Development of Semisynthetic Apoptosis-Inducing Agents Based on Natural Phenolic Acids Scaffold: Design, Synthesis and In-Vitro Biological Evaluation.

A crucial target in drug research is magnifying efficacy and decreasing toxicity. Therefore, using natural active constituents as precursors will enhance both safety and biological activities. Despite having many pharmacological activities, caffeic and ferulic acids showed limited clinical usage due to their poor bioavailability and fast elimination. Therefore, semisynthetic compounds from these two acids were prepared and screened as anticancer agents. In this study, CA and FA showed very potent anticancer activity against Caco-2 cells. Consequently, eighteen derivatives were tested against the same cell line. Four potent candidates were selected for determination of the selectivity index, where compound 10 revealed a high safety margin. Compound 10 represented a new scaffold and showed significant cytotoxic activity against Caco-2. Cell-cycle analysis and evaluation of apoptosis showed that derivatives 10, 7, 11, 15 and 14 showed the highest proportion of cells in a late apoptotic stage.

Development of potential anticancer agents and apoptotic inducers based on 4-aryl-4H chromene scaffold: Design, synthesis, biological evaluation and insight on their proliferation inhibition mechanism.

An array of 4-aryl-2-amino-4H chromene derivatives were designed, synthesized, and evaluated for cytotoxic activity against four cancer cell lines and two non-cancerous cell lines. The most active candidates were further screened for their in vitro anticancer activity on NCI panel of 60 human cancer cell lines where compounds 2a, 2b, 4a-2, and 2e showed promising activity against various leukemia, non-small lung, renal, prostate, and breast cancer cell lines, particularly against NCI-H522 non-small lung cancer cell line (GI50 of 0.35-0.60 µM), MCF7 breast cancer cell line (GI50 of 0.34-0.59 µM), and MDA-MB-468 breast cancer cell line (GI50 of 0.23-0.40 µM). Compound 2b was the most potent against all leukemia and prostate cancer cell lines with GI50 values (0.29-0.60 µM). Compound 2b inhibited the proliferation of MCF-7 and HepG2 cells by inducing cell cycle arrest and apopotosis. 2b downregulated the mRNA abundance of BAX, Apaf-1 and caspase-3 and upregulated BCL-2. The activities of caspase-3 and caspase-9 were declined in MCF-7 and HepG2 cells treated with compound 2b. Compounds 2b and 4a-2 inhibited tubulin polymerization, with an IC50 values of 0.92 and 1.13 µM, respectively. These findings indicate that these synthesized compounds may represent potential drug candidates to inhibit the proliferation of different types of cancer cells.

Design, synthesis and assessment of new series of quinazolinone derivatives as EGFR inhibitors along with their cytotoxic evaluation against MCF7 and A549 cancer cell lines.

New acetamide (IV a-e) and 1,3-thiazolidinone derivatives (VII a-e) were designed, synthesized and assessed for their cytotoxic activity against MCF-7 and A549 cell lines along with their lead compounds (erlotinib and gefitinib). The newly designed compounds were prepared according to the adopted procedures in schemes 1 and 2 from their quinazolinone parents. 3D QSAR pharmacophore and docking molecular modeling protocols were conducted using Discovery Studio program, beside a full biological assay for these compounds. The cytotoxicity evaluation demonstrated that compounds IVb, IVc, VIIa, VIIb, VIId exhibited potent cytotoxic activities against both MCF-7 and A549 cell lines. Moreover, the molecular modeling studies corroborated to the affinity of the compounds towards EGFR. Consequently, these five compounds were then screened for their EGFR inhibition and evaluated as well for their toxicity to normal cells, which revealed that the acetamide derivative IVc and the thiazolidinone derivative VIIa were the most potent and least toxic. DNA flow cytometry analysis was conducted for compounds IVc and VIIa, which indicated that they both induced arrest at G2/M phase of the cell cycle.

Design, synthesis, and biological evaluation of new pyrazoloquinazoline derivatives as dual COX-2/5-LOX inhibitors.

