co.) . Laser densitometry is used to quantitate the extent of degradation.
- the effects of the macromolecules linkage are determined for specific nucleases and compared with the results obtained from the serum and cytoplasmic systems. As with the serum and cytoplasmic nucleases, it is expected that the oligonucleotide- mimicking macromolecules of the invention will be completely resistant to endo- and exo-nucleases.
- PROCEDURE 2 5-Lipoxygenase Analysis and Assays A. Therapeutics
- an animal suspected ' of having a disease characterized by excessive or abnormal supply of 5-lipoxygenase is treated by administering the macromolecule of the invention.
- Persons of ordinary skill can easily determine optimum dosages, dosing methodologies and repetition rates. Such treatment is generally continued until either a cure is effected or a diminution in the diseased state is achieved. Long term treatment is likely for some diseases.
- the oligonucleotide-mimicking macromolecules of this invention will also be useful as research reagents when used to cleave or otherwise modulate 5-lipoxygenase mRNA in crude cell lysates or in partially purified or wholly purified RNA preparations.
- This application of the invention is accomplished, for example, by lysing cells by standard methods, optimally extracting the RNA and then treating it with a composition at concentrations ranging, for instance, from about 100 to about 500 ng per 10 Mg of total RNA in a buffer consisting, for, example, of 50 mm phosphate, pH ranging from about 4-10 at a temperature from about 30° to about 50° C.
- the cleaved 5-lipoxygenase RNA can be analyzed by agarose gel electrophoresis and hybridization with radiolabeled DNA probes or by other standard methods.
- the oligonucleotide-mimicking macromolecules of the invention will also be useful in diagnostic applications, particularly for the determination of the expression of specific mRNA species in various tissues or the expression of abnormal or mutant RNA species.
- the macromolecules target a abnormal mRNA by being designed complementary to the abnormal sequence, they would not hybridize to normal mRNA.
- Tissue samples can be homogenized, and RNA extracted by standard methods.
- the crude homogenate or extract can be treated for example to effect cleavage of the target RNA.
- the product can then be hybridized to a solid support which contains a bound oligonucleotide complementary to a region on the 5' side of the cleavage site. Both the normal and abnormal 5' region of the mRNA would bind to the solid support. The 3' region of the abnormal RNA, which is cleaved, would not be bound to the support and therefore would be separated from the normal mRNA.
- Targeted mRNA species for modulation relates to 5- lipoxygenase; however, persons of ordinary skill in the art will appreciate that the present invention is not so limited and it is generally applicable.
- the inhibition or modulation of production of the enzyme 5-lipoxygenase is expected to have significant therapeutic benefits in the treatment of disease.
- an assay or series of assays is required. D. In Vitro Assays
- the cellular assays for 5-lipoxygenase preferably use the human promyelocytic leukemia cell line HL-60. These cells can be induced to differentiate into either a monocyte like cell or neutrophil like cell by various known agents. Treatment of the cells with 1.3% dimethyl sulfoxide, DMSO, is known to promote differentiation of the cells into neutrophils. It has now been found that basal HL-60 cells do not synthesize detectable levels of 5-lipoxygenase protein or secrete leukotrienes (a downstream product of 5-lipoxygenase) . Differentiation of the cells with DMSO causes an appearance of 5-lipoxygenase protein and leukotriene biosynthesis 48 hours after addition of DMSO.
- DMSO dimethyl sulfoxide
- 5-lipoxygenase protein synthesis can be utilized as a test system for analysis of oligonucleotide- mimicking macromolecules which interfere with 5-lipoxygenase synthesis in these cells.
- a second test system for oligonucleotide-mimicking macromolecules makes use of the fact that 5-lipoxygenase is a "suicide" enzyme in that it inactivates itself upon reacting with substrate.
- Treatment of differentiated HL-60 or other cells expressing 5 lipoxygenase, with 10 ⁇ M A23187, a calcium ionophore promotes translocation of 5-lipoxygenase from the cytosol to the membrane with subsequent activation of the enzyme.
- a direct effect which oligonucleotide-mimicking macromolecules can exert on intact cells and which can be easily be quantitated is specific inhibition of 5-lipoxygenase protein synthesis.
- cells can be labelled with 35 S-methionine (50 ⁇ Ci/mL) for 2 hours at 37° C to label newly synthesized protein.
- Cells are extracted to solubilize total cellular proteins and 5-lipoxygenase is immunoprecipitated with 5-lipoxygenase antibody followed by elution from protein A Sepharose beads.
- the immunoprecipitated proteins are resolved by SDS-polyacrylamide gel electrophoresis and exposed for autoradiography.
- the amount of immunopre ⁇ cipitated 5-lipoxygenase is quantitated by scanning densitometry.
- a predicted result from these experiments would be as follows.
