Bonnie J. Bowdon

Biological and biochemical anti-HIV activity of the benzothiadiazine class of nonnucleoside reverse transcriptase inhibitors

A series of benzothiadiazine derivatives were screened against the human immunodeficiency virus (HIV) and certain structure-activity relationships were defined for anti-HIV activity in this chemical class. The selected representative NSC 287474 was a highly potent inhibitor of HIV-induced cell killing and HIV replication in a variety of human cell lines, as well as in fresh human peripheral blood lymphocytes and macrophages. The compound was active against a panel of biologically diverse laboratory and clinical strains of HIV-1, including the AZT-resistant strain G910-6. However, the agent was inactive against HIV-2, and also against both nevirapine- and pyridinone-resistant strains (N119 and A17) of HIV-1, which are cross-resistant to several structurally diverse nonnucleoside reverse transcriptase inhibitors. The compound selectively inhibited HIV-1 reverse transcriptase, but not HIV-2 reverse transcriptase. Combination of NSC 287474 with AZT synergistically inhibited HIV-1-induced cell killing in vitro. The compound did not inhibit the replication of the Rauscher murine leukemia retrovirus or the simian immunodeficiency virus. The benzothiadiazine class of compounds represents a new active anti-HIV-1 chemotype within the diverse group of nonnucleoside reverse transcriptase inhibitors.

Comparison of the properties of metabolites of CCNU

Abstract Properties of the six isomeric N -(2-chloroethyl- N ′-(hydroxycyclohexyl- N -nitrosoureas, which have been identified by other investigators as metabolites of N -(2-chloroethyl- N ′-cyclohexyl- N -nitrosourea (CCNU), have been compared with those of CCNU and 2-[[[(2-chloroethyl)nitrosoamino]-carbonyl]amino]-2-deoxy- D -glucose (chlorozotocin). There are significant differences in the physicochemical, chemical, and biological properties of these metabolites, and the properties of some of them are significantly different from those of CCNU and chlorozotocin. The position of the hydroxy group and the steric configuration of the compound markedly affect the alkylating and carbamoylating activities of the compounds. The metabolites having the higher alkylating activities and the lower carbamoylating activities produce lethal toxicity to mice at lower molar doses but have somewhat better therapeutic indexes. The data are consistent with the hypothesis that the biological effects observed following the administration of CCNU are due to a large extent to the major metabolites with lesser effects contributed by the minor metabolites. Some of the metabolites have slightly better therapeutic indexes against murine leukemia L1210 than CCNU and chlorozotocin, and they are more soluble in water than CCNU but are active against both intraperitoneally implanted and intracerebrally implanted L1210 leukemia. There might be some therapeutic advantage to administering one of the minor metabolites instead of CCNU or chlorozotocin to cancer-bearing animals.

The Cell Cycle of Leukemia L1210 Cells in vivo and in vitro.

Summary The cell cycles of Leukemia L1210 cells proliferating in mice after serial transplantation, proliferating in mice following inoculation of cultured cells, and proliferating in vitro in spinner cultures have been examined by the method of waves of labeled mitoses following pulse exposure to thymidine-(methyl-3H). The cycles for the 3 groups of cells were essentially the same. The following mean values were obtained: TC, 15.7 hr; TG2, 1.5 hr; TM, 0.5 hr; Ts, 11.7 hr; TG1, 2.0 hr.

6-Substituted Derivatives of Carbovir: Anti-HIV Activity

Abstract A series of 6-alkoxy and 6-alkylamino carbovir derivatives were synthesized in order to evaluate prodrug approaches to increased bioavailability of the anti-HIV agent, carbovir. All of the compounds were active against HIV with the N-alkyl derivatives less active than the corresponding O-alkyl derivatives. The adenosine deaminase inhibitor, EHNA, had no effect on the anti-HIV activity of 6-propoxycarbovir, while the adenylic acid deaminase inhibitor, 2′-deoxycoformycin, significantly decreased antiviral activity. These observations suggest that the 6-alkoxycarbovirs are metabolized directly to the monophosphates and are subsequently converted to carbovir monophosphate via adenylic acid deaminase

Evaluation of anti-AIDS drugs in conventional mice implanted with a permeable membrane device containing human T cells infected with HIV

We now report the confirmation of the work of Hollingshead et al. (1995) on development of a cell based hollow fiber (HF) system for evaluating potential anti-AIDS drugs in vivo using conventional mice rather than SCID mice. CD4 +, CEM-SS cells infected with HIV/1, strain RF, at a multiplicity of infection of 0.1 were placed into HFs. The fibers were implanted into the peritoneal cavity of outbred Swiss mice. Using this model, the antiviral activity of azidothymidine (AZT) at doses of approximately 150, 75 and 37.5 mg/kg/day was evaluated by administering AZT to the mice in drinking water. Upon fiber removal on day 6, AZT treatment was shown to significantly increase CEM cell viability over the untreated, virus control group and significantly reduced the levels of HIV p24 and HIV RT activity.

Chemical properties and biological effects of 2-haloethyl sulfonates☆

Data for the alkylating activities, DNA cross-linking activities, and proliferation-inhibitory activities toward cultured L1210 cells for twenty-four 2-haloethyl sulfonates are reported. Previously reported activities against P388 leukemia in vivo are also presented to permit correlation of in vitro and in vivo properties. Since these compounds are believed to be 2-haloethylating agents, their properties and effects were compared with those of chlorozotocin, which is a recognized 2-chloroethylating agent. 2-Chloroethyl chloromethanesulfonate, which was the most effective compound against P388 leukemia, had a moderate level of alkylating activity and a low level of cross-linking activity, but it was quite active in inhibiting proliferation of cultured L1210 cells. Although its alkylating activity was about the same as that of chlorozotocin, it caused much less cross-linking of DNA. The in vitro tests were useful for gaining information relating structure to the individual properties, but results obtained for one of the properties might not be predictive of the relative values obtained for other properties nor for in vivo activity against P388 leukemia. These results indicate that additional experiments to define the mechanism of action of these agents are needed.

Safety factors involved in the extraction of biologically active proteins from human immunodeficiency virus

The disruption of the viral coat of human immunodeficiency virus by Triton X-100, a nonionic detergent, is a time-dependent process which requires incubation times of 30 min or longer. Conditions for the production of a noninfectious sample from a viral pellet that can be used to measure reverse transcriptase activity were determined.