Computer-assisted molecular modeling of tumor promoters: rationale for the activity of phorbol esters, teleocidin B, and aplysiatoxin

Jeffrey, A.M. and Liskamp, R.M. (1986) Computer-assisted molecular modeling of tumor promoters: rationale for the activity of phorbol esters, teleocidin B, and aplysiatoxin. Proceedings of the National Academy of Sciences of the United States of America, 83(2), pp. 241-245.

Full text not currently available from Enlighten.

Publisher's URL: http://www.pnas.org/content/83/2/241

Abstract

In the two-stage model of skin carcinogenesis, it is believed that initiators bind to DNA and that tumor promoters such as phorbol 12-tetradecanoate 13-acetate (TPA) bind noncovalently to membrane-associated high-affinity receptors, probably protein kinase C. Two other types of potent tumor-promoting substances, aplysiatoxin and teleocidin, appear to act also by binding to and activating protein kinase C, even though their chemical structures are quite different. Therefore, we have undertaken computer modeling of the special relationship of various functional groups in these three chemical classes of tumor promoters in an attempt to explain how these diverse structures bind to the same receptor molecule. We propose a stereochemical model in which the oxygens in TPA at C-3, C-4, C-9, and C-20 (O-3, O-4, O-9, and O-20) correspond to the O-11, N-13, N-1, and O-24 positions in teleocidin and the O-27, O-3, O-11, and O-30 oxygens in aplysiatoxin, respectively. In this model all distances with respect to overlap of the corresponding atoms are less than 1 A. In addition, all three types of molecules have their hydrophobic moieties oriented in a similar position. This model is further discussed with respect to other compounds showing various degrees of activity as tumor promoters, including mezerein, ingenol, and 4 alpha-TPA. The model explains how chemically diverse structures can have similar biological activity as tumor promoters and provides a basis for designing both agonists and antagonists of tumor promoters.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Liskamp, Professor Robert
Authors: Jeffrey, A.M., and Liskamp, R.M.
College/School:College of Science and Engineering > School of Chemistry
Journal Name:Proceedings of the National Academy of Sciences of the United States of America
ISSN:0027-8424

University Staff: Request a correction | Enlighten Editors: Update this record