The spongipyrans, a new family of sponge metabolites available only in minute quantities, appear to be the most potent inhibitors of cancer cell growth discovered to date. Pettit, et al., described the first examples, spongistatins, in 1993 (Pettit, et al., J. Org. Chem. 1993, 58, 1302) and subsequently isolated congeners thereof (Pettit, Pure & Appl. Chem. 1994, 66, 2271). Spongistatin 1 (1, FIG. 1), the most abundant compound, proved to be active against several chemoresistant tumor types, including human melanoma and lung, colon, and brain cancers, with GI.sub.50 's of 2.5-3.5.times.10.sup.-11 M (see, e.g., Bai, et al., Biochemistry 1995, 34, 9714). Further investigators revealed that 1 inhibits mitosis by binding to tubulin and blocking microtubule assembly. Other sponges produce cinachyrolide A and the altohyrtins A-C, isolated by the Fusetani (see, Fusetani, et al., J. Am. Chem. Soc. 1993, 115, 3977), and Kitagawa groups (see, Kobayashi, et al., Tetrahedron Lett. 1993, 34, 2795; Kobayshi, et al., Tetrahedron Lett. 1994, 35, 1243; Kobayashi, et al., Chem. Pharm. Bull. 1996, 44, 2142). These substances likewise display cytotoxicity against cancer cell lines but, likewise, are difficult to obtain from natural sources yet are structurally complex and, thus, difficult to synthesize.
There is, therefore, a need for improved synthetic methods and/or less complex compounds having similar levels of cytotoxicity.
USPTO Backgrounds
USPTO Backgrounds