Design, synthesis and molecular modeling study of certain 4-Methylbenzenesulfonamides with CDK2 inhibitory activity as anticancer and radio-sensitizing agents.

Two series of 2-aminopyridine derivatives 6-17 and tyrphostin AG17 analogs 18-22 bearing 4-methylbenzenesulfonamide moiety were designed and synthesized as anticancer compounds. The synthesized compounds were biologically evaluated for their cytotoxic activity against human breast cancer cell line MCF-7. From 2-aminopyridine and tyrphostin AG17 series, compounds 14, 16 and 20 showed the best activities with IC50 values of 20.4, 18.3 and 26.3 µM, respectively compared to E7070 IC50 36.3 µM. Further biological evaluation of 14, 16 and 20 against cyclin dependent kinase-2 (CDK2) revealed good inhibitory activity with IC50 of 2.53, 1.79 and 2.92 µM, respectively compared to roscovitine IC50 0.43 µM. Additionally, capability of γ-radiation to augment the cytotoxic activity of 14, 16 and 20 was studied and showed a dramatic increase in the cell killing effect at lower concentrations after irradiation. Docking was used to investigate the possible binding modes of compounds 14, 16 and 20 inside the active site of CDK2 enzyme.

Novel thioureido-benzenesulfonamide derivatives with enaminone linker as potent anticancer, radiosensitizers and VEGFR2 inhibitors.

In this study, novel series of thioureido-benzenesulfonamide derivatives bearing an enaminone linker either meta or para oriented and having terminal linear or substituted aromatic or heteroaromatic ring system 5-16a,b were designed and synthesized based on the general pharmacophoric features of type II VEGFR2 inhibitors. Evaluation of the synthesized compounds against HEPG2 hepatocellular carcinoma cells in vitro identified compounds 5b, 6b and 10-13b as most active anticancer agents with IC50 equal to 0.12, 0.29, 0.58, 0.44, 0.42 and 0.66 µM, respectively. These compounds were evaluated for their ability to in vitro inhibit VEGFR2 kinase enzyme. The results demonstrated highly potent dose-related VEGFR2 inhibition with IC50 values in nanomolar range (33, 57, 210, 37, 37 and 220 nM, respectively). The radiosensitizing ability of the most promising compounds was studied which showed an increase in the cell killing effect of radiation after combination with the synthesized compounds which revealed lowered IC50 by nearly 50%. Molecular docking for the most potent compounds was performed to predict their possible binding mode within VEGFR2 active site and they showed binding affinity in a similar way to sorafenib.

Design and synthesis of some novel 4-Chloro-N-(4-(1-(2-(2-cyanoacetyl)hydrazono)ethyl)phenyl) benzenesulfonamide derivatives as anticancer and radiosensitizing agents.

A novel series of sulfonamide derivatives 4-21 have been synthesized starting from the strategic starting material (E)-4-Chloro-N-(4-(1-(2-(2-cyanoacetyl)hydrazono)ethyl)phenyl) benzenesulfonamide 4. Two series of hydrazone 5-9, and pyridone 10-21 derivatives bearing a sulfonamide moiety were obtained. All the newly synthesized compounds were evaluated for their in vitro cytotoxic activity against human liver cancer cell line (HepG2). Compounds 4-6, 8, 9, 10-14 and 16-18 showed higher activity compared to doxorubicin as a positive control. The radiosensitizing ability of the most promising compounds 4, 10 and 12 was studied which showed an increase in the cell killing effect of γ-radiation after combination with these derivatives. The molecular design was performed to predict the binding mode of the most promising compounds 4, 10 and 12 with the active site of hCA IX, that showed appropriate fitting with the relevant amino acids in the binding pocket on the basis of standard bond lengths, angles, S score and E conformation data.

Synthesis, anticancer and radiosensitizing evaluation of some novel sulfonamide derivatives.