- the amount of 5-lipoxygenase protein immuno- precipitated from control cells would be normalized to 100%.
- Treatment of the cells with 1 ⁇ M, 10 ⁇ M, and 30 ⁇ M of the macromolecules of the invention for 48 hours would reduce immunoprecipitated 5-lipoxygenase by 5%, 25% and 75% of control, respectively.
- Cytosolic proteins are incubated with 10 ⁇ M 14 C-arachidonic acid, 2mM ATP, 50 ⁇ M free calcium, 100 ⁇ g/ml phosphatidylcholine, and 50 mM bis-Tris buffer, pH 7.0, for 5 min at 37° C.
- the reactions are quenched by the addition of an equal volume of acetone and the fatty acids extracted with ethyl acetate.
- the substrate and reaction products are separated by reverse phase HPLC on a Novapak C18 column (Waters Inc., Millford, MA) . Radioactive peaks are detected by a Beckman model 171 radiochromatography detector. The amount of arachidonic acid converted into di-HETE's and mono-HETE's is used as a measure of 5-lipoxygenase activity.
- a predicted result for treatment of DMSO differentiated HL-60 cells for 72 hours with effective the macromolecules of the invention at 1 ⁇ M, 10 ⁇ M, and 30 ⁇ M would be as follows. ' Control cells oxidize 200 pmol arachidonic acid/ 5 min/ 10 6 cells. Cells treated with 1 ⁇ M, 10 ⁇ M, and 30 ⁇ M of an effective oligonucleotide-mimicking macromolecule would oxidize 195 pmol, 140 pmol, and 60 pmol of arachidonic acid/ 5 min/ 10 s cells respectively.
- a quantitative competitive enzyme linked immunosorbant assay (ELISA) for the measurement of total 5-lipoxygenase protein in cells has been developed. Human 5-lipoxygenase expressed in E.
- coli and purified by extraction, Q-Sepharose, hydroxyapatite, and reverse phase HPLC is used as a standard and as the primary antigen to coat microtiter plates. 25 ng of purified 5-lipoxygenase is bound to the microtiter plates overnight at 4°C. The wells are blocked for 90 min with 5% goat serum diluted in 20 mM Tris-HCL buffer, pH 7.4, in the presence of 150 mM NaCl (TBS) .
- Cell extracts (0.2% Triton X- 100, 12,000 x g for 30 min.) or purified 5-lipoxygenase were incubated with a 1:4000 dilution of 5-lipoxygenase polyclonal antibody in a total volume of 100 ⁇ L in the microtiter wells for 90 min.
- the antibodies are prepared by immunizing rabbits with purified human recombinant 5-lipoxygenase.
- the wells are washed with TBS containing 0.05% tween 20 (TBST) , then incubated with 100 ⁇ L of a 1:1000 dilution of peroxidase conjugated goat anti-rabbit IgG (Cappel Laboratories, Malvern, PA) for 60 min at 25°C.
- the wells are washed with TBST and the amount of peroxidase labelled second antibody determined by development with tetramethylbenzidine.
- Predicted results from such an assay using a 30 mer oligonucleotide-mimicking macromolecule at 1 ⁇ M, 10 ⁇ M, and 30 ⁇ M would be 30 ng, 18 ng and 5 ng of 5-lipoxygenase per 10 6 cells, respectively with untreated cells containing about 34 ng 5-1ipoxygenase.
- a net effect of inhibition of 5-lipoxygenase biosynthesis is a diminution in the quantities of leukotrienes released from stimulated cells.
- DMSO-differentiated HL-60 cells release leukotriene B4 upon stimulation with the calcium ionophore A23187.
- Leukotriene B4 released into the cell medium can be quantitated by radioimmunoassay using commercially available diagnostic kits (New England Nuclear, Boston, MA) .
- Leukotriene B4 production can be detected in HL-60 cells 48 hours following addition of DMSO to differentiate the cells into a neutrophil- like cell. Cells (2 x 10 5 cells/mL) will be treated with increasing concentrations of the macromolecule for 48-72 hours in the presence of 1.3% DMSO.
- the cells are washed and resuspended at a concentration of 2 x 10 6 cell/mL in Dulbecco's phosphate buffered saline containing 1% delipidated bovine serum albumin.
- Cells are stimulated with 10 ⁇ M calcium ionophore A23187 for 15 min and the quantity of LTB4 produced from 5 x 10 5 cell determined by radioimmunoassay as described by the manufacturer. Using this assay the following results would likely be obtained with an oligonucleotide-mimicking macromolecule directed to the 5-LO mRNA.
- Cells will be treated for 72 hours with either 1 ⁇ M, 10 ⁇ M or 30 ⁇ M of the macromolecule in the presence of 1.3% DMSO.
