Aiten M. Soliman

Synthesis of some new thiazolopyrane and thiazolopyranopyrimidine derivatives bearing a sulfonamide moiety for evaluation as anticancer and radiosensitizing agents

A new series of thiazolopyrane 5a–d, 11–13 and thiazolopyranopyrimidine 6–10, 7b, 8b, and 14 derivatives bearing a sulfonamide moiety were designed and synthesized. The molecular design was performed using molecular operating environment software to predict the binding mode of the proposed compounds on hCAII. All the newly synthesized compounds were evaluated for their in vitro anticancer activity against human liver cancer cell line in which hCAII is overexpressed. Compounds 8b and 14 showed higher activities compared with doxorubicin as a positive control. The radiosensitizing ability of the promising compounds 3, 7a, 8b, 12, and 14 was studied which showed an increase in the cell killing effect of γ-radiation after combination with them.

Novel Thiourea Derivatives Bearing Sulfonamide Moiety as Anticancer Agents Through COX-2 Inhibition

BACKGROUND Thiourea derivatives bearing sulfonamide moiety are well known for their anticancer activity. OBJECTIVE The anticancer activity of the target compounds was studied, via inhibition of COX-2 enzyme. METHOD A series of novel thioureas 5a-n, 8, quinazoline 6, benzo[g]quinazoline 7 and benzo[1,3] dioxole 10, bearing a sulfonamide moiety was synthesized from the starting compound N-(2,6-dimethoxypyrimidin-4-yl)-4- isothiocyanatobenzenesulfonamide 2. The target compounds were screened against HepG2, MCF-7, Caco-2, HCT-116, PC-3 cancer cell lines and VERO-B normal cell line. RESULTS Out of all the tested compounds, compound 5c showed a broad selective cytotoxicity against HepG2, MCF-7, Caco-2 and PC-3 cancer cells. Moreover, a sensitization assay was performed on Caco-2 cells, and compound 5c proved to act as a chemosensitizer for cisplatin on colon cancer (Caco-2) cells. The target compounds were further screened in vitro for their anti COX1/COX2 activity and investigated in vivo as antiinflammatory agents against carrageenan-induced rat paw oedema model. CONCLUSION Compound 5g showed the most selective inhibitory activity against COX-2. While, compounds 5a, 6, 5m, 5n, 5g and 5i revealed significant anti-inflammatory effect as presented in carrageenan-induced oedema assay. Molecular docking of the tested compounds disclosed important binding modes which may be responsible for their anticancer activity via inhibition of the COX-2 enzyme.

VEGFR-2 inhibitors and apoptosis inducers: synthesis and molecular design of new benzo[g]quinazolin bearing benzenesulfonamide moiety

Abstract Two series of novel 4-(2-(2-(2-(substituted) hydrazinyl)-2-oxoethylthio)-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 5–17 and 4-(2-(2-(substituted-1H-pyrazol-1-yl)-2-oxoethylthio)-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 18–24 were synthesised from the starting material 4-(2-(2-hydrazinyl-2-oxoethylthio)-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 5, to be evaluated for their inhibitory activity towards VEGFR-2. The target compounds 5–24, were screened for their cytotoxic activity against MCF-7 breast cancer cell line and the percentage inhibition against VEGFR-2. Compounds 9, 20, 22 and 23, showed excellent VEGFR-2 inhibitory activity with IC50 ranging from 0.64 to 1.04 µm. Being the most potent, compound 9 was evaluated for its apoptotic inducer effect by studying the effect on caspase-3, it was found to increase its level. Compound 9 boosted the level of Bax and reduced the level of BCl2, compared to the control. Cell cycle analysis was conducted, compound 9 showed cell cycle arrest at G2/M phase. Moreover, mild cytotoxic effect (IC50 = 29.41 µm, respectively) in normal breast cells MCF-12 A, was observed when treated with the same compound. Finally, a molecular docking study was performed to investigate the possible binding interaction inside the active site of the VEGFR-2 enzyme. Graphical Abstract

