Steven H. Krawczyk

A total synthesis of the naturally occurring pyrrolo[2,3-d]pyrimidine nucleoside, mycalisine A

Abstract The first total synthesis of mycalisine A, a pyrrolo[2,3- d ]pyrimidine nucleoside, was accomplished by a multi-step synthesis from toyocamycin.

Structure-Activity Study of Oligodeoxynucleotides Which Inhibit Thrombin

Abstract The 15-mer oligodeoxynucleotide GGTTGGTGTGGTTGG is a potent inhibitor of thrombin and it forms a stable, highly compact structure in solution. Deletions and substitutions by abasic residues, 2′-deoxyinosine, 7-deaza-2′-deoxyguanosine and 8-methyl-2′-deoxyguanosine show that the structural features of the oligodeoxynucleotide are important for its biological activity.

Synthesis of 4-substituted imidazo[4,5-d][1,2,3]triazine (2-azapurine)nucleosides.

Abstract Several methods for functionalization of the 4-position of imidazo[4,5-d][1,2,3]triazin-4-one were investigated. These investigations were successful and led to the preparation of 4-amino, 4-triazol-1-yl, 4-methoxy, 4-methylthio, 4-methylamino, 4-thio, 4-nitrobenzyl, and 4-unsubstituted 9-(β-D-ribofuranosyl)-imidazo-[4,5-d][1,2,3]triazine (2-azapurine ribosides). The 4-unsubstituted compound (19) was slightly active against HCMV in plaque and yield reduction experiments and was not cytotoxic at 100 μM. The methylamino (15), hydrazino (16), and p-nitrobenzylthio (20) were inactive against HCMV but slightly cytotoxic. The thiomethyl-substituted analog (21) was the most active with activity comparable to ganciclovir but with greater cytotoxicity. We conclude that even though none of the tested compounds had antiviral activity superior to ganciclovir, the new synthetic methods will provide a route to more interesting compounds.

Synthesis of a pyrido[1,2-a]purine nucleoside by a novel ring cleavage-annulation reaction of 3-β-D-ribofuranosylimidazo-[4,5-d]-v-triazin-4-one

Treatment of 7-(2,3,5-tris-O-(t-butyldimethylsilyl)-β-D-ribofuranosyl)imidazo[4,5-d]-v-triazin-4-one (1) with MnO2 in hot pyridine furnished 7-(2,3,5-tris-O-(t-butyldimethylsilyl)-β-D-ribofuranosyl)pyrido[1,2-a]-purine (4). Treatment of 4 with tetra-n-butylammonium fluoride furnished the free nucleoside 5.

2′,3′-Dideoxyadenosine Analogs of the Nucleoside Antibiotics Tubercidin, Toyocamycin and Sangivamycin

Abstract Application of previously described methodologies, for the synthesis of 2′,3′-dideoxy-2′,3′-didehydro nucleosides from the parent ribonucleosides, to the antibiotics tubercidin (1), toyocamycin (6) and sangivamycin (10) has provided the corresponding 2′,3′-unsaturated nucleosides 4, 9, and 13. A reduction of the 2′,3′-unsaturated moiety has afforded the 2′,3′-dideoxynucleoside antibiotics 5, 14, and 15.

A novel approach towards the synthesis of the 3,4,5-trihydro-1,3-diazepin-5-ol ring structure

A catalytic reduction of the nitrile portion of the trimethylsilyl cyanohydrin 7 to a primary amine has produced an situ annulation to generate the 3,4,5-trihydro-1,3-diazepin-5-ol ring. This ring substructure has demonstrated important biological significant.3

Chapter 14. Non-HIV Antiviral Agents

Publisher Summary The search for anti-viral agents targeted against a variety of viruses other than HIV has continued to yield novel compounds for the treatment of nonHIV diseases. Some of these are herpes viruses, hepatitis B and C, influenza virus, respiratory syncytial virus. A retrospective analysis of the association of anti-herpesvirus treatment with the incidence of Kaposis sarcoma in HIV infected individuals has shown that treatment with foscarnet or ganciclovir but not acyclovir reduce the risk of developing Kaposis sarcoma. In harmony with this, HHV-8 (Kaposi sarcoma associated herpesvirus) has been found to be sensitive to ganciclovir, cidofovir, and foscarnet but not acyclovir. Another herpesvirus that has been associated with human malignancies, Epstein-Barr virus (EBV), is sensitive to the L-nucleoside L-FMAU in H1 cells. Among other anti-viral agents, topically applied cidofovir is active against Papilloma virus infections in humans. Cidofovir is also found to have activity in vitro against polyoma viruses and is efficacious in vivo in a murine model of polyoma virus infection. Various cysteine protease inhibitors are active against adenovirus replication, while interferon-α remains the only clinically approved treatment for hepatitis C, the recent determination of the structure of HCV NS3 protease by two independent groups has provided an opportunity for the exploitation of this target for the development of anti-viral agents.