Structure-activity studies of aplysiatoxin-type tumor promoters.
The cellular activities and responses of aplysiatoxin in vitro and in vivo are very similar to those of the diterpene 12-O-tetradecanoylphorbol-13-acetate (TPA) and the indole aklaloids teleocidin B and lyngbyatoxin A. Even though aplysiatoxin, TPA, and teleocidin B are chemically and structurally quite distinct from one another, all three compounds produce essentially the same plethora of biological effects by apparently binding to the same receptor on the cell membrane, the so-called phorboid receptor. Several aplysiatoxin-type compounds have been studied in three test systems for evaluating potential tumor-promoting activity, viz. mouse ear skin for irritation, murine dorsal skin for the induction of ornithine decarboxylase (ODC) activity, and an epidermal particulate fraction of dorsal mouse skin for the inhibition of specific binding of [3H]-TPA. Some of the compounds were tested in a 30-week two-step carcinogenesis experiment in mice. In most cases the results of the 30-week test correlated with the activities of the three preliminary tests. The overall study indicated that the hydroxyl groups on C-3, C-20, and C-30 are essential for maximum activity. Inspection of Dreiding models showed that the oxygens on C-27, C-3, and C-30 of aplysiatoxin are aligned with the oxygens on C-3, C-4, and C-20 of TPA, respectively. The latter oxygens are in functional groups that are known to be necessary for the high activity of TPA.
D000818:Animals; D029742:Caenorhabditis elegans Proteins; D002273:Carcinogens; D002352:Carrier Proteins; D006801:Humans; D008235:Lyngbya Toxins / Q000378:metabolism / Q000633:toxicity*; D008968:Molecular Conformation; D011493:Protein Kinase C; D011955:Receptors, Drug; D011971:Receptors, Immunologic / Q000378:metabolism; D013329:Structure-Activity Relationship
D029742:Caenorhabditis elegans Proteins; D002273:Carcinogens; D002352:Carrier Proteins; D008235:Lyngbya Toxins; D011955:Receptors, Drug; D011971:Receptors, Immunologic; C083141:phorbol ester binding protein; C027776:phorbol ester receptor; C017179:debromoaplysiatoxin; C006610:aplysiatoxin; D011493:Protein Kinase C