Marwa G. El-Gazzar

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.

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

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). Sinteza, in vitro antitumorsko ispitivanje i radiosenzitirajuće vrednovanje novih derivata 4-[3-(supstituiranih)tioureido]-N-(kinoksalin-2-il)benzensulfonamida Derivati sulfonamida i kinoksalina imaju raznoliko biološko djelovanje, između ostalog i antitumorsko djelovanje. U radu je opisana sinteza novih derivata tioureido sulfakinoksalina. Svim novim spojevima ispitano je antitumorsko djelovanje in vitro na humanoj staničnoj liniji jetre (HEPG 2). Svi ispitani spojevi pokazuju jači učinak nego referentni lijek doksorubicin. Najjači učinak imali su 4-(3-(4-etilbenzoat)tioureido)-N-(kinoksalin-2-il)benzensulfonamid (9) (IC50 = 15,6 μmol L-1), N-(piridin-2-il)-4-(3-(4-(N-kinoksalin-2-il-sulfamoil)fenil)tioureido)-benzensulfonamid (10) (IC50 = 26,8 μmol L-1) i N-(kinoksalin-2-il)-4-(3-(4-(N-tiazol-2-ilsulfamoil)fenil)tioureido)benzensulfonamid (11) (IC50 = 24,4 μmol L-1), dok je IC50 vrijednost bila 71,8 μmol L-1. Najaktivniji spojevi 9, 10 i 11 evaluirani su kao radiosenzitirajuća sredstva nakon izlaganja spojeva γ-zračenju (8 kGy).

Synthesis of novel pyrazole and pyrimidine derivatives bearing sulfonamide moiety as antitumor and radiosensitizing agents

Several novel pyrazole 10–16 and pyrimidine 17–19 derivatives bearing Sulfonamide moieties were synthesized in order to study their antitumor activity. The synthesized compounds were characterized by elemental analysis, IR, 1H-NMR, and mass spectral data, then screened as antitumor agents against human tumor liver and breast cell lines (HEPG2 and MCF7). All the tested compounds were more potent than the reference drug doxorubicin on human liver (HEPG2) cell line, while on human breast cancer (MCF7) cell line, they were less potent than the reference drug. Additionally, some of the synthesized compounds were evaluated for their ability to enhance the cell killing effect of γ-radiation.

Design, Synthesis and Anticancer Evaluation of Novel Quinazoline-Sulfonamide Hybrids.

By combining the structural features of quinazoline and sulfonamides, novel hybrid compounds 2–21 were synthesized using a simple and convenient method. Evaluation of these compounds against different cell lines identified compounds 7 and 17 as most active anticancer agents as they showed effectiveness on the four tested cell lines. The anticancer screening results of the tested compounds provides an encouraging framework that could lead to the development of potent new anticancer agents.

Synthesis, Characterization and Anti-Breast Cancer Activity of New 4-Aminoantipyrine-Based Heterocycles

4-Aminoantipyrine was utilized as key intermediate for the synthesis of pyrazolone derivatives bearing biologically active moieties. The newly synthesized compounds were characterized by IR, 1H- and 13C-NMR spectral and microanalytical studies. The compounds were screened as anticancer agents against a human tumor breast cancer cell line MCF7, and the results showed that (Z)-4-((3-amino-5-imino-1-phenyl-1H-pyrazol-4(5H)-ylidene)methylamino)-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-one 5, 3-(4-bromophenyl) -1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile 13, 1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1-Hpyrazol- 4-yl)-3-(4-iodophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile 14, 3,3′-(4,4′-sulfonylbis(4,1-phenylene))bis(1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol- 4-yl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile) 16, (Z)-1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-hydrazono-4-oxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carbonitrile 17, (Z)-1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-4-oxo-3-phenyl-2-(2-phenylhydrazono)-1,2,3,4-tetrahydro pyrimidine-5-carbonitrile 18, and (Z)-4-(3-amino-6-hydrazono-7-phenyl-6,7-dihydro pyrazolo[3,4-d]pyrimidin-5-yl)-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-one 19 were the most active compounds with IC50 values ranging from 30.68 to 60.72 μM compared with Doxorubicin as positive control with the IC50 value 71.8 μM.

