Structure-activity studies of the indole alkaloid tumor promoter teleocidins.
New teleocidin derivatives with various substituents at positions 2, 5 and 7 of the indole ring were prepared from (-)-indolactam V, which is the fundamental structure of teleocidins and has a tumor-promoting activity, to examine the contribution of the alkyl substituents of teleocidins to the activity. Their possible tumor-promoting activities in vivo were evaluated by Epstein-Barr virus early antigen-inducing activity and inhibition of specific binding of [3H]TPA to a mouse epidermal particulate fraction. These two biological activities correlated well for each derivative. Large substituents at positions 2 and 5 remarkably lowered the activities, indicating that the structural requirements for the activities of these domains are especially strict. To investigate in detail the contribution of position 2 of (-)-indolactam V to the activities, new microbial metabolites, (-)-2-oxy-indolactam V, and blastmycetin B and C, were also tested. These compounds proved to be inactive, suggesting that the double bond at position 2 plays an important role for the activities. Substituents at position 7 generally enhanced the activities and even blastmycetin A, which is a dimer of (-)-indolactam V, showed high activities. The effects of the substituents on binding ability to the 12-O-tetradecanoylphorbol-13-acetate receptor were analyzed quantitatively using physicochemical substituent parameters and regression analysis. The results exhibited the fact that hydrophobicity of the substituents plays a critical role for receptor binding, and supported the hypothesis that the monoterpenoid moiety of teleocidins is involved in the non-specific hydrophobic interaction with phospholipids in cell membrane.
D000818:Animals; D000956:Antigens, Viral / Q000096:biosynthesis; D029742:Caenorhabditis elegans Proteins; D002273:Carcinogens; D002352:Carrier Proteins; D008235:Lyngbya Toxins / Q000633:toxicity*; D051379:Mice; D011493:Protein Kinase C; D011955:Receptors, Drug; D011971:Receptors, Immunologic / Q000378:metabolism; D012044:Regression Analysis; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism
D000956:Antigens, Viral; D029742:Caenorhabditis elegans Proteins; D002273:Carcinogens; D002352:Carrier Proteins; C033305:Epstein-Barr virus early antigen; D008235:Lyngbya Toxins; D011955:Receptors, Drug; D011971:Receptors, Immunologic; C083141:phorbol ester binding protein; C027776:phorbol ester receptor; C022176:teleocidins; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate