Straightforward Synthesis of 1-(2,3-Dideoxy-β-D-Glycero-Pent-2-Enofuranosyl)-Thymine

Abstract

A two steps synthesis of the antiviral drug (d4T) 3 from thymidine 1 is proposed, which implies a concomitant deprotection-elimination process by action of t-BuOK in DMF on 5′-O-t-butyldimethylsylil-3′-O-methanesulfonyl-thymidine 2.     

Protection of the Lactam Function of 2′-Deoxyinosine with A 2-(4-Nitrophenyl)-Ethyl Moiety

Abstract

The reaction of O-protected inosine with p-nitrophenyl ethanol under Mitsunobu conditions yields a mixture of the 1- and 0° -alkylated derivatives. 2′-Deoxyinosine protected on 0⁶ -, can be synthesized fairly easy from deoxyguanosine with a Mitsunobu reaction followed by reductive deamination.     

Methodology for the Synthesis of Dinucleoside Monophosphates Containing A 2′-Deoxy-3-Isoadenosine Unit: 3-iso-dApT and Tp(3-iso-dA)

Abstract

2′ -Deoxy-3-isoadenylyl(3′-5′)thymidine and thymidylyl-(3′-5′)-2′-deoxy-3-isoadenosine have been synthesized by mild protection/deprotection methodology that circumvents facile N3-Cl′ hydrolytic cleavage of the 2′-deoxy-3-isoadenosine moiety.

     

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.     

Biodistribution of [77Br]-5-Bromo-2-Deoxyuridine in Rats

Abstract

The feasibility of 5-bromo-2′-deoxyuridine as tumour imaging agent for PET studies in comparison with thymidine is discussed.     

The Synthesis and Antiviral Activity of (E)-5-(2-Nitrovinyl)uridine and (E)-5-(2-Nitrovinyl)-2′-deoxyuridine

Abstract

The protection of the sugar moiety of a 5-formyluracil nucleoside with acid-labile protecting groups allows for the deprotection of the sugar of a subsequently formed nucleoside possessing a 5-nitrovinyl side-chain. The synthesis and antiviral activity of (E) -5-(2-nitrovinyl)-uridine and (E)-5-(2-nitrovinyl)-2′-deoxyuridine are reported.     

Synthesis and Hybridization Properties of Oligonucleotides Containing (2 S ,3 R )-9-(2,3,4-Trihydroxybutyl)Adenine

The synthesis and properties of oligonucleotides (ONs) containing 9-(2,3,4-trihydroxybutyl)adenine, A ^C2 and A ^C3, are described. The ON containing A ^C2 involves the 3′ → 4′ and 3′ → 5′ phosphodiester linkages in the strand, whereas that containing A ^C3 possesses the 3′ → 4′ and 2′ → 5′ phosphodiester linkages. It was found that incorporation of the analogs, A ^C2 or A ^C3, into ONs significantly reduces the thermal and thermodynamic stabilities of the ON/DNA duplexes, but does not largely decrease the thermal and thermodynamic stabilities of the ON/RNA duplexes as compared with the case of the ON/DNA duplexes. It was revealed that the base recognition ability of A ^C2 is greater than that of A ^C3 in the ON/RNA duplexes.     

Synthesis and Biological Activities of Sugar-Modified 2-(p-n-Butylanilino)-2′-deoxyadenosine Analogues

Abstract

Several sugar-modified 2-(p-n-butylanilino)-2′-deoxyadenosine analogues, including arabino and 2′(R)-azido-2′-deoxy analogues and their 5′-triphosphates were synthesized. These nucleosides thus obtained exhibited moderate cytotoxicity against P-388 leukemic cells in culture (IC₅₀ = 13–24 μ). In contrast to above results, the 5′-triphosphates have been shown to exert strong and selective inhibitory effects on mammalian DNA polymerase α (Ki= 0.02–0.04 μ).     

