Y. B. Chavan College of Pharmacy, Dr. Rafiq Zakaria Campus, Rauza Baug, Aurangabad, Maharashtra 431001, India.
Departamento de Química Orgánica, Facultad de Ciencias, Universidad of Santiago De Compostela, Alfonso X el Sabio, 27002 Lugo, Spain.
Molecules. 2018 Aug 8;23(8):1981. doi: 10.3390/molecules23081981.
The work reports the facile synthesis of novel α-aminophosphonate derivatives coupled with indole-2,3-dione moieties, namely the diethyl(substituted phenyl/heteroaryl)(2-(2-oxoindolin-3-ylidene)hydrazinyl)methylphosphonates derivatives (⁻). One-pot three component Kabachnik-Fields reactions were used to synthesize these derivatives. The reaction was carried out at room temperature by stirring in presence of ceric ammonium nitrate (CAN) as a green catalyst. The structures of the synthesized compounds were established by spectral studies. The synthesized derivatives (⁻) were evaluated for their in vitro anticancer activity against six human cancer cell lines by the SRB assay method. The cancer cell lines used in this research work are SK-MEL-2 (melanoma), MCF-7 (breast cancer), IMR-32 (neuroblastoma) MG-63 (human osteosarcoma), HT-29 (human colon cancer) and Hep-G2 (human hepatoma). All the synthesized derivatives inhibited the cell proliferation. Importantly, all the target compounds showed no cytotoxicity towards normal tissue cells (GI > 250 µM). A docking study was performed to predict the mode of action. Docking results indicate that the compounds have good binding with the enzyme tyrosine kinase as well as with microtubules, which makes them dual inhibitors. The result of in-silico bioavailability studies suggests that the compounds from the present series have good oral drug-like properties and are non-toxic in nature. In vivo acute oral toxicity study results indicate that the compounds can be considered safe, and therefore could be developed in the future as good anticancer agents or as leads for the design and synthesis of novel anticancer agents.
本文报道了新型 α-氨基膦酸酯衍生物与吲哚-2,3-二酮部分的简便合成，即二乙基（取代苯基/杂芳基）（2-（2-氧代吲哚啉-3-亚基）肼基）甲基膦酸酯衍生物（⁻）。一锅三步 Kabachnik-Fields 反应被用于合成这些衍生物。反应在室温下，以硝酸铈铵（CAN）作为绿色催化剂搅拌进行。通过光谱研究确定了合成化合物的结构。通过 SRB 测定法评估了合成衍生物（⁻）对六种人癌细胞系的体外抗癌活性。本研究中使用的癌细胞系为 SK-MEL-2（黑色素瘤）、MCF-7（乳腺癌）、IMR-32（神经母细胞瘤）、MG-63（人骨肉瘤）、HT-29（人结肠癌细胞）和 Hep-G2（人肝癌细胞）。所有合成的衍生物都抑制了细胞增殖。重要的是，所有目标化合物对正常组织细胞均无细胞毒性（GI > 250 µM）。进行了对接研究以预测作用模式。对接结果表明，这些化合物与酪氨酸激酶以及微管具有良好的结合能力，使其成为双重抑制剂。基于计算机的生物利用度研究结果表明，本系列化合物具有良好的口服类药物性质，且性质无毒。体内急性口服毒性研究结果表明，这些化合物可以被认为是安全的，因此可以在未来作为良好的抗癌药物或作为设计和合成新型抗癌药物的先导化合物进行开发。
