Inhibition of Vertebrate Telomerases by the Triphosphate Derivatives of Some Biologically Active Nucleosides

Abstract

In order to clarify the effect of the base moiety of nucleotide analogs on telomerase inhibition, triphosphate derivatives of biologically active nucleosides, 3′-azido-3′-deoxythymidine (AZT), 2′-deoxy-2′-fluoroarafuranosylthymine (FaraT), acycloguanosine (ACG) and their guanine or thymine counterparts (AZdG, FaraG and ACT, respectively) were investigated. In all of the present cases, guanine derivatives showed more potent inhibition than their thymine counterparts.     

Phosphonates Derivatives of 2′,3′-Dideoxy-2′,3′-didehydro-pentopyranosyl Nucleosides

Abstract

Adenine and thymine derivatives of 2′,3′-dideoxy-2′,3′-didehydropento-pyranosyl nucleosides carrying a phosphonomethyl moiety at their 4′-O-position and in a cis relationship with the heterocyclic base have been synthesized.     

Synthesis of 2,2′-Anhydro Nucleosides with a Modified Sugar Side-Chain

Abstract

2,2′-Anhydro-1-(5,6-di-O-benzoyl-β-D-altrofuranosyl)thymine 6 and uracil derivative 7 are prepared by transformation of the corresponding 5′,6′-di-O-benzoyl-3′-O-mesyl-β-D-glucofuranosyl nucleosides 4 and 5 into the 2,2′-anhydro derivatives 6 and 7 using DBU.     

Synthesis and antitumor activity of N-sulfonyl derivatives of nucleobases and sulfonamido nucleoside derivatives

The introduction of sulfonamido group on the C-2 position of pyrimidine nucleosides was achieved by ring opening of 2,2'- and 2,3'-anhydronucleosides. N-sulfonyl derivatives of nucleobases and sulfonamido derivatives of nucleosides were assayed for in vitro antitumor activity.     

Synthesis of a Novel Aldehyde: 4-O-Methyl-5-formylmethyl- 2′-deoxyuridine

Abstract

The synthesis of the blocked nucleoside 3′,5′-di-O-p-toluoyl-4-O-methyl-5-formylmethyl-2′-deoxyuridine (19) was accomplishied in eleven steps from gamma-butyrolactone. This aldehyde, which should facilitate the synthesis of nucleosides containing ¹⁸F, was converted to the corresponding blocked dithianyl nucleoside (21), and also to 5-(2,2-difluoroethyl)-substituted derivatives of 2′-deoxyuridine and 2′-deoxycytidine.     

Preparation and Antiviral Activity of Several Deoxygenated Ribavirin and Tiazofurin Derivatives

Abstract

Ribavirin and tiazofurin, two nucleosides of known antiviral activity, have been transformed by previously reported methods to yield several deoxy,epoxy, or dideoxy analogues. The deoxygenated derivatives were evaluated for antiviral activity against a host of DNA and RNA viruses; however, no significant in vitro activity was detected.     

Nucleosides and Nucleotides. 104. Radical and Palladium-Catalyzed Deoxygenation of the Allylic Alcohol Systems in the Sugar Moiety of Pyrimidine Nucleosides§,1

Abstract

New methods for the synthesis of 2′,3′-didehydro-2′,3′-dideoxy-2′ (and 3′)-methyl-5-methyluridines and 2′,3′-dideoxy-2′ (and 3′)-methylidene pyrimidine nucleosides have been developed from the corresponding 2′ (and 3′)-deoxy-2′ (and 3′)-methylidene pyrimidine nucleosides. Treatment of a 3′-deoxy-3′-methylidene-5-methyluridine derivative 8 with 1,1′-thiocarbonyldiimidazole gave the allylic rearranged 2′,3′-didehydro-2′,3′-dideoxy-3′-[(imidazol-1-yl)carbonylthiomethyl] derivative 24. On the other hand, reaction of 8 with methyloxalyl chloride afforded 2′-O-methyloxalyl ester 25. Radical deoxygenation of both 24 and 25 gave 26 exclusively. Palladium-catalyzed reduction of 2′,5′-di-O-acetyl-3′-deoxy-3′-methylidene-5-methyluridine (32) with triethylammonium formate as a hydride donor regioselectively afforded the 2′,3′-dideoxy-3′-methylidene derivative 35 and 2′,3′-didehydro-2′,3′-dideoxy-3′-methyl derivative 34 in a ratio of 95:5 in 78% yield. These reactions were used on the corresponding 2′-deoxy-2′-methylidene derivatives. An alternative synthesis of 2′,3′-dideoxy-2′-methylidene pyrimidine nucleosides (43, 52, and 54) was achieved from the corresponding 1-(3-deoxy-β-D-thero-pentofuranosyl)pyrimidines (44 and 45). The cytotoxicity against L1210 and KB cells and inhibitory activity of the pathogenicity of HIV-1 are also described     

Deaza- and Deoxyadenosine Derivatives: Synthesis and Inhibition of Animal Viruses as Human Infection Models

Abstract

N⁶-Cycloalkyl-2′,3′-dideoxyadenosine derivatives and (2-chloro)-N⁶-cycloheptyl-3-deazaadenosine have been synthesized and tested, along with other (deaza)purine (deoxy)nucleosides from our chemical library, as inhibitors of virus replication against Bovine Herpes Virus 1 (BHV-1) and sheep Maedi/Visna Virus (MVV). Most compounds demonstrated good antireplicative activity against MVV, showing also low cell toxicity.     

