Investigation of reactions postulated to occur during inhibition of ribonucleotide reductases by 2′-azido-2′-deoxynucleotides

Model 3′-azido-3′-deoxynucleosides with thiol or vicinal dithiol substituents at C2′ or C5′ were synthesized to study reactions postulated to occur during inhibition of ribonucleotide reductases by 2′-azido-2′-deoxynucleotides. Esterification of 5′-(tert-butyldiphenylsilyl)-3′-azido-3′-deoxyadenosine and 3′-azido-3′-deoxythymidine (AZT) with 2,3-S-isopropylidene-2,3-dimercaptopropanoic acid or N-Boc-S-trityl-L-cysteine and deprotection gave 3′-azido-3′-deoxy-2′-O-(2,3-dimercaptopropanoyl or cysteinyl)adenosine and the 3′-azido-3′-deoxy-5′-O-(2,3-dimercaptopropanoyl or cysteinyl)thymidine analogs. Density functional calculations predicted that intramolecular reactions between generated thiyl radicals and an azido group on such model compounds would be exothermic by 33.6–41.2 kcal/mol and have low energy barriers of 10.4–13.5 kcal/mol. Reduction of the azido group occurred to give 3′-amino-3′-deoxythymidine, which was postulated to occur with thiyl radicals generated by treatment of 3′-azido-3′-deoxy-5′-O-(2,3-dimercaptopropanoyl)thymidine with 2,2′-azobis-(2-methyl-2-propionamidine) dihydrochloride. Gamma radiolysis of N₂O-saturated aqueous solutions of AZT and cysteine produced 3′-amino-3′-deoxythymidine and thymine most likely by both radical and ionic processes.     

Syntheses of dibenzo[c,e][1,2]diselenin and related novel chalcogenide heterocyclic compounds

Reaction of 2,2′-dilithio-1,1′-binaphthyl with selenium followed by air oxidation gives a mixture of dinaph-thoselenophene and dimer and oligomers of 2,2′-diseleno-1,1′-binaphthyl. 2,2′-Dilithio-1,1′-biphenyl reacts with selenium to afford dibenzo[c,e][1,2]diselenin. Structures of the dimeric 2,2′-diseleno-1,1′-binaphthyl and dibenzo[c,e][1,2]diselenin have been confirmed by X-ray crystallographic analyses. Similar reaction of 2,2′-dilithio-1,1′-binaphthyl with sulfur or tellurium gives a mixture of dinaphthothiophene and dinaphtho[2,1-c:-1′,2′-e][1,2]dithiin or a mixture of dinaphthotellurophene and oligomer of 2,2′-ditelluro-1,1′-binaphthyl, respectively. Dibenzotellurophene and oligomer of 2,2′-ditelluro-1,1′-biphenyl are obtained from reaction of 2,2′-dilithio-1,1′-biphenyl with tellurium.     

Nucleotides. Part XXXI. Modified Oligomeric 2′–5′ A Analogues: Synthesis of 2′–5′ oligonucleotides with 9-(3′-azido-3′-deoxy-β-D-xylofuranosyl)adenine and 9-(3′-amino-3′-deoxy-β-D-xylofuranosyl)adenine as modified nucleosides

A series of new 2′–5′ oligonucleotides carrying the 9-(3′-azido-3′deoxy-β-D-xylofuranosyl)adenine moiety as a building block has been synthesized via the phosphotriester method. The use of the 2-(4-nitrophenyl)ethyl (npe) and 2-(4-nitrophenyl)ethoxycarbonyl (npeoc) blocking groups for phosphate, amino, and hydroxy protection guaranteed straightforward syntheses in high yields and easy deblocking lo form the 2′–5′ trimers 21 , 22 , and 25 and the tetramer 23 . Catalytic reduction of the azido groups in [9-(3′-azido-3′-deoxy-β-D-xylofuranosyl)adenine]2′-yl-[2′-(O^p-ammonio)→ 5′]-[9-(3′-azido-3′-deoxy-β-D-xylofuranosyl)adenin]-2′-yl-[2′-(O^p-ammonio)→ 5′]-9-(3′-azido-3′-deoxy-β-D-xylofuranosyl)adenine ( 21 ) led to the corresponding 9-(3′-amino-3′-deoxy-β-D-xylofuranosyl)-adenine 2′–5′ trimer 26 in which the two internucleotidic linkages are formally neutralized by intramolecular betaine formation.     

