title: HIV-1 neutralization and tumor cell proliferation inhibition in vitro by simplified analogues of pyrido[4,3,2-mn]thiazolo[5,4-b]acridine marine alkaloids.
abstract: The antiviral/antitumor marine alkaloid dercitin was used as a lead compound to design analogues with anti-HIV and tumor inhibitory activities. Deletion of structural features contributing to cytotoxicity led to analogues with lowered T-lymphocyte toxicity profiles. One compound, 5, induced complete protection against HIV-1 infectivity in vitro at 12.5 micrograms/mL (38 microM) without T-cell toxicity up to 400 micrograms/mL. Compound 4 and 5 also inhibited the binding of HIV-1 to H-9 lymphocytes. These compounds may exert antiviral activity by a unique dual extracellular and intracellular mode of action--both preventing viral attachment to lymphocytes as well as intercalating with viral nucleic acid. Analogues with higher cytotoxicity such as 2 which retain the thiazole ring of the natural product proved effective in completely inhibiting the cell proliferation of breast, colon, and lung tumor cell lines at 1.5 microM concentration compared to a 70 microM dose level of 5-fluorouracil. A means of molecular separation of antiviral activity from cytotoxicity was thus achieved, and putative pharmacophores for antiviral and antitumor actions of the prototype molecule dercitin have been deduced. The 2-thio-9-acridinone derivatives 4 and 5 represent a new structural type exhibiting activity against HIV in vitro, serving as chemical leads in the design of anti-AIDS agents, while thiazolo[5,4-b]acridines such as 2 provide leads in the drug design of new antitumor agents.
authors.affiliation: Department of Organic Chemistry, Southwest Foundation for Biomedical Research, San Antonio, Texas 78228-0147.
authors.forename: I B
authors.initials: IB
authors.lastname: Taraporewala
authors.forename: J W
authors.initials: JW
authors.lastname: Cessac
authors.forename: T C
authors.initials: TC
authors.lastname: Chanh
authors.forename: A V
authors.initials: AV
authors.lastname: Delgado
authors.forename: R F
authors.initials: RF
authors.lastname: Schinazi
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects*; D002478:Cells, Cultured; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D008214:Lymphocytes / Q000187:drug effects / Q000382:microbiology; D011863:Radioimmunoassay; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000470:Alkaloids; D000998:Antiviral Agents; C060878:dercitin; D007371:Interferon-gamma; D004247:DNA