ABSTRACT
With the aim to discover potent and novel antitumor agents, a series of thiourea compounds bearing 3-(4-methoxyphenyl)azetidine moiety were designed according to the essential pharmacophoric features of the reported VEGFR-2 inhibitors and synthesized. All the synthesized compounds were evaluated for their in vitro anticancer activity against various human cancer cell lines (lung (A549), prostate (PC3), breast (MCF-7), liver (HepG2), colon (HCT-116), ovarian (SKOV-3), skin (A431), brain (U251) and kidney (786-O)). 3-(4-Methoxy-3-(2-methoxypyridin-4-yl)phenyl)-N-(4-methoxyphenyl)azetidine-1-carbothioamide (3B) was found to be most potent member against PC3, U251, A431, and 786-O cancer cell lines with EC50 values 0.25, 0.6, 0.03, and 0.03 µM, respectively and showed more potency than Doxorubicin in PC3, A431, and 786-O cell lines. Compounds 1B to 7B showed EC50 values ranging from 0.03 to 12.55 µM in A431 cell line. Compound 3-(4-methoxy-3-(pyridin-4-yl)phenyl)-N-(4-methoxyphenyl)azetidine-1-carbothioamide (1B) was found to be highly efficient in A431 and 786-O cell line with EC50 values of 0.77 and 0.73 µM respectively. All the compounds exhibited good to moderate cytotoxic activity. The pharmacophoric features and molecular docking studies confirmed the potentialities of compounds 1B, 2B, 3B and 5B to be VEGFR-2 inhibitors. Moreover, in silico ADMET prediction indicated that most of the synthesized compounds have drug-like properties, possess low adverse effects and toxicity. In addition, the DFT studies for the most active compounds (1B and 3B) were carried out. In the end, our studies revealed that the compounds 1B and 3B represent promising anticancer potentialities through their VEGFR-2 inhibition.
Subject(s)
Antineoplastic Agents/pharmacology , Azetidines/pharmacology , Density Functional Theory , Molecular Docking Simulation , Protein Kinase Inhibitors/pharmacology , Thiourea/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Azetidines/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Discovery , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship , Thiourea/chemistry , Vascular Endothelial Growth Factor Receptor-2/metabolismABSTRACT
ETHNOPHARMACOLOGICAL RELAVANCE: The decoction of Carica papaya Linn. leaves is used in folklore medicine in certain parts of Malaysia and Indonesia for the treatment of different types of thrombocytopenia associated with diseases and drugs. There are several scientific studies carried out on humans and animal models to confirm the efficacy of decoction of papaya leave for the treatment of disease induced and drug induced thrombocytopenia, however very little is known about the bio-active compounds responsible for the observed activity. The aim of present study was to identify the active phytochemical component of Carica papaya Linn. leaves decoction responsible for anti-thrombocytopenic activity in busulfan-induced thrombocytopenic rats. MATERIALS AND METHODS: Antithrombocytopenic activity was assessed on busulfan induced thrombocytopenic Wistar rats. The antithrombocytopenic activity of different bio-guided fractions was evaluated by monitoring blood platelet count. Bioactive compound carpaine was isolated and purified by chromatographic methods and confirmed by spectroscopic methods (LC-MS and 1D/2D-1H/13C NMR) and the structure was confirmed by single crystal X-ray diffraction. Quantification of carpaine was carried out by LC-MS/MS equipped with XTerra(®) MS C18 column and ESI-MS detector using 90:10 CH3CN:CH3COONH4 (6mM) under isocratic conditions and detected with multiple reaction monitoring (MRM) in positive ion mode. RESULTS: Two different phytochemical groups were isolated from decoction of Carica papaya leaves: phenolics, and alkaloids. Out of these, only alkaloid fraction showed good biological activity. Carpaine was isolated from the alkaloid fraction and exhibited potent activity in sustaining platelet counts upto 555.50±85.17×10(9)/L with no acute toxicity. CONCLUSIONS: This study scientifically validates the popular usage of decoction of Carica papaya leaves and it also proves that alkaloids particularly carpaine present in the leaves to be responsible for the antithrombocytopenic activity.