A synthesis of 3′-α-fluoro-2′,3′-dideoxyadenosine via a bromine rearrangement during fluorination with MOST reagent

A facile method for the synthesis of 3′-α-fluoro-2′,3′-dideoxyadenosine 6 has been developed. Fluorination of 5′-O-acetyl-3′-β-bromo-3′-deoxyadenosine 3 with MOST gave 2′-β-bromo-3′-α-fluoro-2′,3′-dideoxyadenosine 4 via a rearrangement of the 3′-β-bromine to the 2′-β position during 3′-α fluorination. The 2′-β bromine was reduced by radical reduction and then the 5′-O-acetyl group was removed to afford 3′-α-fluoro-2′,3′-dideoxyadenosine 6 in good yield. A possible mechanism for the rearrangement is discussed.     

Dipole moments of some metal complexes of five new monothio-β-diketones

Dipole moments have been determined for Co(III), Ni(II), Pd(II), Pt(II), Cu(II) and Zn(II) complexes of the fluorinated monothio-β-diketones RC(SH)CHCOCF₃ [R  5′-methyl-2′-thienyl, 5′-chloro-2′-thienyl, 4′-isopropylphenyl, 4′-tert-butylphenyl and 3′-fluoro-4′-methoxyphenyl] from static-polarization measurements. The moments clearly indicate cis-square-planar configurations for the nickel, palladium and platinum complexes. The zinc complexes have tetrahedral structure and copper complexes have distorted cis-square-planar structure. The cobalt complexes perhaps have facial-octahedral structure. The values of dipole moment for the complexes varies with R: 5′-methyl-2′-thienyl > 3′-fluoro-4′-methoxyphenyl > 4′-isopropylphenyl ≈ 4′-tert-butylphenyl > 5′-chloro-2′-thienyl.     

Synthesis and Properties of Brominated 6,6'-Dimethyl-[2,2'-bi-1H-indene]-3,3'-diethyl-3,3'-dihydroxy-1,1 '-diones

Photochromic 6‐bromomethyl‐6′‐methyl‐[2,2′‐bi‐1H‐indene]‐3,3′‐diethyl‐3,3′‐dihydroxy‐1,1′‐dione ( 2 ), 6,6′‐ bis(bromomethyl)‐[2,2′‐bi‐1H‐indene]‐3,3′‐diethyl‐3,3′‐dihydroxy‐1,1′‐dione ( 3 ) and 6,6′‐bis(dibromomethyl)‐[2,2′‐ bi‐1H‐indene]‐3,3′‐diethyl‐3,3′‐dihydroxy‐1,1′‐dione ( 4 ) have been synthesized from 6,6′‐dimethyl‐[2,2′‐bi‐1H‐ indene]‐3,3′‐diethyl‐3,3′‐dihydroxy‐1,1′‐dione ( 1 ). The single crystal of 4 was obtained and its crystal structure was analyzed. The results indicate that in crystal 4 , molecular arrangement is defective tightness compared with its precursor 1 . Besides, UV‐Vis absorption spectra in CH₂Cl₂ solution, photochromic and photomagnetic properties in solid state of 2 , 3 and 4 were also investigated. The results demonstrate that when the hydrogen atoms in the methyl group on the benzene rings of biindenylidenedione were substituted by bromines, its properties could be affected considerably.     

