Conformationally constrained biologically active peptides: tentative identification of the antimitogenic bioactive confomer of the naturally occurring cyclic tetrapeptides
✍ Scribed by Richard E. Shute; Megumi Kawai; Daniel H. Rich
- Book ID
- 104203720
- Publisher
- Elsevier Science
- Year
- 1988
- Tongue
- French
- Weight
- 943 KB
- Volume
- 44
- Category
- Article
- ISSN
- 0040-4020
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✦ Synopsis
In the quest for a greater understandlng of the relationship between "drug" structure and biologlcal actlvlty the study of conformationally constrained peptldes has received considerable attention. 1 Ma~~llan hornOn systems 'have been a particularly fruitful field for investigation of the effects of such modlflcatlons;2 synthetic analogs of the enkephallns.3 a-melanotropin4 and. preeminently, somatostatln5 have all provided valuable exesples of how flexible, blologlcally active compounds may be constrained by the incorporation of cyclic structures to increase their activity and receptor specificity, and often to prolong their biological response. Less frequently studied have been naturally occurring examples of cyclically constrained peptldes with potent antibiotic or antltumr activlty.6*7 This is not surprising when the size and complexity of the majority of these natural products Is considered. There are, however, a few cyclic peptide natural products that are of a sufficiently small size. and with sufficiently interesting biological properties, to have warranted detailed investigation into the structural and conformational requlrewnts needed for their activity, the m)st noteworthy examples being the is-lactam antlblotlcs* and, more recently, the cyclosporlnes.' We describe herein the structure-activity and confomational aspects of another class of cyclic peptlde natural products that possess potent biological activity, namely, the fungally derived cyclic tetrapeptldes. This family of compounds (Table l), whose members, including HC-toxin." chlamydocin." YF 316112 and Cyl-2,13 all possess a peptidyl 12-metiered cyclic ring system, demonstrates significant bioactlvity both as plant toxlns14 and. in vitro, as cytostatic and antimltogenlc agents with IC6O values In the nanomolar range against P-815 mastocytoma cells and arrine lymphocytes.15 Such potency 1s usually indicative of interaction with a very specific receptor or enzyR which is present only at very low concentrations in the particular testing system. Unfortunately, although highly active tn vitro, chlamydocln (and presumably the others) Is rapidly inactivated In viva. l5 which prevented development of these compounds as chemotherapeutic, antitumor agents. However. the convenlence with which these cyclic peptldes can be tested coupled with their extraordinary potency and the comparative rigidity of their medium-sized cyclic ring system makes the cyclic tetrapeptide natural products particularly attractive for structure-activity and conformational study. In this paper, we report some of Qur previously unpubllshed results in this area, collate all the structure-activity data that has to date been published, and attempt to identify the structural and the conformational requlrenents for bioactlvlty In these canpounds. The conformational conclusions will be supported by data fran force field calculations. Table 1: The Cyclic Tetrapeptlde Family of Natural Products. COWWND (No.) HC-Toxin (1) Cyl-1 (2) Cyl-2 (3) Chlamydocln (1) WF 3161 (5) ]Gly14 HC-Toxin (4) SEQUENCE cycle]-L-Aoe'-D-Pro2-L-Ala3-0-Ala4-] cyclo]-L-Aoe1-O-Tyr(One)2-L-Ile3-L-Pro4-] cyclo]-L-Aoe1-O-Tyr