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Acylurea connected straight chain hydroxamates as novel histone deacetylase inhibitors: Synthesis, SAR, and in vivo antitumor activity

2010; Elsevier BV; Volume: 20; Issue: 11 Linguagem: Inglês

10.1016/j.bmcl.2010.04.041

1464-3405

Haishan Wang, Ze-Yi Lim, Yan Zhou, Melvin Ng, Ting Lu, Ken Lee, Kanda Sangthongpitag, Kee Chuan Goh, Xukun Wang, Xiaofeng Wu, Hwee Hoon Khng, Siok Kun Goh, Wai Chung Ong, Zahid Bonday, Eric T. Sun,

Synthetic Organic Chemistry Methods

Thirty-six novel acylurea connected straight chain hydroxamates were designed and synthesized. Structure–activity relationships (SAR) were established for the length of linear chain linker and substitutions on the benzoylurea group. Compounds 5g, 5i, 5n, and 19 showed 10–20-fold enhanced HDAC1 potency compared to SAHA. In general, the cellular potency pIC50 (COLO205) correlates with enzymatic potency pIC50 (HDAC1). Compound 5b (SB207), a structurally simple and close analogue to SAHA, is more potent against HDAC1 and HDAC6 compared to the latter. As a representative example of this series, good in vitro enzymatic and cellular potency plus an excellent pharmacokinetic profile has translated into better efficacy than SAHA in both prostate cancer (PC3) and colon cancer (HCT116) xenograft models.