Synthesis & Mechanism of Cephalostatin Anticancer Drugs

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DESCRIPTION (provided by applicant): A collaboration has been established between the synthesis group of Philip. L. Fuchs (Purdue) and three biological/biochemical groups including Philip. A. Low (Purdue); Peng Huang (M. D. Anderson Cancer Center); and John Beutler (NIH-Bethesda). The goals involve synthesis and testing of about four new mechanism and calculation based analogs of the hyper-potent cephalostatin-1; and to define, compare, and contrast the mechanism of action with structurally and biologically similar compounds: the steroidal glycosides OSW-1 and Solamargene. While new agents are being prepared and evaluated, the collaborators will continue testing the now available, synthetic analog, 23'deoxy-cephalostatin 1 (23'DCST-1). Proposed testing will involve preparing folate-linked dipeptide esters of 23'DCST-1, evaluating a proposed self-immolative cleavage to the free cephalostatin drug after receptor-mediated endocytosis, and characterizing the folate-cephalostatin drugs in vitro and in vivo. A second front will feature mechanistic studies to determine the anticancer activity and selectivity of 23'DCST-1 and other cephalostatin analogs in vitro, elaborating the newly-determined mitochondrial-based mechanism of action using TEM to probe the mitochondria ultrastructure, probing the mitochondria function with respect to the apoptotic end point, and testing cephalostatin analogs as potential inhibitors of the mitochondria! respiration chain. Therapeutic activity of lead compounds will then be compared in animal models. Continued testing of all new analogs using the NCI 60 cell panel will be combined with using new affinity probes including 23'DCST-1-glycine-biotin to determine which proteins, if any, undergo formation of covalent bonds to this class of drugs. The PI's group will prepare and maintain a web-based information site on the chemistry/biology/pharmacology/ medicine of the cephalostatin analogs, actively recruit new collaborators, and supply interested scientists with synthetic material for testing. The overall goal of this program is to ultimately provide one or more collaborators with multi-gram quantities of the best agent(s) in order to proceed to Phase I human trials.