2. Academic Validation
  3. Design and synthesis of potent antitumor water-soluble phenyl N-mustard-benzenealkylamide conjugates via a bioisostere approach

Design and synthesis of potent antitumor water-soluble phenyl N-mustard-benzenealkylamide conjugates via a bioisostere approach

  • Eur J Med Chem. 2014 Apr 9:76:155-69. doi: 10.1016/j.ejmech.2014.02.018.
Satishkumar D Tala 1,  Tai-Hsin Ou 2,  Yi-Wen Lin 1,  Kiranben S Tala 1,  Shu-Hsin Chao 1,  Ming-Hsi Wu 1,  Tung-Hu Tsai 3,  Rajesh Kakadiya 1,  Sharda Suman 1,  Ching-Huang Chen 1,  Te-Chang Lee 4,  Tsann-Long Su 5
Affiliations

Affiliations

  • 1 Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
  • 2 Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan; Institute of Pharmacology, National Yang-Ming University, Taipei 11221, Taiwan.
  • 3 Institute of Traditional Medicine, National Yang-Ming University, Taipei 11221, Taiwan.
  • 4 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.
  • 5 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.
PMID: 24583355 DOI: 10.1016/j.ejmech.2014.02.018
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.

Keywords

Apoptosis; Cell cycle; Combination therapy; Cytotoxicity; DNA cross-linking; Water-soluble antitumor agents.

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