Background: Bendamustine, an N-mustard-benzoimidazole hybrid conjugate, was recently approved
for the treatment of chronic lymphocytic leukemia. However, the short half-life of bendamustine may limit its
Objective: The purpose of this study is to design and synthesize compounds with a more favorable pharmacokinetic
Methods: We synthesized a series of hybrid molecules comprising a phenyl N-mustard moiety and benzothiazole
or benzimidazole scaffold linked via a urea linker and evaluated their antitumor activity and plasma
Results: We revealed that these agents exhibited significant cytotoxicity against a panel of human lymphoblastic
leukemia and human solid tumor cells in culture. Human lymphoblastic leukemia CCRM-CEM cells were the
most sensitive to the tested compounds. In general, the new hybrids were as potent as cisplatin, but significantly
more cytotoxic than bendamustine. Phenyl N-mustard-benzothiazole compound 27d and phenyl N-mustardbenzimidaloe
compound 32b possessed significant cytotoxicity and led to apoptotic death in the treated tumor
cells. These two agents were able to induce DNA interstrand cross-linking and arrested cell cycle progression
at the G2/M phase. Furthermore, we showed that these new hybrids were more chemically stable than bendamustine
in rat plasma.
Conclusion: Our results suggest that conjugation of phenyl N-mustard pharmacophore at C6 of benzimidazole
or at C8 of the benzothiazole ring via a urea linker is likely an approach to increase the chemical stability and
⇒ Series of benzimidazoles and benzothiazoles linked to N-mustard were synthesized.
⇒ The newly synthesized derivatives induced DNA interstrand cross-links.
⇒ These derivatives induced cell cycle arrest in the G2/M phase and triggered apoptosis in H460 cells.
⇒ The new compounds are more cytotoxic than bendamustine.
⇒ The new compounds were chemically more stable than bendamustine in rat plasma.