Synthesis of new thiazolo-pyrrolidine-(spirooxindole) tethered to 3-acylindole as anticancer agents

被引:79
作者
Islam, Mohammad Shahidul [1 ]
Ghawas, Hussien Mansur [1 ]
El-Senduny, Fardous F. [2 ]
Al-Majid, Abdullah Mohammed [1 ]
Elshaier, Yaseen A. M. M. [3 ]
Badria, Farid A. [4 ]
Barakat, Assem [1 ,5 ]
机构
[1] King Saud Univ, Coll Sci, Dept Chem, POB 2455, Riyadh 11451, Saudi Arabia
[2] Mansura Univ, Fac Sci, Dept Chem, Mansoura, Egypt
[3] Univ Sadat City, Fac Pharm, Dept Organ & Med Chem, Menoufia, Egypt
[4] Mansoura Univ, Fac Pharm, Dept Pharmacognosy, Mansoura 35516, Egypt
[5] Alexandria Univ, Fac Sci, Dept Chem, POB 426, Alexandria 21321, Egypt
关键词
Spirooxindole; 1,3-dipolar cycloaddition; Azomethine ylide; Anticancer activity; LE; LLE; Molecular docking; SMALL-MOLECULE INHIBITORS; STRUCTURE-BASED DESIGN; MAMMALIAN-CELL CYCLE; HEPATOCELLULAR-CARCINOMA; ALCOHOL INTAKE; P53; PATHWAY; MDM2; POTENT; DISCOVERY; SPIROOXINDOLES;
D O I
10.1016/j.bioorg.2018.10.036
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Anticancer therapeutics with profiles of high potency, low toxicity, and low resistance is of considerable interest. A new series of functionalized spirooxindole linked with 3-acylindole scaffold is reported, starting from chalcones derived from 3-acetyl indole with isatin, and l-4-thiazolidinecarboxylic acid. The reactions proceeded regioselectivity, stereoselectivity, without side products in high yield (71-89%). The new spirooxindole hybrids have been evaluated in vitro for their antiproliferative effects against colon cancer (HCT-116), hepatocellular carcinoma (HepG2) and prostate cancer (PC-3). The selectivity of their activity was evaluated. Some of the synthesized compounds showed considerable anticancer activities. Compound 4k proved to retain a high cytotoxic activity and selectivity against colon cancer cells HCT-116 (IC50 = 7 +/- 0.27 mu M, SI: 3.7), and HepG2 (IC50 = 5.5 +/- 0.2 mu M, SI: 4.7) in comparison to (IC50 = 12.6 +/- 0.5, SI: 0.4 and 5.5 +/- 0.3 mu M, SI: 0.9, respectively). Compound 4k was less active (IC50 = 6 +/- 0.3 mu M, SI: 4.3) than cisplatin (IC50 = 5 +/- 0.56 mu M, SI: 1.0) but showed greater selectivity towards prostate cancer cells PC-3 in comparison to cisplatin. The details of the binding mode of the active compounds were clarified by molecular docking. Ligand Efficiency (LE) and Ligand Lipophilic Efficiency (LLE) were evaluated and revealed that compound 4k had acceptable value.
引用
收藏
页码:423 / 430
页数:8
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