title: Hybrids from Farnesylthiosalicylic Acid and Hydroxamic Acid as Dual Ras-Related Signaling and Histone Deacetylase (HDAC) Inhibitors: Design, Synthesis and Biological Evaluation.
abstract: A novel series of hybrids was designed and synthesized by combining key elements from farnesylthiosalicylic acid (FTS) and hydroxamic acid. Several 3,7,11-trimethyldodeca-2,6,10-trien-1-yl) thio)benzamide derivatives, particularly those with branched and linear aliphatic linkers between the hydroxamic zinc binding group (ZBG) and the benzamide core, not only displayed significant antitumor activities against six human cancer cells but also exhibited histone deacetylase (HDAC) inhibitory effects in vitro. Among them, N-(4-(hydroxyamino)-4-oxobutyl)-2-(((2E,6E)-3,7,11-trimethyldodeca-2,6, 10-trien-1-yl)thio)benzamide (8 d) was the most potent, with IC50 values of 4.9-7.6 μM; these activities are eight- to sixteen-fold more potent than FTS and comparable to that of suberoylanilide hydroxamic acid (SAHA). Derivative 8 d induced cell cycle arrest in the G0/G1 phase, inhibited the acetylation of histone H3 and α-tubulin, and blocked Ras-related signaling pathways in a dose-dependent manner. The improved tumor growth inhibition and cell-cycle arrest in vitro might result from the dual inhibition. These findings suggest dual inhibitors of Ras-related signaling pathway and HDAC hold promise as therapeutic agents for the treatment of cancer.
authors.affiliation: School of Pharmacy, Nantong University, Nantong 226001 (P. R. China). Lyyy111@sina.com.|State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009 (P. R. China). Lyyy111@sina.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ling
authors.affiliation: School of Pharmacy, Nantong University, Nantong 226001 (P. R. China).
authors.forename: Xuemin
authors.initials: X
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Nantong University, Nantong 226001 (P. R. China).
authors.forename: Chenniu
authors.initials: C
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Nantong University, Nantong 226001 (P. R. China).
authors.forename: Chenjun
authors.initials: C
authors.lastname: Xu
authors.affiliation: School of Pharmacy, Nantong University, Nantong 226001 (P. R. China).
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Nantong University, Nantong 226001 (P. R. China).|State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009 (P. R. China).
authors.forename: Yihua
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Nantong University, Nantong 226001 (P. R. China). zhangyanan@gmail.com.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D002460:Cell Line; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005204:Farnesol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology*; D012459:Salicylates / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012459:Salicylates; C093323:farnesylthiosalicylic acid; D005204:Farnesol
keywords: antitumor agents; farnesylthiosalicylic acids; histone deacetylases; hydroxamic acids; ras-related signaling pathways