DESCRIPTION: Phorboxazoles A and B are natural products isolated recently from the marine sponge Phorbas sp. The isolation, partial structure determination, and cytostatic activity towards the US National Cancer Institute's panel of 60 human cancer lines (mean GI50 values of less than 7.9 x 10 to the -10 power M; most cell lines were 100 percent inhibited) were reported in August, 1995. The phorboxazoles represent an entirely new class of cytostatic agents, and have been characterized as being "among the most potent cytostatic agents yet discovered." The phorboxazoles' likely mechanism of action has not been reported. Structurally, the phorboxazoles contain a macrolide; 6 additional rings, including 4 substituted pyrans and 2 oxazoles; and 15 stereogenic carbons. The relative configurations of two stereogenic carbons (C38 and C43), as well as the relative stereochemistry between the macrolide (C1-C26) and a distal side chain oxane ring (C33-C37) are unknown. Coupled with the structural ambiguity and unidentified mode of action, is the scarcity of these marine sponge isolates. The overall goal of this proposal is to aid the development of these promising new lead compounds by fully determining their structures and identifying the essential structural features required for their cytostatic activity. The complete stereochemistry of the phorboxazoles will be determined via the synthesis and spectral comparison with the natural product's data of 5-10 different enantiomerically pure intermediates of increasing complexity, culminating in the synthesis of phorboxazole A. The relative cytostatic activity of the diastereomeric synthetic products will be used to guide a systematic mapping of the natural product's essential pharmacophore through analog synthesis and biological testing. Clonogenic assays will be performed using 10 different human cancer cell lines, including brain, neoroblastoma, breast, osteosarcoma, lymphoma, and lymphoblastic and myeloid leukemia. This successful outcome of this project will provide an alternative source of the phorboxazole natural products and analogs unavailable by other means, identify the minimal set of structural features required for the phorboxazoles' exceptional level of cytostatic activity, as well as new cytostatic compounds, and develop new and generally applicable methods for complex molecule synthesis.
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NIH ExPorter