In this study, novel series of sulfonamide derivatives were synthesized starting from 2-cyanoacetyl)hydrazono)ethyl)phenyl)benzenesulfonamide 4a and 2-cyanoacetyl)hydrazono)ethyl)phenyl)-4-methylbenzenesulfonamide 4b. Different biologically active moieties as pyrazol, thiophene, pyridine and pyrimidines were introduced in order to investigate their in-vitro anticancer activity, in addition to a novel series of sulfonamide chalcones were synthesized from the reported 4-acetyl-N-(P-tolyl) benzenesulfonamide 3b. The newly synthesized sulfonamide derivatives were characterized by FT-IR, (1)H NMR, (13)C NMR, mass spectroscopy and elemental analyses and were tested for their in-vitro anticancer activity against human tumor liver cell line (HEPG-2). The most potent compounds in this study were compounds 4a, 4b, 5a, 6a, 6b, 8, 9, 11, 13, 18 and 19 which showed higher activity than doxorubicin with IC50 ranging from 11.0 to 31.8 µM. Additionally, eight compounds among the most potent were evaluated for their ability to enhance the cell killing effect of γ-radiation.

Anticancer and radiosensitizing evaluation of some new pyranothiazole-Schiff bases bearing the biologically active sulfonamide moiety.

The present work reports the synthesis of some new Schiff bases, 5-(substituted benzylideneamino)-6-cyano-7H-7-(4-methoxyphenyl)-2-(4-sulphamoylphenylamino) pyrano[2,3-d]thiazole (5-15). The design of the structures of these compounds complies with the general pharmacophoric requirements for CA inhibiting anticancer drugs. The newly synthesized compounds were evaluated for their in vitro anticancer activity against human breast cancer cell line (MCF7). Most of the screened compounds showed interesting cytotoxic activities compared to doxorubicin as a reference drug. Compounds 4, 6-8 and 11 (IC(50): 27.51, 10.25, 9.55, 9.39 and 9.70 µM, respectively) exhibited higher cytotoxic activities than the reference drug doxorubicin (IC(50): 32.00 µM). Additionally, the previously mentioned compounds were evaluated again for their ability to enhance the cell killing effect of γ-radiation.

Novel 4-(4-substituted-thiazol-2-ylamino)-N-(pyridin-2-yl)-benzenesulfonamides as cytotoxic and radiosensitizing agents.

A series of novel 4-(4-substituted-thiazol-2-ylamino)-N-(pyridin-2-yl) benzene-sulfonamides were synthesized and screened for their cytotoxic activity against human breast cancer cell line (MCF-7). Compounds 6, 7, 9, 10, 11, and 14 displayed significant activity against MCF-7 when compared to doxorubicin, which was used as a reference drug. The synergistic effect of Gamma radiation for the most active derivatives 7, 9, and 11 was also studied and their IC(50) values markedly decreased to 11.9 µM, 11.7 µM, and 11.6 µM, respectively.

Synthesis, in vitro anticancer screening and radiosensitizing evaluation of some new 4-[3-(substituted)thioureido]-N-(quinoxalin-2-yl)-benzenesulfonamide derivatives.

Sulfonamides and quinoxaline derivatives possess many types of biological activities and have been recently reported to show substantial antitumor activity. This paper reports the synthesis of novel thioureido sulfaquinoxaline derivatives. All the newly synthesized compounds were evaluated for their in vitro anticancer activity against a human liver cell line (HEPG2) and showed higher activity than the reference drug doxorubicin. 4-(3-(4-Ethylbenzoate) thioureido)-N-(quinoxalin-2-yl)benzenesulfonamide (9) (IC50 = 15.6 µmol L⁻¹), N-(pyridin-2-yl)-4-(3-(4-(N-quinoxalin-2-yl-sulfamoyl)phenyl)thioureido)benzenesulfonamide (10) (IC50 = 26.8 µmol L⁻¹) and N-(quinoxalin-2-yl)-4-(3-(4-(N-thiazol-2-ylsulfamoyl)phenyl)thioureido)benzenesulfonamide (11) (IC50 = 24.4 µmol L⁻¹) were the most potent compared to doxorubicin (IC50 = 71.8 µmol L⁻¹). The most potent compounds 9, 10 and 11 were evaluated as radiosensitizing agents by subjecting the compounds to γ-irradiation (8 kGy).

