INHIBITORY EFFECT OF COUMARIN BENZOYLHYDRAZONES ON MCL-1 PROTEIN

Dušica M Simijonović, M. Antonijević, Edina H. Avdović, Z. Petrović, Z. Marković
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Abstract

The protein that controls cell differentiation in acute myeloid leukemia is MCL-1. High-level of this protein causes the carcinogenesis. In this paper inhibitory effect of two coumarin benzoylhydrazones,(E)-2-hydroxy-N’-(1-(2-oxo-2H-chromen-3-yl)ethylidene)benzohydrazide (A) and (E)-4-hydroxy-N’-(1-(2-oxo-2H-chromen-3-yl)ethylidene)benzohydrazide (B) against MCL-1 protein was investigated. For this purpose, a molecular docking simulations were used. The obtained results showed that compound A showed better activity than compound B. Also, the docking simulations against MCL-1 protein were performed for melphalan or (2S)-2-amino- 3-{4-[bis(2-chloroethyl)amino]phenyl}propanoic acid and two 4-chlorocoumarin benzoylhydrazone derivatives, N′-[(E)-(4-chloro-2-oxo-2H-chromen-3-yl)- methylidene]benzohydrazide (4a) and N′-[(E)-(4-chloro-2-oxo-2H-chromen-3-yl)- methylidene]-4-hydroxybenzohydrazide (4b). In this study, melphalan as a chemotherapy drug commonly used in treating multiple myeloma and compounds 4a and 4b as structurally similar compounds with A and B were used as reference compounds. It was shown that these reference compounds exhibited similar activity as compound B. In addition, the potential toxicology of compounds A and B, as well as reference compounds was determined by the ProTox-II webserver. The results revealed that compounds A and B are 3 to 5 times lower toxic than reference compounds.
香豆素苯甲酰腙对McL-1蛋白的抑制作用
在急性髓系白血病中控制细胞分化的蛋白是MCL-1。高水平的这种蛋白质会导致癌变。本文研究了香豆素苯甲酰腙(E)-2-羟基- n′-(1-(2-氧- 2h -3-基)乙基)苯并肼(A)和(E)-4-羟基- n′-(1-(2-氧- 2h -3-基)乙基)苯并肼(B)对MCL-1蛋白的抑制作用。为此,采用分子对接模拟。结果表明,化合物A比化合物b具有更好的活性。此外,还对melphalan或(2S)-2-氨基-3-{4-[双(2-氯乙基)氨基]苯基丙酸和2个4-氯香豆素苯甲酰腙衍生物N ' -[(E)-(4-氯-2-氧- 2h -铬-3-基)-亚甲基]苯甲酰肼(4a)和N ' -[(E)-(4-氯-2-氧- 2h -铬-3-基)-亚甲基]-4-羟基苯甲酰肼(4b)进行了对MCL-1蛋白的对接模拟。本研究以治疗多发性骨髓瘤常用的化疗药物melphalan和与a、B结构相似的化合物4a、4b作为参比化合物。结果表明,这些参比化合物与化合物B具有相似的活性。此外,通过ProTox-II webserver对化合物A、B及参比化合物进行了潜在毒理学分析。结果表明,化合物A和B的毒性比对照化合物低3 ~ 5倍。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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