Novel N-mustard-benzimidazoles/benzothiazoles Hybrids, Synthesis and Anticancer Evaluation

Title:Novel N-mustard-benzimidazoles/benzothiazoles Hybrids, Synthesis and Anticancer Evaluation

Volume: 17 Issue: 13

Author(s): Dilip Detroja, Tai-Lin Chen, Yi-wen Lin, Tsai-Yi Yen, Ming-Hsi Wu, Tung-Hu Tsai, Krunal Mehariya, Rajesh Kakadiya, Te-Chang Lee*, Anamik Shah and Tsann-long Su*

Affiliation:

• Institute of Biomedical Sciences, Academia Sinica, Taipei 115,Taiwan

• Institute of Biomedical Sciences, Academia Sinica, Taipei 115,Taiwan

Keywords: Bendamustine, nitrogen mustards, DNA interstrand crosslinking, cell cycle, antitumor agent, hybrid.

Abstract: 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 clinical applications.

Objective: The purpose of this study is to design and synthesize compounds with a more favorable pharmacokinetic profile.

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 stability.

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 bioavailability.

Highlights

⇒ 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.

Cite this article as:

Detroja Dilip , Chen Tai-Lin , Lin Yi-wen, Yen Tsai-Yi , Wu Ming-Hsi , Tsai Tung-Hu , Mehariya Krunal , Kakadiya Rajesh , Lee Te-Chang *, Shah Anamik and Su Tsann-long *, Novel N-mustard-benzimidazoles/benzothiazoles Hybrids, Synthesis and Anticancer Evaluation, Anti-Cancer Agents in Medicinal Chemistry 2017; 17 (13) . https://dx.doi.org/10.2174/1871520617666170522120200