Novel N-mustard-benzimidazoles/benzothiazoles Hybrids, Synthesis and Anticancer Evaluation
| Autor: | Yi-Wen Lin, Tsai-Yi Yen, Tung Hu Tsai, Tsann-Long Su, Anamik Shah, Rajesh Kakadiya, Tai-Lin Chen, Krunal Maheriya, Ming-Hsi Wu, Dilip P Detroja, Te-Chang Lee |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Bendamustine Cancer Research Benzimidazole Stereochemistry Chronic lymphocytic leukemia Antineoplastic Agents Apoptosis 01 natural sciences 03 medical and health sciences chemistry.chemical_compound Drug Stability Cell Line Tumor medicine Animals Humans Benzothiazoles 0101 mathematics Cytotoxicity Pharmacology medicine.disease Combinatorial chemistry Rats 010101 applied mathematics 030104 developmental biology chemistry Benzothiazole Molecular Medicine Benzimidazoles Pharmacophore Drug Screening Assays Antitumor Linker Conjugate medicine.drug |
| Zdroj: | Anti-cancer agents in medicinal chemistry. 17(13) |
| ISSN: | 1875-5992 |
| Popis: | 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.The purpose of this study is to design and synthesize compounds with a more favorable pharmacokinetic profile.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.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.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. |
| Databáze: | OpenAIRE |
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