Institut des Biomolécules Max Mousseron, UMR 5247, CNRS, Universités Montpellier, UFR des Sciences Pharmaceutiques et Biologiques, Montpellier, France.
Department of Biochemistry, Medical Research Institute, University of Alexandria, Alexandria, Egypt.
J Enzyme Inhib Med Chem. 2020 Dec;35(1):935-949. doi: 10.1080/14756366.2020.1748024.
A series of 19 novel pyrido-imidazodiazepinones, with modulations of positions 2, 3 and 4 of the diazepine ring were synthesised and screened for their cytotoxic activities against two melanoma cell lines (A375 and MDA-MB-435) and for their potential toxicity against NIH-3T3 non-cancerous cells. Selected compounds were also evaluated on the NCI-60 cell line panel. The SAR study revealed that the molecular volume and the LogP of compounds modified at position 2 were significantly correlated with the activity of these compounds on melanoma cell lines. Moreover, introduction of a heterocyclic group at position 2 or an azido-alkyl chain at position 4 led to compounds displaying a significantly different activity profile on the NCI-60 cell line panel, compared to phenyl-substituted compounds at position 2 of the diazepinone. This study provides us crucial information for the development of new derivatives active against melanoma.
一系列 19 种新型吡啶并咪唑二氮杂卓，对二氮杂环戊烷环的 2、3 和 4 位进行了修饰，对两种黑素瘤细胞系（A375 和 MDA-MB-435）进行了细胞毒性筛选，并对 NIH-3T3 非癌细胞的潜在毒性进行了筛选。还对选定的化合物进行了 NCI-60 细胞系小组的评估。SAR 研究表明，在 2 位修饰的化合物的分子体积和 LogP 与这些化合物对黑素瘤细胞系的活性显著相关。此外，在 2 位引入杂环基团或在 4 位引入叠氮烷基链，与在二氮杂环戊烷的 2 位取代苯基的化合物相比，导致在 NCI-60 细胞系小组上显示出明显不同的活性谱。这项研究为开发针对黑色素瘤的新型衍生物提供了重要信息。
