Deletion of the C26 Methyl Substituent from the Bryostatin Analogue Merle 23 Has Negligible Impact on Its Biological Profile and Potency. (27th April 2018)

• Record Type: Journal Article
• Authors: Zhao, Xiguang; Kedei, Noemi; Michalowski, Alexandra; Lewin, Nancy E.; Keck, Gary E.; Blumberg, Peter M.
• Is Part Of: Chembiochem. Volume 19:Number 10(2018)
• Page Start: 1049
• Page End: 1059
• Publication Date: 2018-04-27
• Subjects: drug design -- natural products -- protein kinase C -- signal transduction -- structure–activity relationships; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201700677
• Languages: English
• ISSNs: 1439-4227

Abstract

Abstract: Important strides are being made in understanding the effects of structural features of bryostatin 1, a candidate therapeutic agent for cancer and dementia, in conferring its potency toward protein kinase C and the unique spectrum of biological responses that it induces. A critical pharmacophoric element in bryostatin 1 is the secondary hydroxy group at the C26 position, with a corresponding primary hydroxy group playing an analogous role in binding of phorbol esters to protein kinase C. Herein, we describe the synthesis of a bryostatin homologue in which the C26 hydroxy group is primary, as it is in the phorbol esters, and show that its biological activity is almost indistinguishable from that of the corresponding compound with a secondary hydroxy group. Abstract : Missing but not missed : Work is underway to understand how bryostatin 1, a potential therapeutic agent for cancer and dementia, confers potency toward protein kinase C and induces unique biological responses. Although the secondary C26 hydroxy group was considered a critical pharmacophoric element, the presence or absence of C26 methyl substitution of bryostatin analogues did not affect their induced biological responses.