Dawood Dina H, Srour Aladdin M, Saleh Dalia O, Huff Kelley J, Greco Francesca, Osborn Helen M I
Chemistry of Natural and Microbial Products Department, Pharmaceutical and Drug Industries Research Division, National Research Centre 33 El Bohouth St., Dokki Giza 12622 Egypt.
Department of Therapeutic Chemistry, National Research Centre 33 El Bohouth St., Dokki Giza 12622 Egypt
RSC Adv. 2021 Sep 2;11(47):29441-29452. doi: 10.1039/d1ra04758b. eCollection 2021 Sep 1.
Based on studies that have reported the association between cancer and cardiovascular diseases, new series of pyridine- (3a-o) and/or chromene- (4a-e) carbonitrile analogous were designed, synthesized and screened for their vasodilation and cytotoxic properties. The majority of the new chemical entities demonstrated significant vasodilation efficacies, compounds 3a, 3h, 3j, 3m, 3o, 4d and 4e exhibited the most promising potency with IC = 437.9, 481.0, 484.5, 444.8, 312.1, 427.6 and 417.2 μM, respectively, exceeding prazosin hydrochloride (IC = 487.3 μM). Compounds 3b-e, 3k and 3l also, revealed moderate vasodilation activity with IC values ranging from 489.7 to 584.5 μM. In addition, the anti-proliferative activity evaluation of the experimental compounds at 10 μM on the MCF-7 and MDA-MB 231 breast cancer cell lines illustrated the excellent anti-proliferative properties of derivatives 3d, 3g and 3i. Compound 3d was the most potent analogue with IC = 4.55 ± 0.88 and 9.87 ± 0.89 μM against MCF-7 and MDA-MB 231, respectively. Moreover, compound 3d stimulated apoptosis and cell cycle arrest at the S phase in MCF-7 cells in addition to its capability in accumulation of cells in pre-G1 phase and activating caspase-3. Furthermore, the molecular docking of 3d was performed to discover the binding modes within the active site of caspase-3. 3d, as the only common bi-functional agent among the tested hits, demonstrated that new pyridine-3-carbonitrile derivatives bearing cycloheptyl ring systems offer potential as new therapeutic candidates with combined vasodilation and anticancer properties.
基于已报道的癌症与心血管疾病之间关联的研究，设计、合成并筛选了一系列新的吡啶 -（3a - o）和/或色烯 -（4a - e）腈类似物，以研究其血管舒张和细胞毒性特性。大多数新化学实体表现出显著的血管舒张功效，化合物3a、3h、3j、3m、3o、4d和4e表现出最有前景的效力，其IC50分别为437.9、481.0、484.5、444.8、312.1、427.6和417.2 μM，超过了盐酸哌唑嗪（IC50 = 487.3 μM）。化合物3b - e、3k和3l也显示出中等程度的血管舒张活性，IC50值在489.7至584.5 μM之间。此外，对实验化合物在10 μM浓度下对MCF - 7和MDA - MB 231乳腺癌细胞系的抗增殖活性评估表明，衍生物3d、3g和3i具有优异的抗增殖特性。化合物3d是最有效的类似物，对MCF - 7和MDA - MB 231的IC50分别为4.55 ± 0.88和9.87 ± 0.89 μM。此外，化合物3d除了能够使细胞在G1期前积累并激活caspase - 3外，还能诱导MCF - 7细胞凋亡并使细胞周期停滞在S期。此外，进行了3d的分子对接以发现其在caspase - 3活性位点内的结合模式。3d作为测试命中物中唯一的常见双功能剂，表明带有环庚基环系统的新型吡啶 - 3 - 腈衍生物具有作为具有血管舒张和抗癌特性的新治疗候选物的潜力。