Synthesis and Anti-cancer Activity of Some Novel 5-Azacytosine Nucleosides

Abstract

1-O-Acetyl-2-deoxy-3,5-di-O-toluoyl-4-thio-D-erythro-pentofuranose and 2-deoxy-1,3,5-tri-O-acetyl-4-thio-L-threo-pentofuranose were coupled with 5-azacytosine to obtain α and β anomers of nucleosides. All four nucleosides were reduced to the corresponding dihydro derivatives and deblocked to give target compounds. All eight target compounds were evaluated in a series of human cancer cell lines in culture. Only 2′-deoxy-4′-thio-5-azacytidine (3β) was found to be cytotoxic in all the cell lines and was further evaluated in vivo. Details of the synthesis and biological activity are reported.     

Synthesis of Some Purine Carbocyclic Isosteres of 2′,3′-Dideoxy-3′-C-Hydroxymethyl Nucleosides as Potential Inhibitors of HIV

Abstract

The synthesis of some enantiomerically pure carbocyclic 2′,3′-dideoxy-3′-C-hydroxymethyl derivatives of adenine, inosine and guanine is described. The Mitsunobu reaction was used in the coupling procedure giving exclusively N⁹-coupling. The nucleosides were tested for inhibition of HIV multiplication in vitro and were found to be inactive in the assay.     

A Convenient Synthesis of Deoxynebularine Phosphoramidite

Abstract

Enzyme catalysis by a cell free preparation from Lactobacillus leichmannii is used to accomplish the transformation of thymidine to deoxynebularine in the presence of purine. The resulting mixture of nucleosides is then converted to their 5′-dimethoxytrityl derivatives which are easily separated using conventional chromatography. Phosphitylation of the 5′-dimethoxytrityl-deoxynebularine then gives the phosphoramidite derivative suitable for incorporation into oligonucleotides.     

Nucleosides and Nucleotides. 125. Synthesis and Biological Evaluation of 2′,3′-Dideoxy-3′-fluoro-2′-methylidene Pyrimidine Nucleosides

Abstract

Reaction of 2′-deoxy-2′-methylidene-5′-O-trityluridine (1) with diethylamino-sulfur trifluoride (DAST) in CH₂Cl₂ resulted in the formation of a mixture of (3′R)-2′,3′-dideoxy-3′-fluoro-2′-methylidene derivative 3 and 2′,3′-didehydro-2′,3′-dideoxy-2′-fluoromethyl derivative 4 (3:4 = 1:1.5) in 65% yield. A similar treatment of 1-(2-deoxy-2-methylidene-5-O-trityl-β-D-threo-pentofuranosyl)uracil (19) with DAST in CH₂Cl₂ afforded (3′S)-2′,3′-dideoxy-3′-fluoro-2′-methylidene derivatives 20 and 4 in 38% and 17% yields respectively. Transformation of the uracil nucleosides 4, 12, and 20 into cytosines followed by deprotection furnished the corresponding cytidine derivatives 29, 18, and 25, respectively. The corresponding thymidine congener 27 was also synthesized in a similar manner. All of the newly synthesized nucleosides were evaluated for their inhibitory activities against HIV and for their antiproliferative activities against L1210 and KB cells.     

Synthesis of 3′-Amino and 5′-Amino Hydantoin 2′-Deoxynucleosides

Abstract

3′-Amino and 5′-amino derivatives of hydantoin 2′-deoxynucleosides have been prepared from the corresponding 3′-phthalimido and 5′-azido nucleosides, respectively, which in turn were prepared by condensation of appropriate sugars with 5-benzylidenehydantoin. The amino nucleosides were tested for their potential activity against HIV and HSV.     

Chiral 1′, 2′-Seco-Nucleosides: Synthesis of D and L-Threitol-2′-O-Methylenyl Nucleosides

Abstract

1′, 2′-Seco-nucleoside derivatives of adenine, cytosine, guanine and thymine with a D or L-threitol side-chain configuration have been synthesized from D or L dimethyl tartarate respectively. Biological evaluation of the four enantiomeric pairs of nucleosides revealed they were inactive against various viruses in cell cultures.     