Cyclopropanation of 2-arylmethylidenemalononitriles,alkyl 3-aryl-2-cyanoprop-2-enoates,and N-substituted 3-aryl-2-cyanoprop-2-enamides with bromine-containing zinc enolates

Zinc enolates derived from 2,2-dibromoindan-1-one and 2,2-dibromo-1,2,3,4-tetrahydronaphthalen-1-one reacted with 2-arylmethylidenemalononitriles, alkyl 3-aryl-2-cyanoprop-2-enoates, and N-substituted 3-aryl-2-cyanoprop-2-enamides to give, respectively, 3-aryl-1′-oxo-1′,3′-dihydrospiro[cyclopropane-1,2′-indene]-2-2-dicarbonitriles, 3-aryl-1′-oxo-3′,4′-dihydro-1′H-spiro[cyclopropane-1,2′-naphthalene]-2,2-dicarbonitriles, alkyl 3-aryl-2-cyano-1′-oxo-1′,3′-dihydrospiro[cyclopropane-1,2′-indene]-2-carboxylates, alkyl 3-aryl-2-cyano-1′-oxo-3′,4′-dihydro-1′H-spiro[cyclopropane-1,2′-naphthalene]-2-carboxylates, and N-substituted 3-aryl-2-cyanol-1′-oxo-3′,4′-dihydro-1′H-spiro[cyclopropane-1,2′-naphthalene]-2-carboxamides as a single diastereoisomer. The stereoconfiguration of the products was determined by ¹H and ¹³C NMR spectroscopy.     

Cyclisation of benzils

Treatment of several substituted benzils [3,3′- and 4,4′-dimethyl-; 2,2′-, 3,3′- and 4,4′-dichloro-; 3,3′-dibromo-; 4-(N,N-dimethylamino)-] with an excess of chlorosulfonic acid gave the corresponding 3-chloro-2-phenylbenzofuran disulfonyl dichlorides. Disubstitution was confirmed by microanalytical and spectral data for the corresponding bis(N,N-dimethylaminsulfonamides). The positions of electrophilic substitution were not confirmed with 3,3′-dimethyl-, 2,2′- and 3,3′-dichlorobenzils. With 4,4′-dichlorobenzil, a smaller amount of chlorosulfonic acid enabled the isolation of 3,6,4′-trichloro-2-phenylbenzofuran-5-sulfonyl chloride, which was identified by X-ray analysis of the N,N-dimethylsulfonamide. The cyclisation failed with 3,3′-dimethoxy-, and 3,3′- and 4,4′-dinitrobenzils. The results have been interpreted mechanistically.     

Syntheses of Bissydnone Derivatives and Studies of Their Biological Activities

A new method to prepare 3,3′-ethylenebissydnone (40%), 3,3′-tetramethylenebissydnone (37%) and 3,3′-hexamethylenebissydnone (43%) from the corresponding alkylene diamine with paraformaldehyde and potassium cyanide were investigated. Some new bissydone: ?3,3′-trimethylenebissydnone (6%), 3,3′-(4,4′-diphenyl)bissydnonylmethane (9%) and 3,3′-(4,4′-diphenyi)bissydnonyl ether (28%) were synthesized from the corresponding diamine, paraformaldehyde, sodium bisulfite and potassium cyanide. Biological test of 3,3′-(4,4′-diphenyl)bissydnonylmethane shows significant response for coronary dilgtion test, inhibition of collagen induced platelet aggregation and moderate carditropic response. 3,3′-(4,4′-Diphenyl)bissydnonyl ether also shows inhibition of collagen induced platelet aggregation and moderate carditropic response.     

Carbocyclic analogs of anhydrothymidines

The carbocyclic analog of thymidine (C-Thymidine, 2 ) was converted to the analog of 3′-(O-methanesulfonyl)-5′-O-tritylthymidine, which was cyclized in alkaline solution or with 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU) to the carbocyclic analog of 5′-O-trityl-2,3′-anhydrothymidine ( 6 ). Hydrolysis of the latter compound produced the carbocyclic analog of all-cis-thymidine. C-Thymidine was also converted to the carbocyclic analog of 3′-O-acetyl-2,5′-anhydrothymidine ( 12 ) by treating the 5′-O-methanesulfonyl analog with DBU. Hydrolysis of the anhydro derivative gave back C-Thymidine. The carbocyclic analog ( 3 ) of 3′-deoxy-2′-hydroxythymidine was converted similarly to the corresponding 2,2′-anhydrothymidine ( 15 ) and 2,5′-anhydrothymidine ( 21 ) analogs. As expected, C-5′-O-trityl-2,2′-anhydrothymidine formed more readily than did the 2,3′-anhydrothymidine analog. Hydrolysis of these 2,2′- and 2,5′-anhydrothymidine analogs gave, respectively, the carbocyclic analog of all-cis-3′-deoxy-2′-hydroxythymidine and 3 .     