- the quantity of LTB 4 produced from 5 x 10 5 cells would be expected to be about 75 pg, 50 pg, and 35 pg, respectively with untreated differentiated cells producing 75 pg LTB 4 .
- the edematous response is quantitated by measurement of ear thickness and wet weight of a punch biopsy. Measurement of leukotriene B 4 produced in biopsy specimens is performed as a direct measurement of 5- lipoxygenase activity in the tissue. Oligonucleotide-mimicking macromolecules will be applied topically to both ears 12 to 24 hours prior to administration of arachidonic acid to allow optimal activity of the compounds. Both ears are pretreated for 24 hours with either 0.1 ⁇ mol, 0.3 ⁇ mol, or 1.0 ⁇ mol of the macromolecule prior to challenge with arachidonic acid. Values are expressed as the mean for three animals per concentration.
- Inhibition of polymorphonuclear cell infiltration for 0.1 ⁇ mol, 0.3 ⁇ mol, and 1 ⁇ mol is expected to be about 10%, 75% and 92% of control activity, respectively. Inhibition of edema is expected to be about 3%, 58% and 90%, respectively while inhibition of leukotriene B 4 production would be expected to be about 15%, 79% and 99%, respectively.
- PROCEDURE 3 Solid Support Biochemistry Reagents
- Oligomers of the present invention also can advantageously be used as solid-phase biochemistry reagents (see, e . g. , "Solid-Phase Biochemistry - Analytical and Synthetic Aspects” , W. H. Scouten, ed. , John Wiley & Sons, New York, 1983) , notably in solid-phase biosystems, especially bioassays or solid-phase techniques which concerns diagnostic detection/quantitation or affinity purification of complementary nucleic acids ( see, e. g. , "Affinity Chromatography - A Practical Approach” , P. D. G. Dean, W. S. Johnson and F. A.
- PROCEDURE 4 Investigation of mutant ⁇ -amyloid precursor protein ( ⁇ APP)
- Point mutations in the gene encoding ⁇ -amyloid have been suggested in familial Alzheimer's disease (FAD) .
- FAD familial Alzheimer's disease
- MMI oligomers are used to probe for such point mutation expressed proteins.
- a MMI containing oligomer of the selected sequence coding for the protein of interest is synthesized as above.
- a fluorescein label is added to the oligomer using fluorescein phosphoramidite (Cat. No. 10-1963-95, Glen Research Corp., Sterling VA) . This amidite is attached in the normal manner as the last phosphate residue added.
- the oligomers can be labeled with other reporter molecules (acridine or psoralen, both also available from Glen Research or rhodamine) before or after oligomer synthesis.
- Labeled oligomers are contacted with tissue or cell samples suspected of abnormal ⁇ APP expression under conditions in which specific hybridization can occur, and the sample is washed to remove unbound oligomers. Label remaining in the sample indicates bound oligonucleotide and is quantitated using a fluorimeter, fluorescence microscope or other routine means.
- Tissue or cell samples suspected of expressing a point mutation in the ⁇ APP gene are incubated with a fluorescein- labeled oligomer which is targeted to the mutant codon 717, codon 670 or codon 671 of ⁇ APP mRNA.
- An identical sample of cells or tissues is incubated with a second labeled oligomer which is targeted to the same region of normal ⁇ APP mRNA, under conditions in which specific hybridization can occur, and the sample is washed to remove unbound oligomer. Label remaining in the sample indicates bound oligomer and can be quantitated using a fluorimeter or other routine means.
- mutant ⁇ APP is indicated if the first sample binds labeled oligomer and the second sample does not bind fluorescent label. Double labeling can also be used with the oligomers to specifically detect expression of mutant ⁇ APP.
- a single tissue sample is incubated with a rhodamine-labeled oligomer which is targeted to codon 717, codon 670 or codon 671 of mutant ⁇ APP mRNA and a fluorescein-labeled oligomer which is targeted to the translation initiation site of mutant ⁇ APP mRNA, under conditions in which specific hybridization can occur.
- the sample is washed to remove unbound oligomer and labels are detected by and fluori etry with appropriate filters.
- the presence of mutant ⁇ APP is indicated if the sample does not bind rhodamine-labeled oligomer but does retain the fluorescein label.
- PROCEDURE 5 Detection of mutant H-ras gene expression
- MMI oligomers are labeled after synthesis with fluorescein or other fluorescent tag as illustrated above.
- the oligomers are labeled with other reporter molecules before or after oligomer synthesis.
- Labeled oligomers are contacted with tissue or cell samples suspected of abnormal ras expression under conditions in which specific hybridization can occur, and the sample is washed to remove unbound oligomer. Label remaining in the sample indicates bound oligomer and is quantitated using a fluorimeter, fluorescence microscope or other routine means.
