SYNTHESIS OF ANTI-HIV MICHELLAMINES A AND B ANALOGS

Two structurally unprecedented Ancistrocladus alkaloids, michellamine A and michellamine B, were recently described (J. Med. Chem. December, 1991).[1] These compounds have attracted considerable interest at the National Cancer Institute because they demonstrate important anti-HIV properties. Michellamines A and B completely inhibit the cytopathic effects of HIV-1 in CEM-SS cells with an EC50 approximately 20 micromoles; they are cytotoxic to uninfected cells (IC50 approximately 200 micromoles). Michellamine B is particularly tantalizing because it shows the same level of antiviral potency against both HIV- 1 and HIV-2, thus raising the possibility that it is operating by a heretofore unrecognized mechanism. Although the in vitro therapeutic index is narrow, encouraging initial in vivo data have now shown no significant toxicity in mice or a dog at blood levels near the EC50 concentrations. Particularly exciting is the fact that michellamine B is cytoprotective against the AZT-resistant variant and toward the pyridinone-resistant (L-697639) Al7 strain of HIV-1. Michellamine B is the lead preclinical anti-HIV candidate at the NCI. It was elevated to DN Stage IIA and then to IIB following meetings of the NCI Decision Network Committee in January and June of this year, respectively. The michellamines vary from the structures of previously known naphthylisoquinoline natural products in three important ways: 1) they have a unique linkage site joining the naphthalene to the isoquinoline ring; 2) they are the only members to be found as oxidatively coupled dimers; 3) they contain the highest degree of non-methylated free phenolic oxygens of any of this family of alkaloids. Procurement issues are of concern. It has recently been determined that the natural source is a previously unrecognized variant, tentatively named Ancistocladus sp. novum. This liana vine grows in the canopy of a very limited range of rain forest of Cameroon, wherein political instability issues exist as well. As of the beginning of this year, in fact, only a single plant had given rise to the michellamines. The major aims of the proposed research are a) to definitively prove the absolute stereochemistry of the natural products, b) to prepare the michellamines by total synthesis, and c) to prepare numerous structural analogs of the michellamines for biological evaluation. Efficiency, opportunity for structural variation, and convergency are principles which have and will guide our planning and implementation of the synthetic design. We will borrow heavily from previous synthetic work to prepare a pool of precursor monomer units which will then be covalently coupled by various strategies. Thus, it will be possible to produce in parallel both the michellamines A and B themselves as well as an additional diverse array of structural analogs for biological evaluation. The last aim is of highest priority. An increase in anti-HIV potency by even one order of magnitude would greatly enhance prospects for both preclinical and clinical development of this unique new structural class of very promising agents.