Isotactic Glycero Oligothymidylate. a Convenient Preparation of (R) and (S) 1′, 2′-Seco 2′-Nor Thymidine

Abstract

(R) and (S) dimethoxytrityl derivatives of 1′, 2′-seco 2′-nor thymidine were synthesized in an efficient way. Isotactic dodecaoligoglycerothymidylate was obtained by a solid support phosphoramidite approach. The lack of hybridization with poly rA makes this acyclooligonucleotide useless as antisense or sense agent.     

Synthesis of Bis(Aziridinyl) Phosphinic Amide Derivatives of Thymidine as Potential Anticancer Agents

Abstract

3′- and 5′-Bis(aziridinyl)phosphinic amide derivatives of thymidine have been synthesized as potential anticancer agents from 3′-amino-3′-deoxythymidine and 5′-amino-5′-deoxythymidine, respectively. The aziridine-containing compounds were tested for their cytotoxic action in vitro against the L1210 leukemia; the 3′-bis(aziridinyl)phosphinic amide derivative was found to be about 11-times more active than its 5′-counterpart in inhibiting the replication of these leukemic cells, with ED₅₀ values of 0.6 and 7 μM, respectively, being obtained.     

Syntheses of 1-[(2-Hydroxyethoxy)methyl]- and 1-[(1,3-Dihydroxy-2-Propoxy)methyl]- Derivatives of 5-Substituted-2,4-difluorobenzene: Unnatural Acyclo Thymidine Mimics for Evaluation as Anticancer and Antiviral Agents

Abstract

A group of 1-[(2-hydroxyethoxy)methyl]- (12) and 1-[(1,3-dihydroxy-2-propoxy)methyl]- (13) derivatives of 2,4-difluorobenzene possessing a variety of C-5 substituents (R = Me, H, I, NO₂) were designed with the expectation that they may serve as acyclic 5-substituted-2′-deoxyuridine (thymidine) mimics. Compounds 12 and 13 (R = Me, H, I) were inactive as anticancer agents (C₅₀ = 10^?3 to 10^?4 M range), whereas the 5-nitro compounds (12d, 13d) exhibited weak-to-moderate cytotoxicity (CC₅₀ = 10^?5 to 10^?6 M range) against a variety of cancer cell lines. All compounds prepared (12a-d, 13a-d) were inactive as antiviral agents in a broad-spectrum antiviral screen that also included the human immunodeficiency virus (HIV-1 and HIV-2) and herpes simplex virus (HSV-1 and HSV-2).     

Disaccharide Pyrimidine Nucleosides and Their Derivatives: A Novel Group of Cell-Penetrating Inhibitors of Poly(ADP-Ribose) Polymerase 1

Nearly 30 synthetic nucleosides were tested with human recombinant poly(ADP-ribose) polymerase 1 as potential inhibitors of this enzyme. The most active compounds were some disaccharide analogues of thymidine: 3′-O-β-D-ribofuranosyl-5-iodo-dUrd (2d; IC₅₀ = 45 μM), 3′-O-β-D-ribofuranosyl-2′-deoxythymidine (2e; IC₅₀ = 38 μM), and 3′-O-β-D-ribofuranosyl-2′-deoxythymidine oxidized (4; IC₅₀ = 25 μM). These compounds also reduced H₂O₂-induced synthesis of poly(ADP-ribose) in cultured human ovarian carcinoma (SKOV-3) cells in a dose-dependent manner. Furthermore, compounds 2d or 2e until a concentration of 1 mM did not affect growth of SKOV-3 cells, whereas dialdehyde compound 4, as well as thymidine, exhibited a significant cytotoxicity.     

A Simple Synthesis of N4 -(6-Aminohexyl)-2′-Deoxy-5′-O-(4,4′-Dimethoxytrityl)Cytidine

Abstract

The title compound was synthesized by a transamination reaction between N⁴ -benzoyl-2′-deoxy-5′-O-(4,4′-dimethoxytrityl)cytidine and hexane-1,6-diamine in the presence of 1,5,7-triazabicyclo(4.4.0)dec-5-ene (TBD).     

