title: Acylurea connected straight chain hydroxamates as novel histone deacetylase inhibitors: Synthesis, SAR, and in vivo antitumor activity.
abstract: 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 pIC(50) (COLO205) correlates with enzymatic potency pIC(50) (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.
authors.affiliation: Department of Chemistry Discovery, S *BIO Pte Ltd, 1 Science Park Road, #05-09 The Capricorn, Singapore Science Park II, Singapore 117528, Singapore. haishan_wang@sbio.com
authors.forename: Haishan
authors.initials: H
authors.lastname: Wang
authors.forename: Ze-Yi
authors.initials: ZY
authors.lastname: Lim
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Melvin
authors.initials: M
authors.lastname: Ng
authors.forename: Ting
authors.initials: T
authors.lastname: Lu
authors.forename: Ken
authors.initials: K
authors.lastname: Lee
authors.forename: Kanda
authors.initials: K
authors.lastname: Sangthongpitag
authors.forename: Kee Chuan
authors.initials: KC
authors.lastname: Goh
authors.forename: Xukun
authors.initials: X
authors.lastname: Wang
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Wu
authors.forename: Hwee Hoon
authors.initials: HH
authors.lastname: Khng
authors.forename: Siok Kun
authors.initials: SK
authors.lastname: Goh
authors.forename: Wai Chung
authors.initials: WC
authors.lastname: Ong
authors.forename: Zahid
authors.initials: Z
authors.lastname: Bonday
authors.forename: Eric T
authors.initials: ET
authors.lastname: Sun
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D014508:Urea / Q000494:pharmacology*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D014508:Urea