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

• A series of water-soluble phenyl N-mustard-benzenealkylamides were synthesized.
• These compounds shows broad spectrum activity against a panel of tumor cell lines.
• Compound 18b was found to have potent therapeutic efficacy in xenograft models.
• The combination of 18b and 5-FU almost completely suppressed HCT-116 xenografts.
• Current studies, suggest that 18b is a promising candidate for preclinical studies.

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.

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