Aboul-Fadl Tarek, Al-Hamad Suliman S, Lee Kevin, Li Nan, Gary Bernard D, Keeton Adam B, Piazza Gary A, Abdel-Hamid Mohammed K
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
Med Chem Res. 2014 Sep;23(9):4177-4188. doi: 10.1007/s00044-014-0979-z.
A structure-based medicinal chemistry strategy was applied to design new naproxen derivatives that show growth inhibitory activity against human colon tumor cells through a cyclooxygenase (COX)-independent mechanism. In vitro testing of the synthesized compounds against the human HT-29 colon tumor cell line revealed enhanced growth inhibitory activity compared to the parent naproxen with showing IC of 11.4 μM (two orders of magnitude more potent than naproxen). Selectivity of was investigated against a panel of three tumor and one normal colon cell lines and showed up to six times less toxicity against normal colonocytes. Compound was shown to induce dose-dependent apoptosis of HT116 colon tumor cells as evidenced by measuring the activity of caspases-3 and 7. None of the synthesized compounds showed activity against COX-1 or COX-2 isozymes, confirming a COX-independent mechanism of action. Compound was found to have no ulcerogenic effect in rats as indicated by electron microscope scanning of the stomach after oral administration. A pharmacophore model was developed for elucidating structure-activity relationships and subsequent chemical optimization for this series of compounds as colorectal cancer chemopreventive drugs.
应用基于结构的药物化学策略设计新的萘普生衍生物，这些衍生物通过不依赖环氧化酶（COX）的机制对人结肠肿瘤细胞表现出生长抑制活性。对合成化合物针对人HT-29结肠肿瘤细胞系进行的体外测试显示，与母体萘普生相比，其生长抑制活性增强，IC50为11.4 μM（比萘普生强两个数量级）。研究了该化合物对三种肿瘤细胞系和一种正常结肠细胞系的选择性，结果显示其对正常结肠细胞的毒性低至六倍。通过测量半胱天冬酶-3和7的活性证明，该化合物可诱导HT116结肠肿瘤细胞发生剂量依赖性凋亡。所有合成化合物均未显示出对COX-1或COX-2同工酶的活性，证实了其不依赖COX的作用机制。口服给药后对大鼠胃进行电子显微镜扫描表明，该化合物对大鼠无致溃疡作用。开发了一个药效团模型，以阐明构效关系，并对该系列化合物作为结直肠癌化学预防药物进行后续化学优化。
