The principal investigator indicates that the cryptophycins, natural products isolated from blue-green algae, will be studied. She reports that the cryptophycins are currently considered one of the most exciting new leads in cancer chemotherapy and are expected to enter clinical trials in 1996. She also states that they have been identified as extraordinarily potent antitumor agents with demonstrated excellent in vivo activity in subcutaneously transplanted solid tumors of mouse and human origin and that of special importance are the findings that they possess tumor-selective toxicity and greatly reduced susceptibility to P-glycoprotein-mediated multiple drug resistance in comparison to vinblastine, colchicine and taxol. The goals of this study are two-fold. The principal investigator notes that she will conduct studies to identify the pharmacophore of the cryptophycins through structure-activity relationship (SAR) studies and characterize their binding site on tubulin and that these studies are ultimately of utility for the design of clinically effective analogues with improved pharmacological profiles. It is planned to carry out the SAR studies through semisynthesis from cryptophycin 1, which is to be obtained from algal cultures. For the preparation of analogues, which cannot be obtained by semisynthesis, the principal investigator is to develop synthetic methods for their synthesis. The proposed syntheses are to utilize readily available starting materials and convergent strategies for the synthesis of cryptophycin 1 and its analogues. The SAR studies are to include: investigations of stereochemistry, regiochemistry, lipophilicity, electronic and steric effects, bioisosteres, and conformational properties. The novel derivatives are to be investigated in-house in a microtubule assembly assay and in cell cultures of cancer and non-cancer cells. Active analogues are to be sent to NCI for an in-depth study of these analogues in NCI's in vitro disease-oriented primary antitumor screen against a panel of 60 cancer cell lines. The principal investigator notes that since the cryptophycins are antimitotic agents, she plans to determine their binding characteristics and whether cryptophycin shares sites with other antimitotic agents. She also indicates that she plans to use affinity analogues of cryptophycin 1 to locate the tubulin peptide(s) which interact with cryptophycin.
