Synthesis of sorafenib analogues incorporating a 1,2,3-triazole ring and cytotoxicity towards hepatocellular carcinoma cell lines.

A series of 1,2,3-triazole-containing Sorafenib analogues, in which the aryl urea moiety of Sorafenib (1) was replaced with a 1,2,3-triazole ring linking a substituted phenoxy fragment, were prepared successfully via Huisgen 1,3-dipolar cycloaddition and nucleophilic aromatic substitution. The studies of cytotoxicity towards human hepatocellular carcinoma (HCC) cell lines, HepG2 and Huh7, indicated that p-tert-butylphenoxy analogue 2m showed significant inhibitory activity against Huh7 with IC50 = 5.67 ± 0.57 µM. More importantly, 2m showed low cytotoxicity against human embryonal lung fibroblast cell line, MRC-5, with IC50 > 100 µM, suggesting its highly selective cytotoxic activity (SI > 17.6) towards Huh7 which is much superior to that of Sorafenib (SI = 6.73). The molecular docking studies revealed that the analogue 2m bound B-RAF near the binding position of Sorafenib, while it interacted VEGFR2 efficiently at the same binding position of Sorafenib. However, 2m exhibited moderate inhibitory activity toward B-RAF, implying that its anti-Huh7 effect might not strictly relate to inhibition of B-RAF. Wound healing and BrdU cell proliferation assays confirmed anti-cell migration and anti-cell proliferative activities towards Huh7. With its inhibitory efficiency and high safety profile, 2m has been identified as a promising candidate for the treatment of HCC.

Design, synthesis, biological evaluation, and modeling studies of novel conformationally-restricted analogues of sorafenib as selective kinase-inhibitory antiproliferative agents against hepatocellular carcinoma cells.

Sorafenib is one of the clinically used anticancer agents that inhibits several kinases. In this study, novel indole-based rigid analogues of sorafenib were designed and synthesized in order to enhance kinase selectivity and hence minimize the side effects associated with its use. The target compounds possess different linkers; urea, amide, sulfonamide, or thiourea, in addition to different terminal aryl moieties attached to the linker in order to investigate their impact on biological activity. They were tested against Hep3B, Huh7, and Hep-G2 hepatocellular carcinoma (HCC) cell lines to study their potency. Among all the tested target derivatives, compound 1h exerted superior antiproliferative potency against all the three tested HCC cell lines compared to sorafenib. Based on these preliminary results, compound 1h was selected for further biological and in silico investigations. Up to 30 µM, compound 1h did not inhibit 50% of the proliferation of WI-38 normal cells, which indicated promising selectivity against HCC cells than normal cells. In addition, compound 1h exerted superior kinase selectivity than sorafenib. It is selective for VEGFR2 and VEGFR3 angiogenesis-related kinases, while sorafenib is a multikinase inhibitor. Superior kinase selectivity of compound 1h to sorafenib can be attributed to its conformationally-restricted indole nucleus and the bulky N-methylpiperazinyl moiety. Western blotting was carried out and confirmed the ability of compound 1h to inhibit VEGFR2 kinase inside Hep-G2 HCC cells in a dose-dependent pattern. Compound 1h induces apoptosis and necrosis in Hep-G2 cell line, as shown by caspase-3/7 and lactate dehydrogenase (LDH) release assays, respectively. Moreover, compound 1h is rather safe against hERG. Thus, we could achieve a more selective kinase inhibitor than sorafenib with retained or even better antiproliferative potency against HCC cell lines. Furthermore, molecular docking and dynamic simulation studies were carried out to investigate its binding mode with VEGFR2 kinase. The molecule has a unique orientation upon binding with the kinase.

Carbonic anhydrase inhibitors based on sorafenib scaffold: Design, synthesis, crystallographic investigation and effects on primary breast cancer cells.

