Quantitative structure-activity studies on indole alkaloid tumor promoter indolactam congeners.
Nine indolactam congeners with L-Abu, gamma,delta-delta-Nva, Nva, Phg, tert-Leu, Leu, Ile, allo-Ile, Nle, instead of L-Val in (--)-indolactam-Val, were synthesized by microbial conversion and examined using two biological tests related to tumor promotion. The tests were inhibition of the specific binding of [3H]12-O-tetradecanoylphorbol-13-acetate (TPA) to the mouse epidermal particulate fraction, and stimulation of radioactive inorganic phosphate incorporation into phospholipids of HeLa cells. These two biological activities correlated well for each derivative. (--)-Indolactam-Ile with L-Ile in place of L-Val in (--)-indolactam-Val, which we have recently confirmed to occur naturally, was the most active of the ten indolactam congeners tested, suggesting that (--)-indolactam-Ile is a more potent tumor promoter than (--)-indolactam-Val in vivo. The effects of the substituents at position 12 on the TPA receptor binding were analyzed quantitatively using physicochemical substituent parameters and regression analysis. The results indicated that both hydrophobicity and bulkiness of the substituents at position 12 increased the binding ability to the TPA receptor, supporting the recent hypothesis that the isopropyl group at position 12 of (--)-indolactam-Val is involved in the hydrophobic interaction on the receptor site.
Irie
K
K
Department of Food Science and Technology, Faculty of Agriculture, Kyoto University, Japan.
Okuno
S
S
Kajiyama
S
S
Koshimizu
K
K
Nishino
H
H
Iwashima
A
A
D000470:Alkaloids / Q000009:adverse effects / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D029742:Caenorhabditis elegans Proteins; D002273:Carcinogens / Q000494:pharmacology*; D002352:Carrier Proteins; D006367:HeLa Cells / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000378:metabolism* / Q000494:pharmacology; D007769:Lactams / Q000494:pharmacology*; D051379:Mice; D009374:Neoplasms, Experimental / Q000139:chemically induced; D010710:Phosphates / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D011493:Protein Kinase C; D011955:Receptors, Drug / Q000378:metabolism; D013268:Stimulation, Chemical; D013329:Structure-Activity Relationship
D000470:Alkaloids; D029742:Caenorhabditis elegans Proteins; D002273:Carcinogens; D002352:Carrier Proteins; D007211:Indoles; D007769:Lactams; D010710:Phosphates; D010743:Phospholipids; D011955:Receptors, Drug; C083141:phorbol ester binding protein; C027776:phorbol ester receptor; D011493:Protein Kinase C