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, Su Tsann-Long
Institute of Biomedical Sciences, Academia Sinica, Taipei 115. Taiwan.
Institute of Traditional Medicine, National Yang-Ming University, Taipei 11221. Taiwan.
Anticancer Agents Med Chem. 2017;17(13):1741-1755. doi: 10.2174/1871520617666170522120200.
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.
苯达莫司汀是一种N-氮芥-苯并咪唑杂合共轭物，最近被批准用于治疗慢性淋巴细胞白血病。然而，苯达莫司汀的半衰期较短可能会限制其临床应用。
本研究的目的是设计并合成具有更优药代动力学特征的化合物。
我们合成了一系列杂合分子，其包含通过脲连接子连接的苯基氮芥部分和苯并噻唑或苯并咪唑骨架，并评估了它们的抗肿瘤活性和血浆稳定性。
我们发现这些药物在培养中对一组人淋巴细胞白血病和人实体瘤细胞表现出显著的细胞毒性。人淋巴细胞白血病CCRM-CEM细胞对测试化合物最为敏感。总体而言，新的杂合物与顺铂一样有效，但细胞毒性明显高于苯达莫司汀。苯基氮芥-苯并噻唑化合物27d和苯基氮芥-苯并咪唑化合物32b具有显著的细胞毒性，并导致处理后的肿瘤细胞发生凋亡性死亡。这两种药物能够诱导DNA链间交联，并使细胞周期进程停滞在G2/M期。此外，我们表明这些新的杂合物在大鼠血浆中比苯达莫司汀更具化学稳定性。
我们的结果表明，通过脲连接子在苯并咪唑的C6位或苯并噻唑环的C8位连接苯基氮芥药效团可能是提高化学稳定性和生物利用度的一种方法。要点⇒合成了一系列与氮芥相连的苯并咪唑和苯并噻唑。⇒新合成的衍生物诱导了DNA链间交联。⇒这些衍生物诱导细胞周期停滞在G2/M期并触发H460细胞凋亡。⇒新化合物比苯达莫司汀具有更强的细胞毒性。⇒新化合物在大鼠血浆中的化学稳定性高于苯达莫司汀。
