Search

In the current study, a new series of benzenesulfonamides 6a-r was designed and synthesized as dual VEGFR-2 and FGFR1 kinase inhibitors with anti-cancer activity. The 4-trifluoromethyl benzenesulfonamide 6l exhibited the highest dual VEGFR-2/FGFR1 inhibitory activity with IC 50 values of 0.025 and 0.026 µM, respectively. It showed a higher activity than sorafenib and staurosporine by 1.8- and 1.3-fold, respectively. Furthermore, compound 6l was further tested on EGFR and PDGFR-β kinases showing IC 50 values of 0.106 and 0.077 µM, respectively. The target compounds were tested for their anticancer activity against NCI-60 panel of cancer cell lines at 10 µM concentration, where compound 6l displayed the highest mean growth inhibition percent % (GI%) of 60.38%. Compounds 6a, 6b, 6e, 6f, 6h-l, and 6n-r revealed promising GI% on breast cancer cell lines (MCF-7, T-47D, and MDA-MB-231), and were subjected to IC 50 determination on these cell lines. The tested compounds showed a higher activity on T-47D and MCF-7 cell lines over MDA-MB-231 cell line compared to the used reference standard; sorafenib. Compounds 6e, 6h-j, 6l and 6o revealed IC 50 values ≤ 20 µM against T-47D cell line, furthermore, they were found to be non-cytotoxic on Vero normal cell line. Furthermore, the effect of the most active compounds 6i, and 6l in T-47D cells on cell cycle analysis progression, cell apoptosis, and apoptosis markers was investigated. Both compounds arrested cell cycle progression at G1 phase, furthermore, they enhanced early and late apoptosis, as well as necrosis. The capability of compounds 6i, and 6l to induce apoptosis was further confirmed by their ability to raise BAX/BCl-2 ratio and caspase-3 level in the treated cells. Cell migration assay revealed that both compounds 6i and 6l have anti-migratory effects compared to control T-47D cells after 24, and 48 h. Molecular docking studies for compounds 6a-r on VEGFR-2 and FGFR1 binding sites showed that they exhibit an analogous binding mode in both target kinases which agrees with that of type II kinase inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In the current study, a novel series of diaryl urea incorporating oxindole moiety was rationally designed as type II BRAF inhibitors targeting BRAF and KRAS mutant cancers. Molecular hybridization between the diaryl urea scaffold which binds to the inactive conformation of protein kinases on one side and the oxindole core which exhibit adenine mimic properties to be settled in the hinge region on the other side was performed. Studying the antiproliferative activity of the synthesized candidates 9a-t on NCI cancer cell lines showed that they exhibit potent and broad spectrum of antiproliferative activity on the tested cancer cell lines with compounds 9c, 9p, 9q, 9s, and 9t demonstrating potent GI 50 reaching 0.01 µM. Noteworthy, compound 9s demonstrated a potent GI 50 on cell lines expressing mutant KRAS and those express BRAF V600E with GI 50 ranges of 1.79 and 7.94 µM and 1.68 to 2.0 µM, respectively. Further analysis on A375 and Mel501 cell lines expressing BRAF V600E revealed that compound 9s has a potent growth inhibitory activity with IC 50 of 0.7 and 1.5 µM, respectively, in reference to sorafenib (IC 50  = 8.7 and 0.3 µM, respectively). Additionally, nearly all the target candidates did not show any cytotoxic effect on the normal fibroblast cell line BJ-1 with compound 9s showing IC 50 of 20.2 µM in reference to sorafenib (IC 50  = 6.1 µM). Further cellular assays on A375 cell line, revealed the ability of compound 9s to halt the cell cycle progression at the G2 phase besides its ability to induce apoptosis. In parallel, all the synthesized candidates 9a-t were biochemically evaluated for their inhibitory activity on BRAF WT and compounds 9b, 9c, and 9n revealed a sub-micromolar IC 50 of 0.11, 0.84 and 0.80 µM, respectively. Further investigation of selected compounds on BRAF V600E showed that compounds 9c, 9n, 9s, and 9t exhibit a sub-micromolar IC 50 range of 0.17 to 0.89 µM. Noteworthy, the examined candidates demonstrated a higher selectively towards BRAF V600E over BRAF WT highlighting their promising optimization for treating BRAF V600E expressing cancers. Molecular docking and molecular dynamics simulations in the inactive DFG-out kinase domain of BRAF WT / V600E protein kinases confirmed the planned design strategy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In the current study, series of 2-arylbenzimidazole-thiopyrimidine and -thioquinazolin-4(3H)-ones conjugates 12a-d, 13a,b and 14a-l have been synthesized. All the synthesized compounds were tested in vitro for their anticancer activities against a panel of cancer cell lines at NCI - US and their growth inhibition (GI) % were determined at 10 µM. Compounds 14c and 14g-i were selected to be screened at the five dose assay and were found to exhibit GI 50 values 1.1-30.0 µM. The benzimidazole-quinazolinone derivative 14c, in particular, showed potent anticancer activity against the tested cancer cell lines (GI 50 of 1.3-4.2 µM). In addition, compounds 12a,b, 13a, 14a-e, 14g, 14i and 14j were selected to be tested against some cancer cell lines using MTT assay and the benzimidazole-quinazolinone 14g was found to have potent anticancer activities against melanoma (Mel-501 and A-375), breast (MCF-7), colon (HCT-116), prostate (PC-3), lung (A-549) and pancreas (Paca-2) cancer cell lines reporting IC 50 values ranging between 0.1 and 6.2 µM. Moreover, the synthesized hybrids were tested in vitro on kinases; BRAF (wt), BRAF (V600E), CRAF and VEGFR-2. The benzimidazole-quinazolinone derivatives 14f,g revealed potent RAF kinases inhibitory activities on BRAF (wt), BRAF (V600E) and CRAF showing IC 50 values 0.002-0.1 µM, whereas, the benzimidazole-quinazolinone derivatives 14i and 14k showed moderate VEGFR-2 inhibitory activity (IC 50  = 20.60 and 6.14 µM, respectively). Moreover, the representative compounds 14g and 14i caused cell cycle arrest of A-375 melanoma cell line at G2/M phase and were found to induce late apoptosis. CRAF in the DFG-out inactive conformation homology modeling was first reported in this study and molecular docking studies on BRAF, CRAF and VEGFR-2 were also performed to investigate the binding modes of the target compounds and their interactions with the key amino acids; BRAF (Glu500, Cys531 and Asp593), CRAF (Glu393, Cys424 and Asp486) and VEGFR-2 (Glu885, Cys919 and Asp1046)., (Copyright © 2022 Elsevier Inc. All rights reserved.)