- New benzenesulfonamide scaffold-based cytotoxic agents: Design, synthesis, cell viability, apoptotic activity and radioactive tracing studies
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A new series of thiazolidinone (5a-g), thiazinone (9a-g) and dithiazepinone (9a-g) heterocycles bearing a benzenesulfonamide scaffold was synthesized. Cytotoxicity of these derivatives was assessed against MCF-7, HepG2, HCT-116 and A549 cancer cell lines and activity was compared to the known cytotoxic agents doxorubicin and 5-FU where the most active compounds displayed better to nearly similar IC50 values to the reference compounds. For assessing selectivity, the most active derivatives against MCF-7, 5b, 5c and 5e, were also assessed against the normal breast cell line MCF-10 A where they demonstrated high selective cytotoxicity to cancerous cells over that to normal cells. Further, the effect of the most active compounds 5b-e on MCF-7 and HepG2 cell cycle phase distribution was assessed and the tested sulfonamide derivatives were found to induce accumulation of cells in the 2n phase. To further confirm apoptosis induction, caspase 8 and 9 levels in MCF-7 and HepG2 were evaluated before and after treatment with compounds 5b-e and were found to be significantly higher after exposure to the test agents. Since 5c was the most active, its effect on the cell cycle regulation was confirmed where it showed inhibition of the CDK2/cyclin E1. Finally, in vivo biodistribution study using radioiodinated-5c revealed a significant uptake and targeting ability into solid tumor in a xenograft mouse model.
- Ahmed, Wafaa A.,Arafa, Reem K.,Ibrahim, Dina M.,Maher, Ahmed,Mohamed, Khaled O.,Motaleb, Mohamed A.,Nissan, Yassin M.,Sakr, Tamer M.,Sharaky, Marwa M.
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- Design, synthesis and biological evaluation of some novel sulfonamide derivatives as apoptosis inducers
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Several novel thiazolidinone and fused thiazolidinone derivatives bearing benzenesulfonamide moiety were synthesized and confirmed via spectral and elemental analyses. The newly synthesized compounds were evaluated for their cytotoxic activity on colorect
- Mohamed, Khaled O.,Nissan, Yassin M.,El-Malah, Afaf A.,Ahmed, Wafaa A.,Ibrahim, Dina M.,Sakr, Tamer M.,Motaleb, Mohamed A.
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- Design, synthesis, and molecular docking of novel indole scaffold-based VEGFR-2 inhibitors as targeted anticancer agents
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A series of new indole derivatives 1–18 was synthesized and tested for their cytotoxic activity on a panel of 60 tumor cell lines. Additionally, molecular docking was carried out to study their binding pattern and binding affinity in the VEGFR-2 active site using sorafenib as a reference VEGFR-2 inhibitor. Based on the molecular docking results, compounds 5a, 5b, 6, 7, 14b, 18b, and 18c were selected to be evaluated for their VEGFR-2 inhibitory activity. Compound 18b exhibited a broad-spectrum antiproliferative activity on 47 cell lines, with GI % ranging from 31 to 82.5%. Moreover, compound 18b was the most potent VEGFR-2 inhibitor with an IC50 value of 0.07 μM, which is more potent than that of sorafenib (0.09 μM). A molecular docking study attributed the promising activity of this series to their hydrophobic interaction with the VEGFR-2 binding site hydrophobic side chains and their hydrogen bonding interaction with the key amino acids Glu885 and/or Asp1046.
- Roaiah, Hanaa M.,Ghannam, Iman A. Y.,Ali, Islam H.,El Kerdawy, Ahmed M.,Ali, Mamdouh M.,Abbas, Safinaz E-S.,El-Nakkady, Sally S.
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- Inhibition studies on a panel of human carbonic anhydrases with N1-substituted secondary sulfonamides incorporating thiazolinone or imidazolone-indole tails
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Being the primary sulfonamide among the most efficient zinc binding group (ZBG) to design inhibitors for the metallo-enzymes carbonic anhydrases (CA, EC 4.2.1.1), herein, we propose an investigation on four physiologically important human (h) CAs (hCA I, II, IV, and IX) with N1-substituted secondary sulfonamides incorporating thiazolinone or imidazolone-indole tails. The effect of the functionalisation of the sulfonamide group with five different substitution patterns, namely acetyl, pyridine, thiazole, pyrimidine, and carbamimidoyl, was evaluated in relation to the inhibition profile of the corresponding primary sulfonamide analogues. With most of these latter being nanomolar inhibitors of all four considered isoforms, a totally counterproductive effect on the inhibition potency can be ascribed to N1-functionalisations of the ZBG primary sulfonamide structure with pyridine, thiazole, and pyrimidine moieties. On the other hand, incorporation of less hindered groups, such as sulfonylacetamides and sulfonylguanidines, maintained a certain degree of activity dependent on the tailing moiety, with KIs spanning in the low micromolar range.
- Awadallah, Fadi M.,Bua, Silvia,Mahmoud, Walaa R.,Nada, Hossam H.,Nocentini, Alessio,Supuran, Claudiu T.
