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Journal Article
Design and synthesis of pyrazolo[3,4-d]pyrimidines: Nitric oxide releasing compounds targeting hepatocellular carcinoma., Elshaier, Yaseen A. M. M., Shaaban Mohamed A., ABD EL HAMID Mohammed K., Abdelrahman Mostafa H., Abou-Salim Mahrous A., Elgazwi Sara M., and Halaweish Fathi , Bioorganic & medicinal chemistry, 2017 06 15, Volume 25, Issue 12, p.2956-2970, (2017) Abstract

A new series of pyrazolo[3,4-d]pyrimidines tethered with nitric oxide (NO) producing functionality was designed and synthesized. Sulforhodamine B (SRB) protein assay revealed that NO releasing moiety in the synthesized compounds significantly decreased the cell growth more than the des-NO analogues. Compounds 7C and 7G possessing N-para-substituted phenyl group, released the highest NO concentration of 4.6% and 4.7% respectively. Anti-proliferative activity of synthesized compounds on HepG2 cell line identified compounds 7h, 7p, 14a and 14b as the most cytotoxic compounds in the series of IC=3, 5, 3 and 5μM, respectively, compared to erlotinib as a reference drug (IC=25μM). Flow cytometry studies revealed that 7h arrested the cells in G0/G1 phase of cell cycle while 7p arrested the cells in S phase. Moreover, docking study of the synthesized compounds on EGFR (PDB code: 1M17) and cytotoxicity study indicated that N-1 phenyl para substitution, pyrazole C-3 alkyl substitution and tethering the nitrate moiety through butyl group had a significant impact on the activity.

Design and synthesis of pyrazolo[3,4-d]pyrimidines: Nitric oxide releasing compounds targeting hepatocellular carcinoma., Elshaier, Yaseen A. M. M., Shaaban Mohamed A., ABD EL HAMID Mohammed K., Abdelrahman Mostafa H., Abou-Salim Mahrous A., Elgazwi Sara M., and Halaweish Fathi , Bioorganic & medicinal chemistry, 2017 06 15, Volume 25, Issue 12, p.2956-2970, (2017) Abstract

A new series of pyrazolo[3,4-d]pyrimidines tethered with nitric oxide (NO) producing functionality was designed and synthesized. Sulforhodamine B (SRB) protein assay revealed that NO releasing moiety in the synthesized compounds significantly decreased the cell growth more than the des-NO analogues. Compounds 7C and 7G possessing N-para-substituted phenyl group, released the highest NO concentration of 4.6% and 4.7% respectively. Anti-proliferative activity of synthesized compounds on HepG2 cell line identified compounds 7h, 7p, 14a and 14b as the most cytotoxic compounds in the series of IC=3, 5, 3 and 5μM, respectively, compared to erlotinib as a reference drug (IC=25μM). Flow cytometry studies revealed that 7h arrested the cells in G0/G1 phase of cell cycle while 7p arrested the cells in S phase. Moreover, docking study of the synthesized compounds on EGFR (PDB code: 1M17) and cytotoxicity study indicated that N-1 phenyl para substitution, pyrazole C-3 alkyl substitution and tethering the nitrate moiety through butyl group had a significant impact on the activity.

Design and synthesis of thienopyrimidine urea derivatives with potential cytotoxic and pro-apoptotic activity against breast cancer cell line MCF-7., Abdelhaleem, Eman F., Abdelhameid Mohammed K., KASSAB ASMAA E., and Kandeel Manal M. , European journal of medicinal chemistry, 2018 Jan 01, Volume 143, p.1807-1825, (2018) Abstract

A series of novel tetrahydrobenzothieno[2,3-d]pyrimidine urea derivatives was synthesized according to fragment-based design strategy. They were evaluated for their anticancer activity against MCF-7 cell line. Three compounds 9c, 9d and 11b showed 1.5-1.03 folds more potent anticancer activity than doxorubicin. In this study, a promising multi-sited enzyme small molecule inhibitor 9c, which showed the most potent anti-proliferative activity, was identified. The anti-proliferative activity of this compound appears to correlate well with its ability to inhibit topoisomerase II (IC = 9.29 μM). Moreover, compound 9c showed excellent VEGFR-2 inhibitory activity, at the sub-micromolar level with ICvalue 0.2 μM, which is 2.1 folds more potent than sorafenib. Moreover, activation of damage response pathway of the DNA leads to cell cycle arrest at G2/M phase, accumulation of cells in pre-G1 phase and annexin-V and propidium iodide staining, indicating that cell death proceeds through an apoptotic mechanism. Compound 9c showed potent pro-apoptotic effect through induction of the intrinsic mitochondrial pathway of apoptosis. This mechanistic pathway was confirmed by a significant increase in the expression of the tumor suppressor gene p53, elevation in Bax/BCL-2 ratio and a significant increase in the level of active caspase-3. Quantitative structure-activity relationship (QSAR) studies delivered equations of five 3D descriptors with R = 0.814. This QSAR model provides an effective technique for understanding the observed antitumor properties and thus could be adopted for developing effective lead structures.

