Design, synthesis, and biological evaluation of novel deguelin-based heat shock protein 90 (HSP90) inhibitors targeting proliferation and angiogenesis

J Med Chem. 2012 Dec 27;55(24):10863-84. doi: 10.1021/jm301488q.

Dong-Jo Chang ¹, Hongchan An, Kyoung-suk Kim, Hyun Ho Kim, Jinkyung Jung, Jung Min Lee, Nam-Jung Kim, Young Taek Han, Hwayoung Yun, Sujin Lee, Geumwoo Lee, Seungbeom Lee, Ju Sung Lee, Jong-Ho Cha, Ji-Hyeon Park, Ji Won Park, Su-Chan Lee, Sang Geon Kim, Jeong Hun Kim, Ho-Young Lee, Kyu-Won Kim, Young-Ger Suh

Affiliations

Affiliation

1 College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Korea.

PMID: 23186287 DOI: 10.1021/jm301488q

Abstract

Deguelin exhibits potent apoptotic and antiangiogenic activities in a variety of transformed cells and Cancer cells. Deguelin also exhibits potent tumor suppressive effects in xenograft tumor models for many human cancers. Our initial studies confirmed that deguelin disrupts ATP binding to HSP90 and consequently induces destabilization of its client proteins such as HIF-1α. Interestingly, a fluorescence probe assay revealed that deguelin and its analogues do not compete with ATP binding to the N-terminus of HSP90, unlike most HSP90 inhibitors. To determine the key parts of deguelin that contribute to its potent HSP90 inhibition, as well as its antiproliferative and antiangiogenic activities, we have established a structure-activity relationship (SAR) of deguelin. In the course of these studies, we identified a series of novel and potent HSP90 inhibitors. In particular, analogues 54 and 69, the B- and C-ring-truncated compounds, exhibited excellent antiproliferative activities with IC(50) of 140 and 490 nM in the H1299 cell line, respectively, and antiangiogenic activities in zebrafish embryos in a dose dependent manner (0.25-1.25 μM).

Name
Email *

	Sorry, but the email address you supplied was invalid.