- Tissue or cell samples suspected of expressing a point mutation in the H-ras gene are incubated with a fluorescein- labeled oligomer which is targeted to the mutant codon 12, codon 13 or codon 61 of H-ras mRNA.
- An identical sample of cells or tissues is incubated with a second labeled oligomer which is targeted to the same region of normal H-ras mRNA, under conditions in which specific hybridization can occur, and the sample is washed to remove unbound oligomer. Label remaining in the sample indicates bound oligomer and can be quantitated using a fluorimeter or other routine means .
- the presence of mutant H-ras is indicated if the first sample binds labeled oligomer and the second sample does not bind fluorescent label.
- Double labeling can also be used with oligomers to specifically detect expression of mutant ras.
- a single tissue sample is incubated with a rhodamine-labeled oligomer which is targeted to codon 12, codon 13 or codon 61 of mutant H-ras mRNA and a fluorescein-labeled oligomer which is targeted to the translation initiation site of ras mRNA, under conditions in which specific hybridization can occur.
- the sample is washed to remove unbound oligomer and labels are detected by and fluorimetry with appropriate filters.
- the presence of mutant ras is indicated if the sample does not bind rhodamine-labeled oligomer but does retain the fluorescein label .
- PROCEDURE 6 Effect of MMI-containing antisense oligonucleotides on PKC- ⁇ mRNA levels: A549 cells were treated with compounds ID No.s 9495 and 9496 as well as a phosphorothioate oligonucleotide standard of the same sequence as compound ID No. 9495 above, at doses from 100 to 400 nM for four hours in the presence of the cationic lipids DOTMA/DOPE, washed and allowed to recover for an additional 20 hours. Total RNA was extracted and 20 ⁇ g of each was resolved on 1.2% gels and transferred to nylon membranes.
- the MMI compounds exhibited greater activity than the test standard.
- the high specific binding of the test compounds to the PKC- ⁇ sequence can also be used to distinguish PKC- ⁇ mRNA from other mRNA of other PKC isozymes such as the ⁇ , T and ⁇ isozymes.
- PROCEDURE 7 Northern blot analysis of ras expression in vivo
- Kingston, R.E. in Current Protocols in Molecular Biology, (F.M. Ausubel, R. Brent, R.E. Kingston, D.D. Moore, J.A. Smith, J.G. Seidman and K. Strahl, eds.), John Wiley and Sons, NY.
- the ras probe was a Sall-Nhel fragment of a cDNA clone of the activated (mutant) H-ras mRNA having a GGC-to-GTC mutation at codon-12.
- the control probe was G3PDH. Blots were prehybridized for 15 minutes at 68 °C with the QuickHyb hybridization solution (Stratagene, La Jolla, CA) .
- the heat- denatured radioactive probe (2.5 x 10 s counts/2 ml hybridization solution) mixed with 100 ⁇ l of 10 mg/ml salmon sperm DNA was added and the membrane was hybridized for 1 hour at 68 °C.
- the blots were washed twice for 15 minutes at room temperature in 2x SSC/0.1% SDS and once for 30 minutes at 60 °C with 0.1XSSC/0.1%SDS. Blots were autoradiographed and the intensity of signal was quantitated using an ImageQuant Phosphorlmager (Molecular Dynamics, Sunnyvale, CA) . Northern blots were first hybridized with the ras probe, then stripped by boiling for 15 minutes in 0.Ix SSC/0.1%SDS and rehybridized with the control G3PDH probe to check for correct sample loading.
- the MMI-containing oligomers had IC 50 s of approximately 100 nM, 90 nM and 120 nM, respectively. All were more active in this assay than a known-active phosphorothioate oligonucleotide of the same sequence that was used as the test standard. This standard phosphorothioate oligonucleotide had C50 of approximately 150 nM.
Abstract
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US6461871B1 (en) | 1997-05-09 | 2002-10-08 | Lightup Technologies Ab | Method for the preparation of a probe for nucleic acid hybridization |
WO1999013105A1 (en) * | 1997-09-05 | 1999-03-18 | Mikael Kubista | Method for the preparation of a probe for nucleic acid hybridization |
GB2344823A (en) * | 1997-09-05 | 2000-06-21 | Kubista Mikael | Method for the preparation of a probe for nucleic acid hybridization |
GB2344823B (en) * | 1997-09-05 | 2002-09-04 | Kubista Mikael | Method for the preparation of a probe for nucleic acid hybridization |
DE19819735A1 (en) * | 1998-05-02 | 1999-11-04 | Novartis Ag | Device and method for producing an arrangement of chain molecules on a carrier material |
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Also Published As
Publication number | Publication date |
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US5541307A (en) | 1996-07-30 |
EP0737201A4 (en) | 1998-12-30 |
EP0737201A1 (en) | 1996-10-16 |
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