Soltani Rad Mohammad Navid, Behrouz Somayeh, Aghajani Saleh, Behrouz Marzieh, Zarenezhad Elham, Ghanbariasad Ali
Medicinal Chemistry Research Laboratory, Department of Chemistry, Shiraz University of Technology Shiraz 71555-313 Iran
Non-communicable Diseases Research Center, Fasa University of Medical Sciences Fasa Iran.
RSC Adv. 2023 Jan 19;13(5):3056-3070. doi: 10.1039/d2ra07683g. eCollection 2023 Jan 18.
In this research the synthesis, characterization, anticancer and the cytotoxicity assessments of novel 8-caffeinyl-triazolylmethoxy hybrid conjugates have been described. These compounds are the first caffeine-1,2,3-triazolyl hybrid molecules that structurally are composed of three compartments comprising caffeinyl, 1,2,3-triazolyl and -alkyl/aryl residues. The evaluations of synthesized compounds on cancer cell lines, including two breast cancer cell lines MDA-MB-468 (ATCC HTB-22), MCF-7 (ATCC HTB-22), melanoma cell line A-375 (ATCC CRL-1619) and normal cell line HEK-293 (ATCC CRL-11268) have determined that 22c (IC < 12.5 μM) demonstrated potent activity against A375 and its toxicity is even stronger than methotrexate (MTX) as a standard drug. Additionally, 22c involves more selectivity than MTX regarding its non-toxicity for the HEK-293 cell line. Among the tested compounds against two breast cancer cell lines, 22f (IC = 136 ± 0.2 and 126 ± 0.6 μM for MCF-7 and MDA-MB-468, respectively) and 22i (IC = 165 ± 1.8 and 175 ± 1.4 μM for MCF-7 and MDA-MB-468, respectively) were the most potent compounds but their activities were less than MTX, moreover 22f showed more selectivity regarding its lower toxicity against HEK-293. Overall, 22f displayed general toxicity and selectivity on all tested cancer cell lines. The physicochemical properties, pharmacokinetic profile, and drug likeness predictions were also carried out for all the studied compounds. Most new compounds exhibited zero violation of Lipinski's rule (RO5). A molecular docking study was also conducted to predict the binding mode and the interaction of 22c as the most active anti-melanoma entry with B-RAF V600E kinase enzyme. The docking results determined that 22c exhibited a strong binding affinity to the active site of the enzyme. These findings demonstrated 22c and 22f as potential future anticancer drug candidates.
本研究描述了新型8-咖啡酰基-三唑基甲氧基杂合共轭物的合成、表征、抗癌及细胞毒性评估。这些化合物是首批咖啡因-1,2,3-三唑基杂合分子，其结构由包含咖啡酰基、1,2,3-三唑基和-烷基/芳基残基的三个部分组成。对合成化合物在癌细胞系上的评估，包括两种乳腺癌细胞系MDA-MB-468（美国典型培养物保藏中心HTB-22）、MCF-7（美国典型培养物保藏中心HTB-22）、黑色素瘤细胞系A-375（美国典型培养物保藏中心CRL-1619）和正常细胞系HEK-293（美国典型培养物保藏中心CRL-11268），已确定22c（IC<12.5μM）对A375表现出强效活性，且其毒性甚至比作为标准药物的甲氨蝶呤（MTX）更强。此外，22c对HEK-293细胞系无毒，相比MTX具有更高的选择性。在针对两种乳腺癌细胞系测试的化合物中，22f（对MCF-7和MDA-MB-468的IC分别为136±0.2和126±0.6μM）和22i（对MCF-7和MDA-MB-468的IC分别为165±1.8和175±1.4μM）是最有效的化合物，但其活性低于MTX，此外22f对HEK-293毒性较低，表现出更高的选择性。总体而言，22f对所有测试的癌细胞系均表现出一般毒性和选择性。还对所有研究化合物进行了物理化学性质、药代动力学概况和类药性质预测。大多数新化合物均未违反Lipinski规则（RO5）。还进行了分子对接研究，以预测作为最具活性的抗黑色素瘤药物的22c与B-RAF V600E激酶的结合模式和相互作用。对接结果确定22c对该酶的活性位点表现出强烈的结合亲和力。这些发现表明22c和22f是未来潜在的抗癌药物候选物。