Carbonic anhydrase inhibitors (CAIs) of the sulfonamide, sulfamate and coumarin classes bearing the phenylureido tail found in the clinically used drug Sorafenib, a multikinase inhibitor actually used for the management of hepatocellular carcinomas, are reported. All compounds were assayed on human (h) CA isoforms I, II, VII and IX, involved in various pathologies. Among the sulfonamides, several compounds were selective for inhibiting hCA IX, with KI values in the low nanomolar ranges (i.e. 0.7-30.2 nM). We explored the binding modes of such compounds by means of X-ray crystallographic studies on isoform hCA I in adduct with one sulfonamide and a sulfamate inhibitor. Antiproliferative properties of some sulfamates on breast tumor cell lines were also investigated.

Biosynthesis of sorafenib coated graphene nanosheets for the treatment of gastric cancer in patients in nursing care.

Sorafenib (SRF) is a well-known tyrosine kinase inhibiting anticancer drug which iseffectual against multiple carcinomas especially gastric cancers by targeting the Ras/Raf/Mek/Erk cascade pathway and blocking the tumor cell proliferation. In the present work, we have reduced graphene oxide (GO) in presence of sorafenib using ascorbic as green reducing agent for the treatment of gastric cancers. Sorafenib reduced graphene oxide (SRGO) were obtained with a transparent and smoothmorphology. The drug loaded SRGO has presented significant cytotoxic effect against SGC7901 cancer cells when compared to that of the free SRF and blank NPs in the equivalent concentrations. Additionally, from the Hoechst 33382 staining study it was evident that the cells in untreated groups remained intact with its round shape and intact nuclei while the SRGO treated cells have shown a cell transformation with apoptosis of gastric cancer cell lines. Based on these results, we can conclude that SRGO might extend an enormous prospective in the treatment of gastric cancers.

Design and discovery of thioether and nicotinamide containing sorafenib analogues as multikinase inhibitors targeting B-Raf, B-RafV600E and VEGFR-2.

New sorafenib derivatives containing thioether and nicotinamide moiety were designed and synthesized as B-Raf, B-RafV600E and VEGFR-2 multikinase inhibitors. Their in vitro enzymatic inhibitory activities against B-Raf, B-RafV600E and VEGFR-2 and their antiproliferative activities against HCT-116 and B16BL6 cell lines were evaluated and described. Most of the compounds showed potent activities against both cell lines and specific kinases. Compounds a1, b1 and c4, which exhibited the most potent inhibitory activities against B-Raf with IC50 of 21 nM, 27 nM and 17 nM, B-RafV600E with IC50 of 29 nM, 28 nM and 16 nM, VEGFR-2 with IC50 of 84 nM, 46 nM and 63 nM, respectively, and good antiproliferative activities, also demonstrated competitive antiangiogenic activities to sorafenib in in vitro HUVEC tube formation assay.

Design and Discovery of Quinazoline- and Thiourea-Containing Sorafenib Analogs as EGFR and VEGFR-2 Dual TK Inhibitors.

Both EGFR and VEGFR-2 play a critical role in tumor growth, angiogenesis and metastasis, and targeting EGFR and VEGFR-2 simultaneously represents a promising approach to cancer treatment. In this work, a series of novel quinazoline- and thiourea-containing sorafenib analogs (10a-v) were designed and synthesized as EGFR and VEGFR-2 dual TK inhibitors. Their in vitro enzymatic inhibitory activities against EGFR and VEGFR-2, and antiproliferative activities against HCT-116, MCF-7 and B16 cell lines were evaluated and described. Most of the compounds showed potent activities against both cell lines and TK kinases. Compounds 10b and 10q which exhibited the most potent inhibitory activities against EGFR (IC50 = 0.02 µM and 0.01 µM, respectively), VEGFR-2 (IC50 = 0.05 µM and 0.08 µM, respectively), and good antiproliferative activities, also displayed competitive anti-tumor activities than sorafenib in vivo by B16 melanoma xenograft model test.