Separation of isomeric and nonisomeric monoribonucleotides by isocratic ion pair high performance liquid chromatography

A simple, isocratic, high performance liquid chromatographic procedure is described for the first time for the separation of nine monoribonucleotides using the ion-pairing technique. An aqueous mobile phase containing 100 mM KH₂PO₄ and 12.5 mM tetramethylammonium hydroxide as the solvophobic ion, pH 3.9, was used with a reverse phase RP-18 column. The nine monoribonucleotides studied were separated and eluted in the following order: cytidine-5′ -phosphate, uridine-5′ -phosphate, cytidine-3′ -phosphate, guanosine-5′ -phosphate, uridine-3′ -phosphate, uridine-2′ -phosphate, adenosine-5′ -phosphate, guanosine-3′ -phosphate, and adenosine-3′ -phosphate. Generally the 5′ nucleotides eluted faster than the 3′ and the order of elution within each series was: cytidine, uridine, guanosine, and adenosine. The only nucleotide where three isomers were studied was uridine, and the 2′ eluted later than the 3′. Baseline separation was attained for a mixture containing four 3′ nucleotides and uridine-2′ -phosphate. When the four 5′ nucleotides were chromatographed, baseline separation was also obtained except between cytidine-5′ -phosphate and uridine-5′ -phosphate. The coefficient of variation of the retention characteristics, which reflected day-to-day variation, averaged 6.4%.     

Reactions of 2,2′,5′,2′-terfuran

Formylation of 2,2′,5′,2′-terfuran ( 1 ) with N-methylformanilide and phosphorus oxychloride gave 5-formyl-2,2′,5′,2′-terfuran ( 2 ) and 5,5′-diformyl-2,2′5′,2′-terfuran ( 3 ). Reduction of 2 and 3 afforded 5-hydroxymethyl-2,2′,5′,2′-terfuran ( 4 ) and 5,5′ dihydroxymethyl-2,2′,5′,2′-terfuran ( 5 ), respectively. Terfuran 1 reacted with phenylmagnesium bromide to give 5-(phenylhydroxymethyl)-2,2′,5′,2′-terfuran ( 6 ), and was carbonated to 5-carboxy 2,2′,5′,2′-terfuran ( 7 ) and 5,5′-dicarboxy-2,2′,5′,2′-terfuran ( 8 ). Bromination of 1 with N-bromosuccinimide gave 5,5′-dibromo 2,2′,5′,2′-terfuran ( 9 ).     

Synthesis of tellurobispyridines

All six isomers of tellurobispyridine, namely 2,2′-tellurobispyridine, 2,3′-tellurobispyridine, 2,4′-tellurobis-pyridine, 3,3′-tellurobispyridine, 3,4′-tellurobispyridine and 4,4′-tellurobispyridine have been synthesised.     

Chromium(VI) oxide-mediated oxidation of polyalkyl-polypyridines to polypyridine-polycarboxylic acids with periodic acid

4,4′-Dicarboxy-2,2′-bipyridine was synthesized quantitatively by chromium(VI) oxide-mediated oxidation of 4,4′-dimethyl-2,2′-bipyridine or 4,4′-diethyl-2,2′-bipyridine with periodic acid as the terminal oxidant in sulfuric acid. 5,5′-Dicarboxy-2,2′-bipyridine and 6,6’-dicarboxy-2,2′-bipyridine were also synthesized by the method from the corresponding dimethyl bipyridines in excellent yields. 4,4′,4″-Tricarboxy-2,2′:6′,2″-terpyridine was obtained in 80% yield from 4,4′,4″-triethyl-2,2′:6′,2″-terpyridine, and 4,4′,4″,4′″-tetracarboxy-2,2′:6′,2″:6″,2′″-quaterpyridine was obtained in 72% yield from 4,4′,4″,4′″-tetraethyl-2,2′:6′,2″:6″,2′″-quaterpyridine by the same procedure.     

