title: Design and synthesis of potent antitumor water-soluble phenyl N-mustard-benzenealkylamide conjugates via a bioisostere approach.
abstract: A series of new, water-soluble phenyl N-mustard-benzenealkylamide conjugates containing hydrophilic ω-dialkylaminoalkylamide or ω-cyclic aminoalkylamide moieties were synthesized via a bioisostere approach. These compounds have a broad spectrum of antitumor activity against a panel of human tumor cell lines. Of these derivatives, compound 18b effectively suppressed the growth of colon cancer (HCT-116), prostate cancer (PC3), and lung cancer (H460) xenografts. The growth of HCT-116 xenografts was almost completely suppressed when co-treated with compound 18b and 5-fluorouracil. Furthermore, compound 18b can induce DNA cross-linking and cell-cycle arrest at the G2/M phase. Early preclinical studies, including pharmacokinetics in rats, inhibition of the hERG, and 14 days of acute intravenous injection toxicity, suggest that compound 18b is a promising candidate for further preclinical studies.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Satishkumar D
authors.initials: SD
authors.lastname: Tala
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan; Institute of Pharmacology, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Tai-Hsin
authors.initials: TH
authors.lastname: Ou
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Lin
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Kiranben S
authors.initials: KS
authors.lastname: Tala
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Shu-Hsin
authors.initials: SH
authors.lastname: Chao
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Ming-Hsi
authors.initials: MH
authors.lastname: Wu
authors.affiliation: Institute of Traditional Medicine, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Tung-Hu
authors.initials: TH
authors.lastname: Tsai
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Kakadiya
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Sharda
authors.initials: S
authors.lastname: Suman
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Ching-Huang
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan; Institute of Pharmacology, National Yang-Ming University, Taipei 11221, Taiwan. Electronic address: bmtcl@ibms.sinica.edu.tw.
authors.forename: Te-Chang
authors.initials: TC
authors.lastname: Lee
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan; Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung 40402, Taiwan. Electronic address: tlsu@ibms.sinica.edu.tw.
authors.forename: Tsann-Long
authors.initials: TL
authors.lastname: Su
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020287:In Situ Nick-End Labeling; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009150:Mustard Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000970:Antineoplastic Agents; D009150:Mustard Compounds
keywords: Apoptosis; Cell cycle; Combination therapy; Cytotoxicity; DNA cross-linking; Water-soluble antitumor agents