Kamal N. Tiwari

Activities of Certain 5-Substituted 4′-Thiopyrimidine Nucleosides against Orthopoxvirus Infections

ABSTRACT As part of a program to identify new compounds that have activity against orthopoxviruses, a number of 4′-thionucleosides were synthesized and evaluated for their efficacies against vaccinia and cowpox viruses. Seven compounds that were active at about 1 μM against both viruses in human cells but that did not have significant toxicity were identified. The 5-iodo analog, 1-(2-deoxy-4-thio-β-d-ribofuranosyl)-5-iodouracil (4′-thioIDU), was selected as a representative molecule; and this compound also inhibited viral DNA synthesis at less than 1 μM but only partially inhibited the replication of a recombinant vaccinia virus that lacked a thymidine kinase. This compound retained complete activity against cidofovir- and ST-246-resistant mutants. To determine if this analog had activity in an animal model, mice were infected intranasally with vaccinia or cowpox virus and treatment with 4′-thioIDU was given intraperitoneally or orally twice daily at 50, 15, 5, or 1.5 mg/kg of body weight beginning at 24 to 120 h postinfection and was continued for 5 days. Almost complete protection (87%) was observed when treatment with 1.5 mg/kg was begun at 72 h postinfection, and significant protection (73%) was still obtained when treatment with 5 mg/kg was initiated at 96 h. Virus titers in the liver, spleen, and kidney were reduced by about 4 log10 units and about 2 log10 units in mice infected with vaccinia virus and cowpox virus, respectively. These results indicate that 4′-thioIDU is a potent, nontoxic inhibitor of orthopoxvirus replication in cell culture and experimental animal infections and suggest that it may have potential for use in the treatment of orthopoxvirus infections in animals and humans.

Antiangiogenic activity of 4′-thio-β-d-arabinofuranosylcytosine

4′-Thio-β-d-arabinofuranosylcytosine (T-araC), a new-generation deoxycytidine nucleoside analogue, showed significant efficacy against numerous solid tumors in preclinical studies and entered clinical development for cancer therapy. It is a structural analogue of cytarabine (araC), a clinically used drug in the treatment of acute myelogenous leukemia, which has no or very limited efficacy against solid tumors. In comparison with araC, the excellent in vivo activity of T-araC against solid tumors suggests that, in addition to inhibition of DNA synthesis, T-araC may target cellular signaling pathways, such as angiogenesis, in solid tumors. We studied T-araC and araC for their antiangiogenic activities in vitro and in vivo. Both compounds inhibited human endothelial cell proliferation with similar IC50s. However, only T-araC inhibited endothelial cell migration and differentiation into capillary tubules. T-araC also abrogated endothelial cell extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, a key signaling molecule involved in cellular processes of angiogenesis. Results from chick chorioallantoic membrane angiogenesis assays revealed that T-araC significantly inhibited the development of new blood vessels in vivo, whereas araC showed much less effect. The findings of this study show a role of T-araC in antiangiogenesis and suggest that T-araC combines antiproliferative and antiangiogenic activity in one molecule for a dual mechanism of drug action to achieve the excellent in vivo efficacy against several solid tumors. This study also provides important information for optimizing dosage and sequence of T-araC administration in clinical investigations by considering T-araC as both an antiproliferative and an antiangiogenic agent. [Mol Cancer Ther 2006;5(9):2218–24]

Synthesis and Biological Activity of 5-Azacytosine Nucleosides Derived from 4-Thio-2-Deoxy-L-threo-Pentofuranose and 4-Thio-2-Deoxy-D-erythro-Pentofuranose

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 alpha and beta anomers of nucleosides.

Biosynthesis of the Naturally Occurring Nucleoside Antibiotics from Adenosine

Abstract 9-β-D-Arabinofuranosyladenine (ara-A, l), first isolated from the culture filtrates of StreDtomyces antibioticus, has a broad spectrum of activity against DNA viruses in cell culture and is successfully used in therapy of herpes simplex encephalitis, neonatal herpes, herpes zoster and chronic myelogenous leukemia1. 2′-Chlorodeoxycoformycin (2′CldCF, 2), 2′-amino-Zt-deoxyadenosine (3) and nucleocidin (4) have been isolated from the culture medium of Fctinomadura and S. clavus, respectively.