Rasha Y. Elbayaa

Synthesis and Anticancer Activity of Novel Benzimidazole and Benzothiazole Derivatives against HepG2 Liver Cancer Cells

Most of cancer chemotherapeutics and chemopreventives exert their effects by triggering apoptotic cell death. In this study, novel benzimidazole and benzothiazole derivatives have been synthesized to investigate their effects on HepG2 liver cancer cell lines after initial screening study. A dose response curve was constructed and the most active derivatives were further studied for apoptotic analysis. Six active benzimidazole derivatives (8, 9, 10, 12, 13 and 14) significantly induced apoptosis compared to control group. Two compounds 10 and 12 induced apoptosis by arresting cells in G1 phase of cell cycle which is confirmed by increased expression level of p21. The activity of caspase-3 which is well known as one of the key executioners of apoptosis was determined in the presence and absence of the tested derivatives. Our results indicated that compounds 10 and 12 significantly increased caspase-3 activity compared to control group. Moreover, a docked pose of compounds 10 and 12 was obtained bound to caspase-3 active site using Molecular Operating Environment module. This study demonstrated that benzimidazole derivatives 10 and 12 provoke cytotoxicity and induced apoptosis in liver cancer cells HepG2.

Novel thiosemicarbazides induced apoptosis in human MCF-7 breast cancer cells via JNK signaling

Abstract In this study, novel thiosemicarbazides and 1,3,4-oxadiazoles were synthesized and evaluated for their anticancer effects on human MCF-7 breast cancer cell lines. Among the synthesized derivatives studied, compound 2-(3-(4-chlorophenyl)-3-hydroxybutanoyl)-N-phenylhydrazinecarbothioamide 4c showed the highest cytotoxicity against MCF-7 breast cancer cells as it reduced cell viability to approximately 15% compared to approximately 25% in normal breast epithelial cells. Therefore, we focused on 4c for further investigations. Our data showed that 4c induced apoptosis in MCF-7 cells which was further confirmed by TUNEL assay. Western blotting analysis showed that compound 4c up-regulated the pro-survival proteins Bax, Bad and ERK1/2, while it down-regulated anti-apoptotic proteins Bcl-2, Akt and STAT-3. Additionally, 4c induced phosphorylation of SAPK/JNK in MCF-7 cells. Pretreatment of MCF-7 cells with 10 µM of JNK inhibitor significantly reduced 4c-induced apoptosis. Molecular docking results suggested that compound 4c showed a binding pattern close to the pattern observed in the structure of the lead fragment bound to JNK1. Collectively, the data of current study suggested that the thiosemicarbazide 4c might trigger apoptosis in human MCF-7 cells by targeting JNK signaling.

Novel 1,5-diphenyl-6-substituted 1H-pyrazolo[3,4-d]pyrimidin-4(5H)-ones induced apoptosis in RKO colon cancer cells

Abstract Novel 1,5-diphenyl-6-substituted-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-ones were synthesized and characterized. All compounds were screened for their anti-proliferative activities in five different cancer cell lines. The results showed that compounds 7a and 7b comprising aminoguanidino or guanidino moiety at position 6 inhibited proliferation of RKO colon cancer cells with IC50 of 8 and 4 μM, respectively. Compounds 7a and 7b induced apoptosis in RKO cells, which was confirmed by TUNEL and annexin V-FITC assays. Flow cytometric analysis indicated that compounds 7a and 7b arrested RKO cells in the G1 phase and the most active compound 7b increased levels of p53, p21, Bax, ERK1/2 and reduced levels of Bcl2 and Akt. Compound 7b also activates release of cytochrome c, which is consistent with activation of caspase-9. Additionally, compound 7b increased caspase-3 activity and cleaved PARP-1 in RKO cells. Collectively, these findings could establish a molecular basis for the development of new anti-cancer agents.

Novel quinuclidinone derivatives induced apoptosis in human breast cancer via targeting p53

Small molecules that can target human cancers have been highly sought to increase the anticancer efficacy, the present work describes the design and synthesis of novel series of five quinuclidinone derivatives (2a-2e). Their anticancer activities were investigated against breast cancer cells MCF-7, MDA-MB-231 breast cancer cells harboring mutant p53 and normal breast counterpart MCF-12a. Derivative 2e reduced proliferation of MCF-7 and MCF-12a while it has no effect on MDA-MB-231. Derivative 2e induced apoptosis in MCF-7 cells which is further confirmed by TUNEL assay and it reduced the percentage of cell in G2/M phase as confirmed by increased expression of cyclin B and reduced expression of cyclin D1. Derivative 2e reduced expression levels of Mdm2, Akt and ERK1/2 by and increased expression level of p53. Moreover, the apoptosis induction by 2e was also inhibited by PFT-α as evidenced by non-significant induction of apoptosis after treatment of MCF-7 cells with both derivative 2e and PFT-α. In addition, docking study reveals that derivative 2e has a binding pattern close to the pattern observed in the structure of the lead fragment 5,6-dimethoxy-2-methylbenzothiazole bound to T-p53C-Y220C. The above findings demonstrate that derivative 2e induces apoptosis in MCF-7 cells via targeting p53 which merits further development.

Design, synthesis, antibacterial evaluation and molecular docking studies of some new quinoxaline derivatives targeting dihyropteroate synthase enzyme

Development of new antimicrobial agents is a good solution to overcome drug-resistance problems. From this perspective, new quinoxaline derivatives bearing various bioactive heterocyclic moieties (thiadiazoles, oxadiazoles, pyrazoles and thiazoles) were designed and synthesized. The newly synthesized compounds were evaluated for their in vitro antibacterial activity against nine bacterial human pathogenic strains using the disc diffusion assay. In general, most of the synthesized compounds exhibited good antibacterial activities. The thiazolyl 11c displayed significant antibacterial activities against P. aeruginosa (MIC, 12.5 µg/mL vs levofloxacin 12.5 µg/mL). Molecular docking studies indicated that the synthesized compounds could occupy both p-amino benzoic acid (PABA) and pterin binding pockets of the dihydropteroate synthase (DHPS), suggesting that the target compounds could act by the inhibition of bacterial DHPS enzyme. The results provide important information for the future design of more potent antibacterial agents.

