Synthesis and biological evaluation of santacruzamate A analogues for anti-proliferative and immunomodulatory activity

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• 作者：Samantha M. Gromek^a ; James A. deMayo^a ; Andrew T. Maxwell^a ; Ashley M. West^a ; Christopher M. Pavlik^a ; Ziyan Zhao^b ; Jin Li^a ; Andrew J. Wiemer^a ; Adam Zweifach^b ; Marcy J. Balunas^a ; ^{marcy.balunas@uconn.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Santacruzamate A ; Natural product analogues ; Enzyme assays ; Anti-proliferative activity ; Immune modulation
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：1 November 2016
• 年：2016
• 卷：24
• 期：21
• 页码：5183-5196
• 全文大小：1261 K

文摘

Santacruzamate A (SCA) is a natural product isolated from a Panamanian marine cyanobacterium, previously reported to have potent and selective histone deacetylase (HDAC) activity. To optimize the enzymatic and cellular activity, 40 SCA analogues were synthesized in a systematic exploration of the zinc-binding group (ZBG), cap terminus, and linker region. Two cap group analogues inhibited proliferation of MCF-7 breast cancer cells, with analogous increased degranulation of cytotoxic T cells (CTLs), while one cap group analogue reduced CTL degranulation, indicative of suppression of the immune response. Additional testing of these analogues resulted in reevaluation of the previously reported SCA mechanism of action. These analogues and the resulting structure–activity relationships will be of interest for future studies on cell proliferation and immune modulation.