Synthesis of P-Thioadenylyl (2′-5′) Adenosine and P-Thioadenylyl (2′-5′)-P-Thioadenylyl-(2′-5′)-Adenosine

Abstract

Dimer and trimer adenylates with 2′-5′ phosphorothioate linkages were synthesized via the phosphoramidite method using p-nitrophenyl-ethyl group for phosphate protection and followed by sulfur oxidation. The various diastereoisomers were separated and characterized.     

Relationship Between Conformation and Antiviral Activity-III. 3′-Azidothymidine (AZT) and 3′-Azido-2′, 3′-dideoxy-5-hydroxymethyluridine

Abstract

3′-Azido-2′,3′-dideoxy-5-hydroxymethyluridine (AZHMddUrd) was synthesized to improve the potency of 5-hydroxymethyl-2′-deoxyuridine (HMdUrd) against human immunodeficiency virus (HIV). AZHMddUrd was a very poor inhibitor of HIV replication (ED₅₀ >200 μM) and was also nontoxic up to 400 μM (highest concentration tested) to HT4-6C (HeLa CD₄) cells. AZT was phosphorylated by human cellular thymidine kinase. In contrast, AZHMddUrd and HMdUrd were poor substrates for the kinase. The relationship between molecular conformation and antiretroviral activity for 3′-azidothymidine (AZT), HMdUrd and AZHMddUrd is discussed.     

Syntheses of Phosphonate Analogues of Dideoxyadenosine (DDA)-, Dideoxycytidine (DDC)-, Dideoxyinosine (DDI)-, and Deoxythymidine (DDT)-5′-Monophosphates

Abstract

Phosphonate derivatives of ddA, ddC, ddI and ddT (5f, 5e, 5c, and 5a) were prepared by condensing the 5′-aldehydes with diphenyl triphenylphosphoranylidenemethylphosphonate, reducing the resultant olefins and hydrolyzing the phosphonate phenyl esters, sequentially, with base and then C. atrox phosphodiesterase.     

SATE (Aryl) Phosphotriester Series. I. Synthesis and Biological Evaluation

Abstract

Synthesis and biological activities of several phosphotriester derivatives of 3′-azido-2′,3′-dideoxythymidine (AZT) bearing a S-pivaloyl-2-thioethyl (tBuSATE) group and aryl residues derived from L-tyrosine are reported. All compounds showed marked anti-HIV activity in thymidine kinase-deficient CEM cells demonstrating their ability to deliver intracellularly the parent 5′-mononucleotide.     

Synthesis,In Vitro Anti-HIV Activity,and Biological Stability of 5′-O-Myristoyl Analogue Derivatives of 3′-Fluoro-2′,3′-Dideoxythymidine (FLT) as Potential Bifunctional Prodrugs of FLT

Abstract

A group of 5′-O-myristoyl analogue derivatives of FLT (2) were evaluated as potential anti-HIV agents that were designed to serve as prodrugs to FLT. 3′-Fluoro-2′,3′-dideoxy-5′-O-(12-methoxydodecanoyl)thymidine (4) (EC₅₀ = 3.8 nM) and 3′-fluoro-2′,3′-dideoxy-5′-O-(12-azidododecanoyl)thymidine (8) (EC₅₀ = 2.8 nM) were the most effective anti-HIV-1 agents. There was a linear correlation between Log P and HPLC Log retention time for the 5 ′-O-FLT esters. The in vitro enzymatic hydrolysis half-life (t½), among the group of esters (3–8) in porcine liver esterase, rat plasma and rat brain homogenate was longer for 3′-fluoro-2′,3′-dideoxy-5 ′-O-(myristoyl)thymidine (7), with t½ values of 20.3, 4.6 and 17.5 min, respectively.