Design and Synthesis of Some New 1,2,4- Triazolo[4,3-a]QuinoxalineDerivatives as Potential Antimicrobial Agents

As a part of an ongoing research program to achieve new chemical entities suitable for development as new class of antimicrobial agents, the present work describes the design and synthesis of a new series of substituted-1-methyl- 1,2,4-triazolo[4,3-a]quinoxalines, The newly synthesized compounds were screened for their in vitro antimicrobial activity. The results revealed that the compounds demonstrated significant activity against Gram negative bacteria. Compounds 3 and 11b exhibited twice the activity of ampicillin against Pseudomonas aeruginosa, while compounds 4, 5b, 7, 9a, 10d, 11a, 11c and 12 were equipotent to ampicillin. On the other hand, the tested compounds demonstrated mild antifungal activity. Compound 11d exhibited nearly one-half the activity of clotrimazole against Candida albicans. The structures of the synthesized compounds have been confirmed by elemental analyses, IR, MS, 1H-NMR and 13 C-NMR spectral data.

Computer-aided Design, Synthesis, and Biological Evaluation of 5- Substituted Aminomethylenepyrimidine-2,4,6-Triones as H 1 Antihistaminic Agents (Part2)

As a part of a research project pertaining to the synthesis of novel candidates as nonsedating, nonclassic H₁ histaminergic (H₁) blockers with low toxicity profiles, some new 5-substituted aminomethylenepyrimidine-2,4,6-triones were designed based on the H₁ histaminic receptor pharmacophore model. The interactions between the designed compounds and the H₁ receptor were studied using molecular docking on the homology model of H₁ receptor. The designed compounds were synthesized and biologically evaluated for H₁-blocking activity; using isolated segments of guinea pig ileum. Compounds 15,18,19 and 21 exhibited comparable activities to acrivastine (22) as reference nonsedating drug. The C log P of designed compounds revealed lower values in reference to acrivastine (22) which might indicate decreased tendency for crossing the blood brain barrier.

Design, Synthesis and Molecular Docking Study of Some Substituted 4,5- dihydro-2H-indazole Derivatives as Potential Anti-inflammatory Agents

A new series of 4,5-dihydro-2H-indazoles was synthesized and evaluated for anti-inflammatory activity using formalin-induced paw edema and turpentine oil-induced granuloma pouch bioassays. In addition, the inhibitory activity of cyclooxygenase, ulcerogenic effect, and acute toxicity (ALD50) values were also determined. Compounds 10, 13, 15, 16, 18 and 22 were proved to display distinctive anti-inflammatory profiles with a fast onset of action. They revealed super GI safety profile and are well tolerated by the experimental animals with high safety margin (ALD50 >300 mg/Kg). The same active compounds exhibited moderate to powerful selectivity profile towards the inhibition of COX-2 enzyme. Docking poses for the most active compounds separately in the active site of human COX-2 enzyme were also obtained.

Potential Anticancer Agents: Design, Synthesis of New Pyrido[1,2-a]benzimidazoles and Related Derivatives Linked to Alkylating Fragments

The incentive of the present work has been primarily directed towards the design and synthesis of some novel pyrido[1,2-a]benzimidazoles with specific functionalities believed to have alkylation ability. This combination of pharmacological agents may enable synergistic anticancer effect. Nine compounds 5b, 13a, 13d, 13e, 14b, 14c, 15, 16, and 17 were selected by the National Cancer Institute (NCI), Bethseda, Maryland, USA to be evaluated for their in vitro antitumor activity. All the selected compounds were tested initially at a single dose (10 μM) in the full NCI 60 cell panel including leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate and breast cancer cell lines. Majority of the test compounds exhibited moderate cytotoxic activity. The highest activity in all the investigated cancer cells was displayed by 14c against melanoma SK-MEL-5 cell line. This may be due to the impact of the lipophilic trifluoromethyl substitution on the biological activity profile.

Design, synthesis and evaluation of some novel pyrazoline derivatives as potential anti-inflammatory and antitumor agents.

A new series of pyrazoline derivatives was designed and synthesized with the objective of developing agents with anti-inflammatory activity together with chemoprevention of hepatobiliary malignancies. The prepared compounds were evaluated for their anti-inflammatory activity using carrageenan-induced granuloma bioassay, using celecoxib as a reference drug. Ulcerogenic effect and acute toxicity profiles (ALD50) for the most active compounds were also determined. Compound 5c was proved to display anti-inflammatory activity better than celecoxib. Compounds 4b, 5d, 5c and 8 were found to be safer than indomethacin with respect to ulcerogenic effect and were well tolerated by the experimental animals with high safety margin (ALD50 >300 mg/Kg). Moreover, histopathological examination was carried out to detect the anti-inflammatory effect of the tested compounds on the livers of carrageenan-injected rats. On the other hand, compounds 4b, 4c, 4d, 5b, 5c, 5d, 6a, 6b, 6c, 6d, 8 and 9 were selected by the NCI to be evaluated for their anticancer activities but none has passed to the 5-dose assay. In addition, the ligand-receptor interactions of the most active compounds with COX-2 were investigated by performing docking studies using Molecular Operating Environment (MOE) version 2008.10.