Synthesis and Evaluation of Simplified Cruentaren A Analogues

Xiaozheng Dou, Bhargav A. Patel, Terin D'Amico, Chitra Subramanian, Eric Cousineau, Yi Yi, Mark Cohen, Brian S.J. Blagg

Research output: Contribution to journalArticlepeer-review


The 90 kDa heat shock protein (Hsp90) belongs to a group of molecular chaperones that regulate homeostasis via the folding of nascent polypeptides into their biologically active proteins, many of which are involved in cancer development and progression. As a result, inhibition of Hsp90 is an exciting area of research for the treatment of cancer. However, most of the 18 Hsp90 N-terminal inhibitors evaluated in clinical trials exhibited deleterious side effects and toxicities. Cruentaren A is a natural product that manifests potent anticancer activity against various human cancer cell lines via disruption of interactions between Hsp90α and F1FOATP synthase, which does not induce the pro-survival, heat shock response, a major limitation associated with current Hsp90 inhibitors. However, the development of cruentaren A as a new anticancer agent has been hindered by its complex structure. Herein, we systematically removed the functionalities present in fragment 2 of cruentaren A and incorporated some key structural modifications from previous work, which produced 12 simplified analogues. Our studies determined that all functional groups present in fragment 2 are essential for cruentaren A's anticancer activity.

Original languageEnglish (US)
Pages (from-to)9940-9956
Number of pages17
JournalJournal of Organic Chemistry
Issue number15
StatePublished - Aug 5 2022
Externally publishedYes

ASJC Scopus subject areas

  • Organic Chemistry


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