Anticancer and radio-sensitizing evaluation of some new thiazolopyrane and thiazolopyranopyrimidine derivatives bearing a sulfonamide moiety.

Recently, it has been reported that compounds bearing a sulfonamide moiety posses many types of biological activities, including anticancer activity. There are a variety of mechanisms for their anticancer activity, and the most prominent mechanism is the inhibition of carbonic anhydrase (CA) isozymes. The present work reports the synthesis of some new thiazolo[4,5-b]pyrane, thiazolo[4,5-b]pyrano[2,3-d]pyrimidine derivatives bearing a sulfonamide moiety. The design of the structures of these compounds complies with the general pharmacophoric requirements for CA inhibiting anticancer drugs. The newly synthesized compounds were evaluated for their in vitro anticancer activity against human breast cancer cell line (MCF7). Most of the screened compounds showed interesting cytotoxic activities compared to doxorubicin as a reference drug. Compounds 5, 6, 10 and 12 (IC(50) values 39.4 µM, 41.6 µM, 35.72 µM and 34.64 µM, respectively) exhibited higher cytotoxic activities than the reference drug doxorubicin (IC(50) = 71.8 µM). Additionally, the previously mentioned compounds were evaluated again for their ability to enhance the cell killing effect of γ-radiation.

Synthesis of novel pyrrole and pyrrolo[2,3-d]pyrimidine derivatives bearing sulfonamide moiety for evaluation as anticancer and radiosensitizing agents.

Pyrroles and pyrrolo[2,3-d]pyrimidines were reported to act as potent anticancer agents, in this work, a series of novel 2-substituted-3-cyano-4-phenyl-pyrrole 5, 6, 11-18, and 5-phenyl-pyrrolo[2,3-d]pyrimidine derivatives 7-10, 19-24 bearing either sulfathiazole or sulfapyridine were synthesized. The structures of these compounds were confirmed by elemental analysis, IR, (1)H NMR and mass spectral data. All the newly synthesized compounds were evaluated for their in vitro cytotoxicity against liver and breast cancer cell line (HEPG2 and MCF7). Most of the screened compounds showed interesting cytotoxic activities compared with the used reference drug (doxorubicin). The radiosensitizing ability of some of the synthesized compounds was studied and the results showed an increase in the cell killing effect of γ-radiation after combination with the tested compounds.

In vitro anticancer screening and radiosensitizing evaluation of some new quinolines and pyrimido[4,5-b]quinolines bearing a sulfonamide moiety.

Sulfonamide bearing compounds possess many types of biological activities and have recently been reported to show substantial antitumor activity in vitro and/or in vivo. There are a variety of mechanisms for the anticancer activity, and the most prominent mechanism is the inhibition of carbonic anhydrase (CA) isozymes. The present work reports the synthesis of twenty novel quinoline and pyrimido[4,5-b]quinoline derivatives bearing a sulfonamide moiety. The new synthesized compounds were designed in compliance with the general pharmacophoric requirements for CA inhibiting anticancer drugs, as this may play a role in their anticancer activity. All the newly synthesized compounds were evaluated for their in vitro anticancer activity against human breast cancer cell line (MCF7). Compounds 6, 9 and 18 showed IC(50) values (72.9 microM, 72.1 microM and 71.9 microM, respectively) comparable to that of the reference drug doxorubicin (IC(50) = 71.8 microM). On the other hand, compound 8 exhibited better activity than doxorubicin with an IC(50) value of 64.5 microM. Additionally, the most potent compounds 8 and 18 were evaluated for their ability to enhance the cell killing effect of gamma-radiation.