Design, synthesis and biological study of hybrid drug candidates of nitric oxide releasing cucurbitacin-inspired estrone analogs for treatment of hepatocellular carcinoma., Abou-Salim, Mahrous A., Shaaban Mohamed A., Abdelhameid Mohammed K., Elshaier Yaseen A. M. M., and Halaweish Fathi , Bioorganic chemistry, Volume 85, p.515-533, (2019) Abstractabou-salim2019.pdf

Development of hybrid drug candidates is well known strategy for designing antitumor agents. Herein, a novel class of nitric oxide donating cucurbitacin inspired estrone analogs (NO-CIEAs) were designed and synthesized as multitarget agents. Synthesized analogs were initially evaluated for their anti-hepatocellular carcinoma activities. Among the tested analogs, NO-CIEAs 17 and 20a exhibited more potent activity against HepG2 cells (IC = 4.69 and 12.5 µM, respectively) than the reference drug Erlotinib (IC = 25 µM). Interestingly, NO-CIEA 17 exerted also a high potent activity against Erlotinib-resistant HepG2 cell line (HepG2-R) (IC = 8.21 µM) giving insight about its importance in drug resistance therapy. Intracellular measurements of NO revealed that NO-CIEAs 17 and 20a showed a significant increase in NO production in tumor cells after 1 h of incubation comparable to the reference prodrug JS-K. Flow cytometric analysis showed that both NO-CIEAs 17 and 20a mainly arrested the HepG2 cells in the G0/G1 phase. Also, In-Cell Based ELISA screening showed that NO-CIEA 17 resulted in a potential inhibitory activity towards the EGFR and MAPK (25% and 29% inhibition compared to untreated control cells, respectively). This data suggests the binding ability of NO-CIEA 17 to the EGFR and ERK to be well correlated along with the docking and cellular studies. Also, treatment of HepG2-R cells with NO-CIEA 17 showed a potential reduction of MRP2 expression in a dose dependent manner providing a significant impact on the chemotherapeutic resistance. Overall, the current study provides a potential new approach for the discovery of a novel antitumor agent against HCC.

Design, synthesis and screening of 1, 2, 4-triazinone derivatives as potential antitumor agents with apoptosis inducing activity on MCF-7 breast cancer cell line, Abdelhameid, Mohammed K. , European Journal of Medicinal Chemistry, Volume 156, Issue 12, p.563e579, (2018) 5.pdf
Design, Synthesis and Screening of 4,6-Diaryl Pyridine and Pyrimidine Derivatives as Potential Cytotoxic Molecules, elhameid, Mohammed Abd K., Ryad Noha, MY Al-Shorbagy, Mohammed Manal R., Ismail Mohammed M., and Elmeligie Salwa , Chem. Pharm. Bull, Volume 66, Issue 10, p.939–952, (2018) 66_c18-00269.pdf
Design, synthesis, and screening of ortho-amino thiophene carboxamide derivatives on hepatocellular carcinoma as VEGFR-2 Inhibitors, Abdelhameid, Mohammed K., Labib Madlen B., Negmeldin Ahmed T., Al-Shorbagy Muhammad, and Mohammed Manal R. , Journal of Enzyme Inhibition and Medicinal Chemistry, Volume VOL. 33, Issue 1, p.472–1493, (2018) 6.pdf
Enhancement to synthesize, design and dock of novel EGFR inhibitors containing pyrazolo[3,4-d]pyrimidine cores of expected anticancer activity, K.Abdel-Hamid, Mohamed, M.Kandeel Manal, and Eman K. A. Abdelall , OCAIJ,, Volume 10, Issue 12, p.1181–1195, (2014) 2-.pdf
Synthesis and in vitro antitumor activity of new benzothiazole and benzoxazole derivatives, HAMID, Mohammed ABD EL K., ABDELGAWAD MOHAMEDA, Abdelall Eman K. A., Philoppes John N., and Kandeel Manal M. , Journal of Chemical and Pharmaceutical Research, Volume 5, Issue 8, p.16-21, (2013) 1-.pdf
Synthesis of certain fused pyrrolothieno[3, 2-e] pyrazine derivatives with possible anxiolytic activity, El-Hameid, Mohammed K.Abd , organic chemistry ,an indian journal , Volume 9, Issue 11, p.[427-436], (2013) 02_ocaij_org2634907.pdf
SYNTHESIS OF NOVEL ARYL SUBSTITUTED PYRAZOLO [3, 4-D] PYRIMIDINES AND THEIR EVALUATION AS CYTOTOXIC AGENTS, El-hamid, Mohammed Abd K. , International Journal of Chemical Science and Technology, Volume 1, Issue 4, p.126-140, (2011) hct_cell_line.pdf
Synthesis of novel pyrazolo[3,4-d]pyrimidine derivatives as potential anti-breast cancer agents., ABD EL HAMID, Mohammed K., Mihovilovic Marko D., and El-Nassan Hala B. , European journal of medicinal chemistry, 2012 Nov, Volume 57, p.323-8, (2012) Abstract

A series of new 1-aryl-4-benzylidenehydrazinyl-3-methylsulphanyl-pyrazolo[3,4-d]pyrimidines 6a-p was synthesized. The cytotoxic activity of the newly synthesized compounds against human breast cancer cell line, MCF7 was investigated. Most of the test compounds showed potent antitumor activity comparable to that of doxorubicin. The 1-phenyl series (6a-i) exhibited better antitumor activity than 1-(4-methoxyphenyl) series (6j-p). 4-[2-(4-Fluorobenzylidene)hydrazinyl]-3-(methylsulphanyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine (6d) was the most active compound in this study with IC(50) equal to 7.5 nM.

Synthesis of Some Novel Thieno[3,2-d]pyrimidines as Potential Cytotoxic Small Molecules against Breast Cancer, Kandeel, Manal, Abdelhameid Mohammed Kamal, Eman Kamal, Eman Kamal, and Labib Madlen Berty , Chemical and Pharmaceutical Bulletin, Volume 61, p.637-647, (2013)
Synthesis, antimicrobial and cytotoxic activity of novel 4-phenoxy and 4-(substitutedamino) pyrazolo [3, 4-d] pyrimidine derivatives, Abdelhameid, Mohammed Kamal , organic chemistry an andian journal, Volume , 9, Issue 9, p. [350-362], (2013) 02_ocaij_org2634482.pdf