PHOTOLABILE DERIVATIVES OF INDOLE ALKALOID TUMOR PROMOTER TELEOCIDINS - SYNTHESIS, BIOLOGICAL-ACTIVITIES AND PHOTOAFFINITY-LABELING STUDIES

New photolabile teleocidin derivatives (Az-A-1, Az-C7 and Az-C2) were synthesized and examined by three in vitro bioassays related to tumor-promoting activity. Az-A-1 (15) and two epimers of Az-C7 (11a, 11b) were approximately 10 to 100-fold more active than (-)-indolactam-V(1), the fundamental structure of teleocidins. Synthesis of the H-3-labeled probes with specific activity of more than 40 Ci/mmol was achieved by use of commercially available H-3-labeled succinimidyl-4-azidobenzoate. Specific binding of [H-3]Az-A-1 and [H-3]Az-C7 to the mouse epidermal particulate fraction, the target tissue of teleocidins, was saturable at approximately 20nM. Photoaffinity labeling on the particulate fraction using [H-3]Az-A-1 supported the recent hypothesis that the alkyl chain at position of teleocidins is involved in the interaction with the phospholipids close to the receptor site. SDS gel electrophoresis of the photolabeled particulate fraction suggested the existence of two proteins (ca.30 and 50kD) specifically photolabeled by [H-3]Az-A-1 and [H-3]Az-C7. However, no specific labeling was detected at the 70 to 80kD region, which corresponded to protein kinase C, a well-characterized receptor for tumor promoters.