N-Dimethylaminomethylene-O-trialkylsilyl Derivatives of Nucleosides for Chromatography and Mass Spectrometry

Abstract

Dimethylformamide dimethyl acetal (DMF-DMA) reacts with nucleosides under mild conditions to give N-dimethylaminomethylene (N-DMAM) derivatives. Silylation provides the DMAM-O-trialkylsilyl mixed derivatives which have good chromatographic and mass spectral properties.     

Synthesis and NMR Spectra of Some New Carbohydrate Modified Uridine Phosphoramidites

Abstract

The one step reaction of 2′- and 3′-keto derivatives of uridine with bromodifluoromethyl[tris(dimethylamino)]phosphonium bromide and zinc gives the corresponding 2′- and 3′-difluoromethylene nucleosides in good yield. Desilylation and phosphitylation of the resultant 2′- or 3′-hydroxyls provides the target 2′- and 3′-phosphoramidites 7 and 8 for use in oligonucleotide synthesis¹.     

Synthesis,Protonation Behavior,Conformational Analysis,and Regioselective Enzymatic Acylation of the Novel Diamino Analogue of (E)-5-(2-Bromovinyl)-2′-deoxyuridine (BVDU)

Abstract

(E)-3′,5′-Diamino-5-(2-bromovinyl)-2′,3′,5′-trideoxyuridine (5), the diamino analogue of BVDU (1), was synthesized from BVDU. The protonation behavior of 5 has been studied by means of pH-metric measurements and NMR spectroscopy. This study allows the determination of the basicity constants and the stepwise protonation sites. Thus, the main species at physiological pH is the monoprotonated form. The conformational analysis of this nucleoside analogue was also carried out through ¹H NMR spectroscopy. In addition, a convenient synthesis of N-3′ and N-5′ acylated derivatives was developed by regioselective enzymatic acylation. Thus, Candida antarctica lipase B (CAL-B) selectively acylated the 5′-amino group, thus furnishing nucleosides 8. On the other hand, immobilized Pseudomonas cepacia lipase (PSL-C) exhibited the opposite selectivity, conferring acylation at the 3′-amino group, thus affording derivatives 9.     

Synthesis and Anti-Hiv Activity of 3′-0-Formyl Derivatives of Thymidine and 2′-Deoxyuridine

Abstract

Reaction of the 5′-O-t-butyldimethylsilyl derivatives of thymidine and 2′-deoxyuridine with the Vilsmeier reagent (POCI₃/DMF), and removal of the t–butyldimethylsilyl protecting group, afforded 3′-O-formylthymidine (5) and 3′-O-formyl-2′-deoxyuridine (6), respectively. In vitro evaluation, determined as the ability of the test compound to inhibit HIV induced cytopathogenicity in CEM cells, indicated that 5 was moderately active, whereas 6 was inactive.     

Design,Efficient Synthesis,and Anti‐HIV Activity of 4′‐C‐Cyano‐ and 4′‐C‐Ethynyl‐2′‐deoxy Purine Nucleosides

Some 4′‐C‐ethynyl‐2′‐deoxy purine nucleosides showed the most potent anti‐HIV activity among the series of 4′‐C‐substituted 2′‐deoxynucleosides whose 4′‐C‐substituents were methyl, ethyl, ethynyl and so on. Our hypothesis is that the smaller the substituent at the C‐4′ position they have, the more acceptable biological activity they show. Thus, 4′‐C‐cyano‐2′‐deoxy purine nucleosides, whose substituent is smaller than the ethynyl group, will have more potent antiviral activity. To prove our hypothesis, we planned to develop an efficient synthesis of 4′‐C‐cyano‐2′‐deoxy purine nucleosides (4′‐CNdNs) and 4′‐C‐ethynyl‐2′‐deoxy purine nucleosides (4′‐EdNs). Consequently, we succeeded in developing an efficient synthesis of six 2′‐deoxy purine nucleosides bearing either a cyano or an ethynyl group at the C‐4′ position of the sugar moiety from 2′‐deoxyadenosine and 2,6‐diaminopurine 2′‐deoxyriboside. Unfortunately, 4′‐C‐cyano derivatives showed lower activity against HIV‐1, and two 4′‐C‐ethynyl derivatives suggested high toxicity in vivo.     

Nucleosides. IX. Synthesis of Purine N 3,5′‐Cyclonucleosides and N 3,5′‐Cyclo‐2′,3′‐seconucleosides via Mitsunobu Reaction as TIBO‐like Derivatives

The Mitsunobu reaction was applied to prepare, in one step, purine N ³,5′‐cyclonucleosides 10a–d. A subsequent ring opening in the ribose moiety of the resultant N ³,5′‐nucleosides by sodium periodate led to the corresponding N ³,5′‐cyclo‐2′,3′‐seconucleosides. These products consist of 5‐, 6‐, and 7‐membered tricyclic system which is the basic skeleton of TIBO derivatives, known antiviral agents.