Showing papers by "James B. McMahon published in 1992"

The calanolides, a novel HIV-inhibitory class of coumarin derivatives from the tropical rainforest tree, Calophyllum lanigerum.

Abstract: Eight new coumarin compounds (1-8) were isolated by anti-HIV bioassay-guided fractionation of an extract of Calophyllum lanigerum. The structures of calanolide A (1), 12-acetoxycalanolide A (2), 12-methoxycalanolide A (3), calanolide B (4), 12-methoxycalanolide B (5), calanolide C (6) and related derivatives 7 and 8 were solved by extensive spectroscopic analyses, particularly HMQC, HMBC, and difference NOE NMR experiments. The absolute stereochemistry of calanolide A (1) and calanolide B (4) was established by a modified Mosher's method. Calanolides A (1) and B (4) were completely protective against HIV-1 replication and cytopathicity (EC50 values of 0.1 microM and 0.4 microM, respectively), but were inactive against HIV-2. Some of the related compounds also showed evidence of anti-HIV-1 activity. Studies with purified bacterial recombinant reverse transcriptases (RT) revealed that the calanolides are HIV-1 specific RT inhibitors. Moreover, calanolide A was active not only against the AZT-resistant G-9106 strain of HIV-1 but also against the pyridinone-resistant A17 strain. This was of particular interest since the A17 virus is highly resistant to previously known HIV-1 specific, non-nucleoside RT inhibitors (e.g., TIBO; BI-RG-587; L693,593) which comprise a structurally diverse but apparently common pharmacologic class. The calanolides represent a substantial departure from the known class and therefore provide a novel new anti-HIV chemotype for drug development.

A nonpromoting phorbol from the samoan medicinal plant Homalanthus nutans inhibits cell killing by HIV-1

Abstract: Extracts of Homalanthus nutans, a plant used in Samoan herbal medicine, exhibited potent activity in an in vitro, tetrazolium-based assay which detects the inhibition of the cytopathic effects of human immunodeficiency virus (HIV-1). The active constituent was identified as prostratin, a relatively polar 12-deoxyphorbol ester. Noncytotoxic concentrations of prostratin from greater than or equal to 0.1 to greater than 25 microM protected T-lymphoblastoid CEM-SS and C-8166 cells from the killing effects of HIV-1. Cytoprotective concentrations of prostratin greater than or equal to 1 microM essentially stopped virus reproduction in these cell lines, as well as in the human monocytic cell line U937 and in freshly isolated human monocyte/macrophage cultures. Prostratin bound to and activated protein kinase C in vitro in CEM-SS cells and elicited other biochemical effects typical of phorbol esters in C3H10T1/2 cells; however, the compound does not appear to be a tumor promoter. In skin of CD-1 mice, high doses of prostratin induced ornithine decarboxylase only to 25-30% of the levels induced by typical phorbol esters at doses 1/30 or less than that used for prostratin, produced kinetics of edema formation characteristic of the nonpromoting 12-deoxyphorbol 13-phenylacetate, and failed to induce the acute or chronic hyperplasias typically caused by tumor-promoting phorbols at doses of 1/100 or less than that used for prostratin.

Anti-HIV and cytotoxic alkaloids from Buchenavia capitata.

Abstract: The anti-HIV activity in the organic solvent extract of leaves of Buchenavia capitata was traced to a series of known flavonoid alkaloids, which represent a new chemotype for anti-HIV activity The 13C-nmr assignments for this series of compounds have been revised O-Demethylbuchenavianine [1] was the most active compound of the series but produced only moderate cytoprotective effects against HIV in cultured human lymphoblastoid (CEM-SS) cells Compound 1 was cytotoxic also in the NCI human disease-oriented in vitro tumor screening panel and produced a pattern of modest differential cellular sensitivity

HIV inhibitory natural products. 6. The peltatols, novel HIV-inhibitory catechol derivatives from Pothomorphe peltata

Abstract: Three new prenylated catechol dimers have been isolated from the tropical shrub Pothomorphe peltata (Piperaceae). The structures of peltatol A (1), peltatol B (2), and peltatol C (3) were determined by extensive spectroscopic analyses. Peltatols A-C inhibited HIV-1 induced cell killing at subcytotoxic concentrations of 1-10 μg/mL. The monomeric catechol derivative 4-nerolidylcatechol (4) was active in a phorbol receptor binding assay (IC 50 =35 μg/mL) but inactive against HIV. The diphenyl ethers, peltatols B (2) and C (3), were interconvertible in solution (MeOH, DMSO) at room temperature

Sulfonic acid dyes: Inhibition of the human immunodeficiency virus and mechanism of action

Abstract: Over 50 different commercially available sulfonic acid-containing dyes were analyzed for their ability to prevent HIV-1-induced cell killing and in inhibiting HIV-1 replication. Compounds of remarkably similar structure, but with differing patterns of sulfonic acid group substitutions, had a wide range of potency in inhibiting HIV-1. Chicago sky blue (CSB) was highly effective in the inhibition of HIV-1 with less toxicity to CEM-SS cells than most of the other sulfonated dyes tested. Synthesis of CSB was undertaken to produce a product greater than 98% pure and this compound was used to elucidate the possible mechanisms by which this class of structurally related compounds inhibits HIV-1. Addition of CSB to cells infected at high multiplicity at any time up to 24 h after infection, unlike dideoxycytidine (ddC) or oxathiin carboxanilide (OC), inhibited HIV-1-induced cell killing. Other postinfection time course studies revealed that CSB had to be present for 24 h or longer immediately after infection to be protective. Virus binding to cells occurred in the presence of CSB, but the requirement for virion envelope-cell membrane fusion was delayed. CSB was a potent inhibitor of the reverse transcriptase (RT) of both HIV-1 and HIV-2, although it was less active against HIV-2 in a cell killing-based assay. CSB also inhibited Rauscher and LP-BM5 murine leukemia viruses. CSB appears to disrupt the interaction between viral proteins and cell membranes, both in the fusion step early in the infection cycle and in the development of syncytia in the late stages of virus infection.

AIDS-Antiviral Natural Products Research at The U.S. National Cancer Institute

Abstract: The Laboratory of Drug Discovery Research and Development (LDDRD) is a new intramural NCI laboratory within the Division of Cancer Treatment’s Developmental Therapeutics Program. The primary research focus in LDDRD includes the development and refinement of the NCI anti-HIV and antitumor screening models, the bioassay-guided isolation of new active compounds and the detailed biological and pharmacological characterization of new leads. The NCI is currently testing crude extracts and pure compounds in an in vitro primary antiviral screen which detects the inhibition of HIV-induced cell killing. Extracts are additionally assayed in a disease-oriented, human 60 cell line in vitro antitumor screen representing 7 major categories of human cancer. Selected natural products extracts and pure compounds which demonstrate activity in these primary in vitro screens are subjected to further preclinical investigation within LDDRD. The goal of these efforts is to expeditiously identify and perform preclinical development studies of promising new clinical candidates.