The synthesis and biological evaluation of new DNA-directed alkylating agents, phenyl N-mustard-4-anilinoquinoline conjugates containing a urea linker

• A series of phenyl N-mustard-4-anilinoquinoline conjugates have been synthesized.
• The SARs showed that the C2-Me derivatives (18a–o) were more potent than the C2-Ph compounds (23a–d).
• Newly synthesized derivatives were able to induce DNA cross-linking.
• The newly synthesized compounds induced cell cycle arrest at the G2/M phase.

We synthesized a series of phenyl N-mustard-4-anilinoquinoline conjugates to study their antitumorigenic effects. These agents were prepared by the condensation of 4-[N,N-bis(2-chloroethyl)amino]phenyl isocyanate with 6-amino-4-methylamino or 4-anilinoquinolines. The structure–activity relationship (SAR) studies revealed that the C2-methylquinoline derivatives (18a–o) were generally more cytotoxic than the C2-phenylquinoline conjugates (23a–d) in inhibiting the cell growth of various human tumor cell lines in vitro. However, the methylamino or aniline substituents at C4 of quinoline did not influence the cytotoxic effects. The title conjugates were capable of inducing DNA cross-linking and promoting cell-cycle arrest at the G2/M phase. This study demonstrates that phenyl N-mustard-4-anilinoquinoline conjugates are generally more potent than phenyl N-mustard-4-anilinoquinazoline conjugates against the cell growth of various tumor cell-lines.

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