Patil Shivaputra A, Addo James K, Deokar Hemantkumar, Sun Shan, Wang Jin, Li Wei, Suttle D Parker, Wang Wei, Zhang Ruiwen, Buolamwini John K
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, 847 Monroe Avenue, Suite 327, Memphis, TN 38163, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, 60064, USA.
Drug Des. 2017 Mar;6(1). doi: 10.4172/2169-0138.1000143. Epub 2017 Mar 1.
There is an urgent need drugs against particularly difficult to treat solid tumors such as pancreatic, triple negative breast, lung, colon, metastatic prostate cancers and melanoma. Thus, the objective of this study was to synthesize compounds based computational modeling that indicated the pyrido[3,4-]indole class bind to MDM2, a new cancer target for which there are still no drug on the market.
Compounds were synthesized by established methods and tested for antiproliferative activity against a broad range of human cancer cell lines, comprising HCT116 colon, HPAC, MIA PaCa-2 and Panc-1 pancreatic, MCF-7 and MDA-MB-468 breast, A375 and WM164 melanoma, A549 lung, and LNCaP, DU145 and PC3 prostate cancer lines. Computational docking was also undertaken.
The novel pyrido[3,4-]indoles synthesized exhibited a clear SAR with regards to antiproliferative activity, with potent broad-spectrum anticancer activity with ICs down to 80, 130, 130 and 200 nM for breast, colon, melanoma and pancreatic cancer cells, respectively. 1-Naphthyl at C1 combined with methoxy at C6 provided the best antiproliferative activity. Thus, compound (1-naphthyl-6-methoxy-9-pyrido[3,4-b]indole) showed the highest potency. A mechanistic feature of the compounds as a group is a strongly selective G2/M cell cycle phase arrest. Docking at on MDM2 suggested a hydrogen bond interaction between the 6-methoxy Tyr106, hydrophobic interaction with Val93, pi-pi stacking interactions with Tyr100 and His96 and hydrophobic interactions with Leu54 and Ile99. An N9-methyl group disrupted binding interactions, such as H-bond interactions involving the N9 hydrogen.
We have identified a novel series of pyrido[3,4-]indoles with potent broad spectrum anticancer activity towards the most aggressive and difficult to treat cancers including metastatic pancreatic cancer, non-small cell lung cancer, triple negative breast cancers, and BRAF mutant melanoma, as well as metastatic colon and prostate cancers. There was also evidence of selectivity towards cancer cells relative to normal cells. These compounds will serve as new leads from which novel therapeutics and molecular tools can be developed for a wide variety of cancers.
迫切需要针对特别难以治疗的实体瘤的药物,如胰腺癌、三阴性乳腺癌、肺癌、结肠癌、转移性前列腺癌和黑色素瘤。因此,本研究的目的是基于计算模型合成化合物,该模型表明吡啶并[3,4 - ]吲哚类与MDM2结合,MDM2是一种新的癌症靶点,目前市场上尚无针对该靶点的药物。
采用既定方法合成化合物,并针对广泛的人类癌细胞系测试其抗增殖活性,这些细胞系包括HCT116结肠癌细胞、HPAC、MIA PaCa - 2和Panc - 1胰腺癌细胞、MCF - 7和MDA - MB - 468乳腺癌细胞、A375和WM164黑色素瘤细胞、A549肺癌细胞以及LNCaP、DU145和PC3前列腺癌细胞系。还进行了计算对接。
合成的新型吡啶并[3,4 - ]吲哚在抗增殖活性方面呈现出明确的构效关系,具有强大的广谱抗癌活性,对乳腺癌、结肠癌、黑色素瘤和胰腺癌细胞的IC50分别低至80、130、130和200 nM。C1位上的1 - 萘基与C6位上的甲氧基组合提供了最佳的抗增殖活性。因此,化合物(1 - 萘基 - 6 - 甲氧基 - 9 - 吡啶并[3,4 - b]吲哚)表现出最高的活性。作为一个整体,这些化合物的一个机制特征是强烈选择性地使G2/M细胞周期阶段停滞。在MDM2上的对接表明,6 - 甲氧基与Tyr106之间存在氢键相互作用,与Val93存在疏水相互作用,与Tyr100和His96存在π - π堆积相互作用,与Leu54和Ile99存在疏水相互作用。N9 - 甲基基团破坏了结合相互作用,例如涉及N9氢的氢键相互作用。
我们已经鉴定出一系列新型的吡啶并[3,4 - ]吲哚,它们对最具侵袭性和最难治疗的癌症具有强大的广谱抗癌活性,包括转移性胰腺癌、非小细胞肺癌、三阴性乳腺癌、BRAF突变型黑色素瘤以及转移性结肠癌和前列腺癌。也有证据表明这些化合物对癌细胞相对于正常细胞具有选择性。这些化合物将作为新的先导物,从中可以开发出针对多种癌症的新型治疗药物和分子工具。