Novel thiophenes, thienopyrimidines, and triazolothienopyrimidines for the evaluation of anticancer and augmentation effects of gamma-radiation.

New derivatives of thiophenes 2, 12, iminoaminothieno[2,3-d]pyrimidines 3, 5, and 6, triazolothieno[2,3-d]pyrimidines 8-11, pyrazolo- and triazinothieno[2,3-d]pyrimidines 4, 7, respectively, have been prepared by different synthetic procedures. Structure elucidation of the newly synthesized compounds was carried out via elemental analyses and spectral data. The antitumor activity of compounds 2, 3, and 9-12 was evaluated against in-vitro cell lines (HEPG-2 and MCF-7). Compounds 2, 3, 10, 11, and 12 showed significant in-vitro cytotoxic activity against hepatocellular carcinoma (HEPG-2) compared to the reference drug Doxorubicin. Compound 2 showed significant in-vitro cytotoxic activity against breast cancer (MCF-7) cells compared to the reference drug Doxorubicin. The augmenting effect of gamma-radiation was assessed; here, compounds 2, 3, 10, and 11 showed the most potent in-vitro anticancer activity.

Synthesis of some new pyrazole and pyrimidine derivatives carrying a sulfonamide moiety of expected antitumor activity and study of the synergistic effect of gamma-irradiation.

Several novel pyrazole (11-18) and pyrimidine (19-23) derivatives were synthesized starting from different sulfonamides and different active methylenes. The synthesized compounds were characterized by elemental analysis, IR, 1H-NMR and mass spectral data. The obtained compounds were screened as antitumor agents against human tumor cell line. Some of the tested compounds were equipotent while the others were more potent than doxorubicin (CAS 25316-40-9). The synergistic effect with gamma-radiation was also studied.

Synthesis, anticancer and radioprotective activities of some new pyrazolo[3,4-d]pyrimidines containing amino acid moieties.

Various isomeric structural purine analogues possessing the pyrazolo[3,4-d]pyrimidine nucleus bearing amino acid moieties have been synthesized. The structures of the synthesized compounds were elucidated by spectral data. Preliminary testing for in vitro anticancer activity of the synthesized compounds against Ehrlich ascites carcinoma cells was carried out. 2-(1-Phenyl-1H-pyrazolo [3,4-d]pyrimidin-4-ylamino)-propanoic acid (3 d), 4-methyl-2-(1-phenyl-1H-pyrazolo [3,4-d] pyrimidin-4-ylamino)-pentanoic acid (3 d), 4-methylthlo-2-(1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-butanoic acid (3e) and phenyl-2-(1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)propanoic acid (3f) were the most active compounds. Moreover, compounds 3e and 1-(1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-pyrrolidine-2-carboxylic acid (4) exhibited significant in vivo radioprotective activity.

Utility of 4-(5,5-dimethyl-3-oxo-cyclohex-1-enylamino)benzenesulfonamide in the synthesis of novel quinolines as possible anticancer and radioprotective agents.

The present work reports the possible utility of 4-(5,5-dimethyl-3-oxo-cyclohex-1-enylamino)benzenesulfonamide in the synthesis of some novel 4-(quinolin-1-yl) benzenesulfonamide derivatives (6a-o). Structures of the newly synthesized compounds were confirmed by elemental analyses and spectral data. All the newly synthesized compounds were evaluated for their in vitro anticancer activity. Compounds 6k, 6j and 6m showed interesting cytotoxic activity compared with doxorubicin (CAS 23214-922-8) as a reference drug. Additionally, compound 6c exhibited in vivo radioprotective activity, against gamma-irradiation, in mice.

Molecular modeling study and synthesis of novel pyrrolo[2,3-d]pyrimidines and pyrrolotriazolopyrimidines of expected antitumor and radioprotective activities.

