Hala B. El-Nassan

Advances in the discovery of kinesin spindle protein (Eg5) inhibitors as antitumor agents.

Cancer is considered as one of the most serious health problems. Despite the presence of many effective chemotherapeutic agents, their severe side effects together with the appearance of mutant tumors limit the use of these drugs and increase the need for new anticancer agents. Eg5 represents an attractive target for medicinal chemists since Eg5 is overexpressed in many proliferative tissues while almost no Eg5 is detected in nonproliferative tissues. Many Eg5 inhibitors displayed potent anticancer activity against some of the mutant tumors with limited side effects. The present review provides an overview about the progress in the discovery of Eg5 inhibitors especially from 2009 to 2012 as well as the clinical trials conducted on some of these inhibitors.

Synthesis of novel pyrazolo[3,4-d]pyrimidine derivatives as potential anti-breast cancer agents.

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, antitumor activity and SAR study of novel [1,2,4]triazino[4,5-a]benzimidazole derivatives

A series of novel 1,2,3,4-tetrahydro[1,2,4]triazino[4,5-a]benzimidazoles carrying variety of aryl and heteroaryl groups at position 1 were synthesized. The newly synthesized compounds were tested in vitro on human breast adenocarcinoma cell line (MCF7). Some of the test compounds showed potent antitumor activity, especially compound 3c [1-(2-chlorophenyl) derivative] which displayed the highest activity among the test compounds.

Synthesis and antitumor activity of novel pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one derivatives.

A series of new pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidines with different substituents at position 3 were synthesized. The effect of the newly synthesized compounds was tested in vitro on human breast adenocarcinoma cell line (MCF7). Some of the synthesized compounds exploited potent antitumor activity, especially the 3-amino derivative 12 which displayed the highest activity among the test compounds with IC50 equal to 3.74 μg/mL.

Synthesis and antitumor activity of novel 6-aryl and 6-alkylpyrazolo[3,4-d]pyrimidin-4-one derivatives

A series of new 6-arylpyrazolo[3,4-d]pyrimidin-4-ones and 6-alkylpyrazolo[3,4-d]pyrimidin-4-ones were synthesized. Some of the newly synthesized compounds were tested in vitro on human colon tumor cell line (HCT116). Most of the test compounds exploited potent antitumor activity, especially compound 10a which displayed the highest activity among the test compounds with IC(50) equal to 0.47 μg/mL.

Synthesis and biological evaluation of novel pyrazoline derivatives as anti-inflammatory and antioxidant agents

A series of novel 5-aryl-3-cyclopropyl-4,5-dihydropyrazole derivatives 2a–p were synthesized via cyclization of chalcones 1a–h with thiosemicarbazide or semicarbazide HCl and evaluated as anti-inflammatory/antioxidant agents. The structures were confirmed by elemental analyses and spectral data. The free radical scavenging activity toward superoxide was determined. Their effect on hepatocytes viability and nitric oxide (NO) production in LPS-stimulated macrophages was also determined. The results showed that compounds 2e and 2n demonstrated the highest free-radical scavenging and anti-inflammatory activities, thus can be useful in the prevention of oxidative stress and inflammation-related disorders.

Synthesis of Novel Substituted Thiourea and Benzimidazole Derivatives Containing a Pyrazolone Ring as Anti‐inflammatory Agents

Two series of new 1‐(alkyl/aryl)‐3‐{2‐[(5‐oxo‐4,5‐dihydro‐1H‐pyrazol‐3‐yl)amino]phenyl}thioureas 2a–h and 5‐[2‐(substituted amino)‐1H‐benzimidazol‐1‐yl]‐4H‐pyrazol‐3‐ols 3a–i were designed and synthesized as anti‐inflammatory agents. The cyclooxygenase inhibitory activity of the newly synthesized compounds was investigated. All the compounds showed non‐selective inhibition of COX‐1 and COX‐2 enzymes which was consistent with their docking results. Compounds 2c, 2f, 2g, 3b, and 3g that showed the highest COX‐2 inhibitory activity were selected for further in vivo testing as anti‐inflammatory agents using diclofenac as a reference drug. Two of the test compounds (2c and 3b) showed potent anti‐inflammatory activity comparable to that of diclofenac with lower ulcerogenic effect relative to indomethacin. SAR study of the two series as cyclooxygenase inhibitors and anti‐inflammatory agents was also provided.

Synthesis and antitumor activity of tetrahydrocarbazole hybridized with dithioate derivatives

Abstract The present study reported the synthesis of tetrahydrocarbazoles hybridized with dithioate derivatives. Three series were synthesized namely alkyl dithiocarbonates (4a–d), heterocyclic dithiocarbamates (6a–g) and dialkyl dithiocarbamate (7). The synthesized compounds were tested in vitro on human breast adenocarcinoma cell line (MCF7) and the human colon tumor cell line (HCT116). Most of the synthesized compounds exploited potent antitumor activity, especially compound 6f [4-chlorophenylpiperazine derivative], which showed cytotoxic activity against MCF7 superior to doxorubicin with IC50 value of 7.24 nM/mL.

Synthesis of new pyridothienopyrimidinone derivatives as Pim-1 inhibitors.

Abstract Four series of pyridothienopyrimidin-4-one derivatives were designed and prepared to improve the pim-1 inhibitory activity of the previously reported thieno[2,3-b]pyridines. Significant improvement in the pim-1 inhibition and cytotoxic activity was achieved using structure rigidification strategy via ring closure. Six compounds (6c, 7a, 7c, 7d, 8b and 9) showed highly potent pim-1 inhibitory activity with IC50 of 4.62, 1.18, 1.38, 1.97, 8.83 and 4.18 μM, respectively. Four other compounds (6b, 6d, 7b and 8a) showed moderate pim-1 inhibition. The most active compounds were tested for their cytotoxic activity on three cell lines [MCF7, HCT116 and PC3]. Compounds 7a [the 2-(2-chlorophenyl)-2,3-dihydro derivative] and 7d [the 2-(2-(trifluoromethyl)-phenyl)-2,3-dihydro derivative] displayed the most potent cytotoxic effect on the three cell lines tested consistent with their highest estimated pim-1 IC50 values.

Synthesis of new thieno[2,3-b]pyridine derivatives as pim-1 inhibitors

Abstract Three series of 5-bromo-thieno[2,3-b]pyridines bearing amide or benzoyl groups at position 2 were prepared as pim-1 inhibitors. All the prepared compounds were tested for their pim-1 enzyme inhibitory activity. Two compounds (3c and 5b) showed moderate pim-1 inhibitory activity with IC50 of 35.7 and 12.71 μM, respectively. Three other compounds (3d, 3g and 6d) showed poor pim-1 inhibition. The most active compounds were tested for their cytotoxic activity on five cell lines [MCF7, HEPG2, HCT116, A549 and PC3]. Compound 3g was the most potent cytotoxic agent on almost all the cell lines tested.