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.
- 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: [email protected].
- 5. Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan; Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung 40402, Taiwan. Electronic address: [email protected].
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.