Benzo[g]quinazolin-based scaffold derivatives as dual EGFR/HER2 inhibitors

Abstract Targeting EGFR has proven to be beneficial in the treatment of several types of solid tumours. So, a series of novel 2-(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydrobenzo[g]quinazolin-2-ylthio)-N-substituted acetamide 5–19 were synthesised from the starting material 4-(2-mercapto-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 4, to be evaluated as dual EGFR/HER2 inhibitors. The target compounds 5–19, were screened for their cytotoxic activity against A549 lung cancer cell line. The percentage inhibition of EGFR enzyme was measured and compared with erlotinib as the reference drug. Compounds 6, 8, 10, and 16 showed excellent EGFR inhibitory activity and were further selected for screening as dual EGFR/HER2 inhibitors. The four selected compounds showed IC50 ranging from 0.009 to 0.026 µM for EGFR and 0.021 to 0.069 µM for the HER2 enzyme. Compound 8 was found to be the most potent in this study with IC50 0.009 and 0.021 µM for EGFR and HER2, respectively. Graphical Abstract

Anticancer and radio-sensitizing evaluation of some new sulfonamide derivatives bearing pyridone, thiophene, and hydrazone moieties

A series of new pyridone 5, 6, 8a–j, hydrazone 7a–j, and thiophene 9–12 derivatives bearing a sulfonamide moiety were synthesized from the starting material 4-chloro-N-(4-(1-(2-(2-cyanoacetyl)hydrazono)ethyl)phenyl) benzenesulfonamide 4. The target compounds were in vitro evaluated for their cytotoxic activity against a human liver cancer cell line (HepG2). Compounds 4 and 8d–j showed higher cytotoxic activity compared to doxorubicin, as a positive control. The radio-sensitizing ability of the promising compounds 4, 8d, and 8h was studied which showed an enhanced cytotoxic activity after combination with γ-radiation. Molecular modeling was performed in CA II/IX mimic active site to predict the binding possibility of the target compounds. All the synthesized compounds showed appropriate fitting with the amino acids in the binding pocket on the basis of their S score data and binding interactions. This binding possibility might contribute at least in part, to their anticancer activity.Graphical AbstractA novel series of sulfonamide derivatives bearing a biologically active pyridone, thiophene, and hydrazone moieties was synthesized and screened for their cytotoxic activity against HepG2 cell line. The most potent compounds in this study 4, 8d, and 8h were evaluated for their radio-sensitizing activity.

Dual EGFR/HER2 inhibitors and apoptosis inducers: New benzo[g]quinazoline derivatives bearing benzenesulfonamide as anticancer and radiosensitizers

Dual targeting of EGFR and HER2 is a proven anticancer strategy for the treatment of solid tumors. An array of new N-substituted-2-(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydrobenzo[g]quinazolin-2-ylthio) acetamides 5-18 were designed and synthesized from the starting compound 4-(2-mercapto-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 4. The targeted compounds were screened for their cytotoxic activity against MDA-MB-231 breast cancer cell line. The IC50 of all the compounds were in the range of 0.36-40.90 µM. The percentage inhibition towards EGFR was measured and found to be in the range of 63.00-16.90 %. The most potent compounds 5, 9, 15, 17 and 18 were further screened for their activity against both EGFR and HER2 receptors. The compounds showed IC50 in the range of 0.64-1.81 µM for EGFR and 1.13-2.21 µM for HER2, in comparison to erlotinib, the reference drug. Compound 17, the most potent towards EGFR in this series, undergoes cell cycle analysis and was found to arrest the cycle at the G2/M phase. Measurement of the cytotoxicity of compound 17 against normal breast cell line showed mild cytotoxic activity. The most potent compounds were subjected to a single dose of 8 Gy of γ-radiation and the cytotoxicity of the tested compounds was found to increase after irradiation, thus proving the synergistic effect of γ-irradiation. Molecular docking was adopted for all the synthesized compounds to confirm their mechanism of action.