Chemistry Department, Faculty of Science, Alexandria University, P.O. Box 426, Alexandria, 21321, Egypt.
Chemistry Department, Faculty of Science, Alexandria University, P.O. Box 426, Alexandria, 21321, Egypt.
Eur J Med Chem. 2019 Apr 15;168:340-356. doi: 10.1016/j.ejmech.2019.02.051. Epub 2019 Feb 22.
Evasion of apoptosis is a hallmark of cancer. Caspases; the key executors of apoptotic cascade are attractive targets for selective induction of apoptosis in cancer cells. Within this approach, various caspase activators were introduced as lead anticancer agents. In the current study, a new series of multifunctional Passerini products was synthesized and evaluated as potent caspase-dependent apoptotic inducers. The synthetic strategy adopted this isocyanide-based multicomponent reaction to possibly mimic the pharmacophoric features of various lead apoptotic inducers, where a series of α-acyloxy carboxamides was prepared from p-nitrophenyl isonitrile, cyclohexanone and various carboxylic acids. Accordingly, the main amide-based scaffold was decorated by substituents with varying nature and size to gain more information about structure-activity relationship. All the synthesized compounds were screened for cytotoxicity against normal human fibroblasts and their potential anticancer activities against three human cancer cell lines; MCF-7 (breast), NFS-60 (myeloid leukemia), and HepG-2 (liver) utilizing MTT assay. Among the most active compounds, 13, 21 and 22 were more potent and safer than doxorubicin with nanomolar IC values and promising selectivity indices. Mechanistically, 13, 21 and 22 induced apoptosis by significant caspase activation in all the screened cancer cell lines utilizing flow cytometric analysis and caspase 3/7 activation assay. Again, 13 and 21 recorded higher activation percentages than doxorubicin, while 22 showed comparable results. Apoptosis-inducing factor1 (AIF1) quantification assay declared that 13, 21 and 22 didn't mediate apoptosis through AIF1-dependent pathway (i.e. only by caspase activation). Physicochemical properties, pharmacokinetic profiles, ligand efficiency metrics and drug-likeness data of all the synthesized compounds were computationally predicted and showed that 13, 21 and 22 could be considered as drug-like candidates. Finally, selected compounds were preliminarily screened for possible antimicrobial activities searching for dual anticancer/antimicrobial agents as an advantageous approach for cancer therapy.
细胞凋亡的逃避是癌症的一个标志。半胱天冬酶；凋亡级联的关键执行者是在癌细胞中选择性诱导凋亡的有吸引力的靶标。在这种方法中，引入了各种半胱天冬酶激活剂作为潜在的抗癌药物。在本研究中，合成了一系列新的多功能帕瑟里尼产物，并将其作为有效的半胱天冬酶依赖性凋亡诱导剂进行了评估。采用这种异氰化物为基础的多组分反应的合成策略，可能模拟各种潜在凋亡诱导剂的药效团特征，其中一系列α-酰氧基酰胺是由对硝基苯异腈、环己酮和各种羧酸制备的。因此，主要的酰胺基支架被具有不同性质和大小的取代基修饰，以获得更多关于构效关系的信息。所有合成的化合物都进行了细胞毒性筛选，以评估它们对正常人成纤维细胞的毒性，以及对三种人类癌细胞系 MCF-7（乳腺癌）、NFS-60（髓样白血病）和 HepG-2（肝癌）的潜在抗癌活性，采用 MTT 法进行评估。在最活跃的化合物中，化合物 13、21 和 22 比阿霉素更有效且更安全，具有纳摩尔 IC 值和有前途的选择性指数。在机制上，化合物 13、21 和 22 通过在所有筛选的癌细胞系中显著的半胱天冬酶激活诱导凋亡，利用流式细胞术分析和 caspase 3/7 激活测定。同样，化合物 13 和 21 的激活百分比高于阿霉素，而化合物 22 的结果相当。凋亡诱导因子 1（AIF1）定量测定表明，化合物 13、21 和 22 不通过 AIF1 依赖性途径（即仅通过半胱天冬酶激活）介导凋亡。所有合成化合物的理化性质、药代动力学特征、配体效率指标和药物样数据都进行了计算预测，结果表明化合物 13、21 和 22 可以被认为是具有药物样特性的候选物。最后，对选定的化合物进行了初步的抗菌活性筛选，寻找具有双重抗癌/抗菌活性的化合物，作为癌症治疗的一种有利方法。