Synthesis and Anti-Breast Cancer Evaluation of Novel N-(Guanidinyl)benzenesulfonamides

A series of 4-(substituted)-N-(guanidinyl)benzenesulfonamides bearing biologically active pyrazole, pyrimidine and pyridine moieties were prepared and evaluated for their anticancer activity against human tumor breast cell line (MCF7). These sulfonamides showed promising activity with IC50 values ranging from 49.5 to 70.2 μM. The structure-activity relationship of the synthesized compounds was studied. Interestingly, it was found that the most potent compounds in this study were the corresponding 2-cyanoacrylate 3, 3-oxobutanoate 4, pyrazole 6, pyridine 9 and pyrazole 13. Compounds 7 and 8 are nearly as active as Doxorubicin as reference drug with (IC50 values = 70.2, 68.1 μM), while compounds 5, 10 and 11 exhibited a moderate activity.

Anticancer Activity of Novel Thiophenes Containing a Biological Active Diphenylsulfone, Diazepin, Piperidine, Oxazepine, Acryladehyde and Sulfonamide Moieties

A variety of thiophene derivatives bearing diphenylsulfone 3,4, diazepines 5b, 6b, phenylamino 7, piperidine 8, benzylpiperidine 9, oxazepines 10b, 11b, acrylaldehydes 12-14 and benzeonesulfanamide 15 were synthesized. some newly synthesized compounds were evaluated for their in vitro cytotoxic activity against human tumor breast cancer cell lines. The tested compounds showed moderate to good cytotoxic activity and indeed, some of them were more potent than doxorubicin as a reference drug.

Antiproliferative activity of novel thiophene and thienopyrimidine derivatives.

A novel series of newly synthesized thiophene derivatives, ethyl-4,5-dimethyl-2-(3-(3,4,5-trimethoxyphenyl)thioureido)thiophene-3-carboxylate 3, ethyl-2-[(2-(dimethylamino)ethoxy)mercapto)methyleneamino)]-4,5-dimethyl-thiophene-3-carboxylate 9, thienopyrimidines 4, 7, 10-20, triazolothienopyrimidines 5, 6 were prepared and tested for their antiproliferative activity. The structures of the synthesized compounds were confirmed on the basis of elemental analysis, IR, (1)H-NMR, (13)C-NMR and mass spectral data. The results showed that the synthesized compounds were more active on breast cancer than on colon cancer cell lines and the most potent compounds in this study are compounds 3 and 13 which exerted remarkable activity against MDA-MB-231 (breast cancer) and HT-29 (colon cancer) cell lines with IC50 values (40.68, 49.22 μM) for compound 3 and (34.04, 45.62 μM) for compound 13. Also, compounds 4-6, 9 showed a moderate activity against breast cancer cell line, while compounds 15, 19 and 20 showed no activity.

Synthesis, in-vitro anticancer screening and radiosensitizing evaluation of some new N-(quinoxalin-2-yl)benzenesulfonamide derivatives.

The objective of this work is to synthesize and investigate the anticancer activity of a new series of sulfaquinoxaline derivatives by incorporating biologically active moieties (thiourethane, thiazole, imidazole, imidazopyrimidine, imidazopyrimido-pyrimidine, thienopyrimidine, benzopyrimidinone, benzothiazole, thiazole and pyridine moieties). All the newly synthesized compounds were evaluated for their in-vitro anticancer activity against human liver cell line (HEPG2). All the tested compounds showed comparable activity to that of the reference drug 5-fluorouracil (IC50=40 µM), and the most potent compounds were found to be compounds 4 and 17 (IC50=4.29 and 11.27 µM, respectively). On the other hand, the most potent compounds 4 and 17 were evaluated as radiosensitizing agents.

Synthesis of novel thiadiazole derivatives as selective COX-2 inhibitors

A novel series of thiadiazole derivatives were designed and synthesized for evaluation as selective COX-2 inhibitors in vitro and were investigated in vivo as anti-inflammatory and analgesic agents against carrageenan-induced rat paw oedema model in irradiated rats, since it is well-known that ionizing radiation plays an important role in exaggerating the inflammatory responses in experimental animals. Ulcerogenic activity and acute toxicity were evaluated for the most potent compounds. In order to understand the binding mode of the synthesized compounds into the active site of the COX-2 enzyme, a docking study was performed. Most of the tested compounds showed high inhibitory ability against COX-2. Among them, thiadiazole derivatives bearing sulfonamide moieties, 7b, c and 13c, e, were the most potent COX-2 inhibitors, with extremely high selectivity indices (SI) compared to celecoxib; they showed high safety margins on gastric mucosa with no ulceration effects, and they were found to be non-toxic in experimental rats. The docking study showed a similar orientation of these compounds to that of celecoxib within the active site of the COX-2 enzyme, and a similar ability to immerge deeply into the additional pocket and bind with Arg513 and His90, the key amino acids responsible for selectivity.