ICMR-National Institute of Occupational Health, Ahmedabad-380016, Gujarat, India.
National Facility for Drug Discovery (NFDD), Saurashtra University, Rajkot-360005, Gujarat, India.
Anticancer Agents Med Chem. 2019;19(10):1285-1292. doi: 10.2174/1871520619666190308122734.
Quinoline analogues exhibited diversified biological activities depending on the structure type. A number of natural products with pyrano[3,2-c]quinolone structural motifs and patented chromenes were reported as promising cytotoxic agents.
The present study is aimed to evaluate a new series of pyrano[3,2-c]quinoline scaffolds derived from the fusion of bioactive quinolone pharmacophore with structurally diverse aryl substituted chromene for its cytotoxicity.
A library of pyrano[3,2-c]quinoline analogues was prepared from one-pot multi component synthesis using various aromatic aldehydes, malononitrile and 2,4-dihydroxy-1-methylquinoline. The new synthetics were primarily screened for its cytotoxicity (IC50) against different human cancer cell lines in vitro. The promising synthetics were further evaluated in vitro for their potency against different kinase activity. The promising compounds were finally tested for their in vivo efficacy in SCID type mice HCT-116 tumor model.
The screening results revealed that compounds 4c, 4f, 4i and 4j showed promising activity in in vitro study. However, compound 4c was found to be the most potent candidate with 23% tumor growth inhibition in HCT-116 tumor mice model.
The structure activity relationship suggested that 3-substitution on the aryl ring at C4 position of the pyrano[3,2 c]quinolone moiety seems to have an important position for cytotoxicity activity. However, 3- chloro substitution at C4 aryl ring showed a significant alteration of the bioactive conformer of the parent scaffold and outcome with compound 4c as the most potent candidate of the series.
喹啉类似物因其结构类型的不同而具有多样化的生物活性。许多具有吡喃并[3,2-c]喹啉结构基序和专利色烯的天然产物被报道为有前途的细胞毒性剂。
本研究旨在评估一系列新型吡喃并[3,2-c]喹啉骨架，这些骨架是通过将生物活性喹啉药效团与结构多样的芳基取代色烯融合而得到的，以评估其细胞毒性。
使用各种芳醛、丙二腈和 2,4-二羟基-1-甲基喹啉，通过一锅多组分合成法制备了吡喃并[3,2-c]喹啉类似物库。新合成物在体外主要针对不同的人癌细胞系进行了细胞毒性（IC50）筛选。有前途的合成物进一步在体外评估了其对不同激酶活性的效力。有前途的化合物最终在 SCID 型小鼠 HCT-116 肿瘤模型中进行了体内功效测试。
筛选结果表明，化合物 4c、4f、4i 和 4j 在体外研究中表现出有希望的活性。然而，化合物 4c 被发现是最有效的候选物，在 HCT-116 肿瘤小鼠模型中抑制肿瘤生长 23%。
构效关系表明，吡喃并[3,2-c]喹啉部分 C4 位芳环上的 3-取代似乎对细胞毒性活性具有重要作用。然而，C4 芳环上的 3-氯取代会显著改变母体支架的生物活性构象，导致化合物 4c 成为该系列中最有效的候选物。
