作为抗癌剂的 4-羟基-1-苯基-2(1H)-喹诺酮衍生物的对接、合成和评价。
Docking, Synthesis and Evaluation of 4-hydroxy-1-phenyl-2(1H)-quinolone Derivatives as Anticancer Agents.
机构信息
Department of Pharmaceutical Chemistry, P.E.S's Rajaram and Tarabai Bandekar College of Pharmacy, Farmagudi, Ponda-Goa, 403401, India.
出版信息
Curr Drug Discov Technol. 2024;21(2):e190723218893. doi: 10.2174/1570163820666230719110932.
BACKGROUND
The estimated number of cancer cases in India for the year 2022 was found to be 14,61,427. The development of chemotherapeutic agents has reduced the mortality rate, however, they have high toxicity which is a disadvantage. Many researchers have found out that quinolin-2- one possesses anticancer activity, with this background we thought of synthesizing the quinolin-2-one derivatives.
OBJECTIVE
This study aimed to carry out docking, synthesis, characterization, and evaluation of 2-(2- (4-Hydroxy-2-oxoquinolin-1(2H)-yl)phenyl/ substituted phenyl)-3-(phenylamino) thiazolidon-4-one derivatives (IVa-g) as an anticancer agent.
METHOD
Diphenylamine and malonic acid treated with phosphoryl chloride gave compound I, which on formylation afforded compound II, which on reaction with various substituted aromatic phenylhydrazine derivatives gave compounds IIIa-g, which on further reaction with thioglycolic acid and anhydrous zinc chloride yielded the compounds IVa-g.
RESULT
Among all the synthesized novel derivatives, compounds IV a-d showed 50% lysis in the IC range of 25-50μg for the A549 cell line, and compounds IVa, and IVb showed 50% lysis in the IC range of 25-50μg for the MDA-MB cell line. The compound, 3-((4-fluorophenyl)amino)-2-(2-(4- hydroxy-2-oxoquinolin-1(2H)-yl)phenyl)thiazolidin-4-one (IVg) was found to be the most active against both the cell line, A549 and MDA-MB with IC value of 0.0298μmol and 0.0338μmol respectively. The docking results revealed that the synthesized compounds exhibited well-conserved hydrogen bonding with one or more amino acid residues in the active pocket of EGFR tyrosine kinase domain with 4-anilinoquinazoline inhibitor erlotinib (PDB ID:1M17). Compound IVg showed the highest MolDock score of -137.813 compared to the standard drug Imatinib having a MolDock score of -119.354.
CONCLUSION
Compound IVg showed the highest MolDock score and was also found to be most potent against both the cell line, A549, and MDA-MB.
背景
据估计，2022 年印度的癌症病例数为 1461427 例。化疗药物的发展降低了死亡率，但它们毒性很高，这是一个缺点。许多研究人员发现喹啉-2-酮具有抗癌活性，在此背景下，我们想到了合成喹啉-2-酮衍生物。
目的
本研究旨在进行对接、合成、表征和评估 2-(2-(4-羟基-2-氧代喹啉-1(2H)-基)苯基/取代苯基)-3-(苯基氨基)噻唑烷-4-酮衍生物（IVa-g）作为抗癌剂。
方法
二苯胺和丙二酸与氯化磷反应生成化合物 I，化合物 I 经甲酰化得到化合物 II，化合物 II 与各种取代的芳基苯肼衍生物反应得到化合物 IIIa-g，化合物 IIIa-g 与硫代甘氨酸和无水氯化锌进一步反应得到化合物 IVa-g。
结果
在所合成的新型衍生物中，化合物 IVa-d 在 A549 细胞系的 IC 范围为 25-50μg 时表现出 50%的溶解，化合物 IVa 和 IVb 在 MDA-MB 细胞系的 IC 范围为 25-50μg 时表现出 50%的溶解。化合物 3-((4-氟苯基)氨基)-2-(2-(4-羟基-2-氧代喹啉-1(2H)-基)苯基)噻唑烷-4-酮（IVg）对 A549 和 MDA-MB 两种细胞系均显示出最强的活性，IC 值分别为 0.0298μmol 和 0.0338μmol。对接结果表明，所合成的化合物与表皮生长因子受体酪氨酸激酶结构域的活性口袋中的一个或多个氨基酸残基表现出良好的氢键相互作用，与 4-苯胺基喹唑啉抑制剂厄洛替尼（PDB ID：1M17）。化合物 IVg 的 MolDock 得分最高，为-137.813，而标准药物伊马替尼的 MolDock 得分为-119.354。
结论
化合物 IVg 的 MolDock 得分最高，对 A549 和 MDA-MB 两种细胞系均显示出最强的活性。
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