Michael R. Boyd

Pellynol I, A New Cytotoxic Polyacetylene from the Sponge Pellina sp

Abstract Bioassay-guidied fractionation of an organic extract of a South African collection of the sponge Pellina sp. afforded six polyacetylenic metabolites. These were identified as pellynols A-D, pellynol F, and a new compound, pellynol I (1). The structure of 1 was elucidated by NMR and MS analyses and by comparison of its spectral data with related compounds. The six pellynols all exhibited cytotoxic activity against human tumor cell lines.

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

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.

High throughput screening for cyanovirin-N mimetics binding to HIV-1 gp41.

The human immunodeficiency virus type-1 (HIV-1) envelope glycoprotein gp4l is an important mediator of viral entry into host cells. Previous studies showed that the virucidal protein cyanovirin-N (CV-N) bound to both gpl20 and gp4l, and that this binding was associated with its antiviral activity. We constructed an HTS assay based on the interaction of europium-labeled CV-N with recombinant glycosylated gp4l ectodomain to support identification of small-molecule mimetics of CV-N that might be developed as antiviral drug leads. Primary screening of over 107,000 natural product extracts in the assay yielded 347 confirmed hits. Secondary assays eliminated extracts that bound directly to labeled CV-N or for which the simple sugars mannose and N-acetylglucosamine blocked the interaction with gp4l (lectin activity). Extracts were further prioritized based on anti-HIV activity and other biological, biochemical, and chemical criteria. The distribution of source organism taxonomy of active extracts was analyzed, as was the cross-correlation of activity between the CV-N-gp4l binding competition assay and the previously reported CV-N-gpl20 binding competition assay. A limited set of extracts was selected for bioassay-guided fractionation.

Antiviral and Antitumor Plant Metabolites

The U.S. National Cancer Institute (NCI) currently has in place a large screening program which supports researchers worldwide in the search for new effective drugs for cancer and AIDS.1–3 While a majority of screening in this program is focused upon pure compounds submitted by non-NCI investigators for NCI testing, a portion of the screening capacity is allocated to the initial testing of natural product extracts from the NCI repository.