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p. 629 - 638
(2018/03/26)
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- Synthesis of 4-(thiazol-2-ylamino)-benzenesulfonamides with carbonic anhydrase I, II and IX inhibitory activity and cytotoxic effects against breast cancer cell lines
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A series of 4-(thiazol-2-ylamino)-benzenesulfonamides was synthesized and screened for their carbonic anhydrase (CA, EC 4.2.1.1) inhibitory and cytotoxic activity on human breast cancer cell line MCF-7. Human (h) CA isoforms I, II and IX were included in the study. The new sulfonamides showed excellent inhibition of all three isoforms, with KIs in the range of 0.84-702 nM against hCA I, of 0.41-288 nM against hCA II and of 5.6-29.2 against the tumor-associated hCA IX, a validated anti-tumor target, with a sulfonamide (SLC-0111) in Phase I clinical trials for the treatment of hypoxic, metastatic solid tumors overexpressing CA IX. The new compounds showed micromolar inhibition of growth efficacy against breast cancer MCF-7 cell lines.
- Abdel Gawad, Nagwa M.,Amin, Noha H.,Elsaadi, Mohammed T.,Mohamed, Fatma M.M.,Angeli, Andrea,De Luca, Viviana,Capasso, Clemente,Supuran, Claudiu T.
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p. 3043 - 3051
(2016/06/13)
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- Synthesis, carbonic anhydrase inhibition and cytotoxic activity of novel chromone-based sulfonamide derivatives
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Four series of sulfonamides incorporating chromone moieties were synthesized and assessed for their cytotoxic activity against MCF-7 and A-549 cell lines, considering the fact that some of these tumors overexpress isoforms of carbonic anhydrase (CA, EC 4.2.1.1) which is inhibited by sulfonamides. Most new sulfonamides showed weak inhibitory activity against the offtarget, cytosolic isoforms hCA I, II but effectively inhibited the tumor-associated hCA IX and XII. The most active compounds featured a primary SO2NH2 group and were active in the low micromolar range against MCF-7 and A-549 cell lines. Compound 4a showed IC50 of 0.72 and 0.50 1/4M against MCF-7 and A-549 cell lines, respectively, and was further evaluated for its proapoptotic activity which proved enhanced in both tumor types.
- Awadallah, Fadi M.,El-Waei, Tamer A.,Hanna, Mona M.,Abbas, Safinaz E.,Ceruso, Mariangela,Oz, Beyza Ecem,Guler, Ozen Ozensoy,Supuran, Claudiu T.
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p. 425 - 435
(2015/05/05)
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- Synthesis of some new thiazolopyrane and thiazolopyranopyrimidine derivatives bearing a sulfonamide moiety for evaluation as anticancer and radiosensitizing agents
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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. Springer Science+Business Media, LLC 2011.
- El Ella, Dalal A. Abou,Ghorab, Mostafa M.,Heiba, Helmy I.,Soliman, Aiten M.
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p. 2395 - 2407
(2012/11/06)
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- Anticancer and radiosensitizing evaluation of some new pyranothiazole- Schiff bases bearing the biologically active sulfonamide moiety
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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 (IC50: 27.51, 10.25, 9.55, 9.39 and 9.70 μM, respectively) exhibited higher cytotoxic activities than the reference drug doxorubicin (IC50: 32.00 μM). Additionally, the previously mentioned compounds were evaluated again for their ability to enhance the cell killing effect of γ-radiation.
- Ghorab, Mostafa M.,Shaaban, Mohamed A.,Refaat, Hanan M.,Heiba, Helmy I.,Ibrahim, Sara S.
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experimental part
p. 403 - 407
(2012/08/28)
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- Anticancer and radio-sensitizing evaluation of some new thiazolopyrane and thiazolopyranopyrimidine derivatives bearing a sulfonamide moiety
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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 (IC50 values 39.4 μM, 41.6 μM, 35.72 μM and 34.64 μM, respectively) exhibited higher cytotoxic activities than the reference drug doxorubicin (IC50 = 71.8 μM). Additionally, the previously mentioned compounds were evaluated again for their ability to enhance the cell killing effect of γ-radiation.
- Ghorab, Mostafa M.,Ragab, Fatma A.,Heiba, Helmy I.,El-Hazek, Reham M.
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scheme or table
p. 5120 - 5126
(2011/11/28)
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- [4-(Imidazol-1-yl)thiazol-2-yl]phenylamines. A novel class of highly potent colchicine site binding tubulin inhibitors: Synthesis and cytotoxic activity on selected human cancer cell lines
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Synthesis and cytotoxic activity in the submicromolar range of a series of [4-(imidazol-1-yl)thiazol-2-yl]-phenylamines are described. Cell cycle dependent cytotoxicity on RKO human colon carcinoma cells with inducible expression of p27kip1 and the influence on microtubule formation were investigated. Considering the significant correlation between the IC50 values of tubulin polymerization inhibition, [3H]colchicine competition, and cytotoxicity of the investigated compounds, tubulin is the main cellular target. The inhibition of microtubule formation was shown to be mediated by interference with the colchicine binding site of tubulin. In depth analysis of the investigated compounds allowed the identification of modifications that altered the pharmacological profile of the compounds from a mitosis-inducing phenotype to a G1 cell cycle arresting phenotype.
- Mahboobi, Siavosh,Sellmer, Andreas,H?cher, Heymo,Eichhorn, Emerich,B?r, Thomas,Schmidt, Mathias,Maier, Thomas,Stadlwieser, Josef F.,Beckers, Thomas L.
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p. 5769 - 5776
(2007/10/03)
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