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

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.

journal_name

Anticancer Agents Med Chem

journal_title

Anti-cancer agents in medicinal chemistry

authors

Detroja D,Chen TL,Lin YW,Yen TY,Wu MH,Tsai TH,Mehariya K,Kakadiya R,Lee TC,Shah A,Su TL

doi

10.2174/1871520617666170522120200

subject

Has Abstract

pub_date

2017-01-01 00:00:00

pages

1741-1755

issue

eissn

1871-5206

issn

1875-5992

pii

ACAMC-EPUB-83602

journal_volume

pub_type

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