Novel pyrrolo[2,3-d]pyrimidine derivatives 4a-e, 10, 14, 15, pyrazolopyrrolopyrimidine 13, pyrrolotriazolopyrimidine 5-9, 17 and pyrrolopyrimidotriazine 18 are reported herein. The design of these compounds was based upon the molecular modeling simulation of the fitting values and conformational energy values of the best-fitted conformers to VEGFRTK inhibitor hypothesis. This hypothesis was generated from its corresponding lead compounds using CATALYST software. The structures of these compounds were confirmed by microanalyses, IR, (1)H NMR, and mass spectral data. Compounds 6 and 15 showed interesting in vitro antitumor activity compared to doxorubicin as positive control. These results are nearly consistent with the molecular modeling studies. Docking studies were made on compound 15 to predict its binding mode. Moreover, compound 10 exhibited a significant radioprotective activity.

Synthesis of some novel quinolines and pyrimido [4,5-b] quinolines bearing A sulfonamide moiety as potential anticancer and radioprotective agents.

Some novel 4-(quinolin-1-yl)-benzenesulfonamide and 4-(pyrimido[4,5-b]quinolin-10-yl)-benzenesulfonamide derivatives have been synthesized. All the newly synthesized target compounds were subjected to in vitro cytotoxic screening to be evaluated for their anticancer activity against Ehrlich ascites carcinoma cells. Among these new compounds, compounds 9a, 11, 12b, 18 and, in particular, 19 showed promising in vitro cytotoxic activity compared with doxorubicin (CAS 23214-92-8) as a reference drug. Moreover, compound 8 exhibited in vivo radioprotective activity against gamma-irradiation in mice.

Synthesis of some novel sulfur containing triazolothienopyrimidines and biscompounds as possible antitumor and radioprotective agents.

The syntheses of novel 1,2,4-triazolothienopyrimidine derivatives (4a,b), thiourea derivatives (5-8) and biscompounds having a thieno[2,3-d]pyrimidine nucleus (13-16) utilizing the 2-isothiocyanato derivatives 2a,b are reported. The structures of these compounds were confirmed by microanalysis, IR, 1H-NMR and mass spectrometry. Preliminary biological studies of some synthesized compounds showed promising antitumor and radioprotective activities.

Synthesis of certain new thiieno [2,3-d] pyrimidines as potential antitumor and radioprotective agents.

During research on anticancer and radioprotective heterocyclic compounds containing thiophene ring 5-10, 15, 19, thieno[2,3-d]pyrimidines 11-14 and biscompound having thieno[2,3-d]pyrimidine 18 were synthesized. The synthesized compounds were characterized by elemental ananlysis, IR, 1H-NMR and mass spectral data. Some of the obtained compounds showed interesting antitumor and radioprotective activities.

Novel antitumor and radioprotective sulfonamides containing pyrrolo [2,3-d]pyrimidines.

Several sulfonamides having pyrrole (5a-c, 8, 11b-19, 23, 24), pyrrolo[2,3-d] pyrimidine (6, 7, 10, 20, 21, 25) and pyrrolo[2,3-b]pyridine (22) were synthesized and evaluated for their antitumor and radioprotective activities. The structure of the synthesized compounds was elucidated by elemental analyses and spectral data. Compounds 5a, 16, 17, 19, and 23 displayed more potent antitumor activities than the reference drug, doxorubicin. On the other hand compounds 19, 23 and 25 exhibited radioprotective activities.

Novel synthesis of pyrrolo [2,3-d] pyrimidines bearing sulfonamide moieties as potential antitumor and radioprotective agents.

A novel series of pyrrolo[2,3-d] pyrimidines bearing sulfonamide moieties have been synthesized and tested for their antitumor activity. Among them, compounds 4, 8b, Bd, 8g and 14 showed promising antitumor activity. Moreover, compound 8d exhibited radioprotective activity. The structures of the newly synthesized compounds were established by their elemental analyses and spectral data.