Syntheses of helical polymers through the combination of axially dissymmetric segments

Wholly aromatic polymers with various helical structures were prepared through the combination of two axially dissymmetric bifunctional compounds. The palladium-catalyzed condensation of (R)-2,2-diethoxy-6,6′-dibromo-1,1′-binaphthyl with (R)-1,1′-binaphthyl-2,2′-diamine and the reaction of (S)-2,2-diethoxy-6,6′-dibromo-1,1′-binaphthyl with (S)-1,1′-binaphthyl-2,2′-diamine produced helical polyamines, and the chiral conformation was confirmed by their circular dichroism spectra and large specific rotations. The combination of (R)-2,2-diethoxy-6,6′-dibromo-1,1′-binaphthyl and (S)-1,1′-binaphthyl-2,2′-diamine afforded polyamines with a zigzag conformation. The condensation of (R)-2,2′-dimethylbiphenyl-6,6′-dicarbonyl chloride with (R)-2,2′-diamino-6,6′-dimethylbiphenyl and the reaction of (S)-2,2′-dimethylbiphenyl-6,6′-dicarbonyl chloride with (S)-2,2′-diamino-6,6′-dimethylbiphenyl predominantly yielded cyclic dimers and tetramers because of the steric proximity of the reactive groups of the propagating species. The experimental results indicated that the structures of the obtained polymers depended on the combination of the chirality of the bifunctional atropisomeric compounds and the position of the functional groups on the aromatic rings. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 4607–4620, 2004     

Synthesis of oligonucleotide inhibitor of protein synthesis: pppA2′p5′A2′p5′A

Oligoadenylates with 2′–5′ linkage were prepared in aqueous solution catalyzed by lead nitrate. Phosphorylation of the resulting triadenylate gave oligonucleotide inhibitor of protein synthesis, ppA2′p5′A2′p5′A.     

The Reaction of 3-Arylsydnone-4-Carbohydroximic Acid Chlorides with Active Methylene Compounds (II)

In the presence of triethylamine, 3-arylsydnone-4-carbohydroximic acid chlorides react not only with active methylene compounds containing keto groups to give 3-aryl-4-(4′,5′-disubstituted-isoxazol-3′-yl)sydnones, but also with compounds containing cyano groups to produce 3-aryl-4-(4′-substituted-5′-aminoisoxazol-3′-yl)sydnones or 3-aryl-4-(4′-cyano-5′-substituted-isoxazol-3′-yl)sydnones.     

Synthesis and characterization of a carbamate-linked oligonucleoside

Reaction of 5′-O-dimethoxytritylthymidine with 1,1′-carbonyldiimidazole gave the 3′-O-carbonylimidazolide, which was condensed in high yield with 5′-amino-5′-deoxythymidine to produce a dinucleoside containing a 3′-O-5′-N-carbamoyl linkage. Four repetitions of carbonyl imidazolide formation and condensation produced a carbamate-linked hexamer. Hydrolytic and thermal denaturation studies did not indicate the presence of intramolecular base stacking.     

Dibenzyl Structuresin a Macromolecular Chain. III. Dibenzyldiisocyanates Reactivity

The reactivity of the 2,2′-, 2,4′-, 4,4′-dibenzyldiisocyanate (2,2′-, 2,4′-, 4,4′-DBDI) with n-butanol in benzene has been studied. The concentrations of all species were monitored by using high performance liquid chromatography (HPLC). The reactivity of 4,4′-DBDI is similar to that of 4,4′-diphenylmethanediisocyanate (4,4′-MDI). Very strong intramolecular catalytic effects were noticed in the case of 2,2′-DBDI, probably due to the variable molecular geometry. These effects are responsible for the whole reaction pattern. The 2,4′-DBDI NCO ortho and para groups reactivities are different and comparable to that of 2,4-toluylenediisocyanate (2,4-TDI).