A new series of pyrazoloquinazoline derivatives equipped with different chalcones was designed, synthesized, and identified through 1 H nuclear magnetic resonance (NMR), 13 C NMR, and infrared spectroscopic techniques. Our design strategy of the quinazolinone-privileged scaffold as a new scaffold was based on merging pharmacophores previously reported to exhibit cyclooxygenase-2 (COX-2)/5-lipoxygenase (5-LOX) inhibitory activity. All the newly synthesized derivatives were biologically evaluated for COX and 5-LOX inhibitory activity and COX-2 selectivity, using celecoxib and zileuton as reference drugs, as they exhibited promising anti-inflammatory activity. Compound 3j was found to be the most promising derivative, with IC50 values of 667 and 47 nM against COX-1 and COX-2, respectively, which are superior to that of celecoxib (IC50 value against COX-2 = 95 nM), showing an SI of 14.2 that was much better than celecoxib. Compounds 3f and 3h exhibited COX-1 inhibition, with IC50 values of 1,485 and 684 nM, respectively. The synthesized compounds showed a significant inhibitory activity against 5-LOX, with IC50 values ranging from 0.6 to 4.3 µM, where compounds 3f and 3h were found to be the most potent derivatives, with IC50 values of 0.6 and 1.0 µM, respectively, in comparison with that of zileuton (IC50 = 0.8 µM). These promising derivatives, 3f, 3h, and 3j, were further investigated in vivo for anti-inflammatory, gastric ulcerogenic effects, and prostaglandin production (PGE2) in rat serum. The molecular docking studies concerning the binding sites of COX-2 and 5-LOX revealed similar orientation, compared with reported inhibitors, which encouraged us to design new leads targeting COX-2 and 5-LOX as dual inhibitors, as a new avenue in anti-inflammatory therapy.

Synthesis and biological evaluation of pyrazolone analogues as potential anti-inflammatory agents targeting cyclooxygenases and 5-lipoxygenase.

New pyrazolone derivatives structurally related to celecoxib and FPL 62064 were synthesized and biologically evaluated for their inhibitory activity against cyclooxygenases (COXs) and 5-lipoxygenase (5-LOX) and their selectivity indices were calculated. The results showed that compounds 3f, 3h, 3l, and 3p have an excellent COX-2 selectivity index. Moreover, they showed potent 5-LOX inhibitory activity relative to celecoxib and zileuton, as positive controls. These promising candidates were further investigated for anti-inflammatory activity using the carrageenan-induced rat paw edema method and ulcerogenic liability. The results showed no ulceration, which implies their gastric safety profile. Moreover, these compounds were evaluated for prostaglandin (PGE2) production in rat serum. Molecular docking in the COX-2 and 5-LOX active sites was performed to rationalize their anti-inflammatory activities. Strong binding interactions and effective docking scores were identified. The results indicated that these derivatives are good leads for dual-acting COX-2/5-LOX inhibitors to be used as potent and safe anti-inflammatory agents.

Pyrrolo and pyrrolopyrimidine sulfonamides act as cytotoxic agents in hypoxia via inhibition of transmembrane carbonic anhydrases.

A series of novel sulfonamide derivatives bearing pyrrole and pyrrolopyrimidine scaffolds were synthesized and screened as carbonic anhydrase inhibitors. The inhibition activity of the synthesized compounds was evaluated against the cytosolic human carbonic anhydrase isoforms I and II and the transmembranal isoforms IX and XII. Several candidates showed potent inhibitory activity against IX and XII isoforms. Furthermore, ex vivo screening of cytotoxic selectivity and activity of the most potent derivatives were carried out against normal cells (WI38) and cervical cancer cell line (HeLa) under normal and hypoxic conditions using acetazolamide as reference drug. Compound 11b potency was nearly three folds higher in hypoxic than normoxic condition whereas that of compound 11f was nearly four folds higher in hypoxic vs. normoxic HeLa cells. All the screened derivatives exhibited less potency on normal cells (WI38). Molecular docking was carried out to discover the possible binding mode of compounds within the active site of isoform CA IX.

Novel thienopyrimidine derivatives as dual EGFR and VEGFR-2 inhibitors: design, synthesis, anticancer activity and effect on cell cycle profile.

AIM: Design and synthesis of thienopyrimidine derivatives as dual EGFR and VEGFR-2 inhibitors. MATERIAL AND METHODS: A series of novel 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidine derivatives with different substituents on C-4 position was synthesized and evaluated for their anticancer activity against MCF-7 cell line. EGFR, VEGFR-2 inhibitory assay, the cell cycle analysis and apoptosis induction ability of the most potent compound 5f were evaluated. RESULTS: Most of the compounds showed moderate to significant anticancer activity. Compound 5f exhibited the most potent anticancer activity being 1.73- and 4.64-folds more potent than erlotinib and doxorubicin, respectively. Compound 5f showed potent EGFR inhibitory activity being 1.18-folds more potent than reference standard erlotinib and it also showed good VEGFR-2 inhibitory activity at the micromolar level with IC50 value 1.23 µM. Compound 5f caused induction of cell cycle arrest at G2/M phase and accumulation of cells in pre-G1 phase. Compound 5f induced cellular apoptosis.

Design, Synthesis, Cytotoxic Activity and Apoptosis-inducing Action of Novel Cinnoline Derivatives as Anticancer Agents.

AIMS: Tyrosine kinases and topoisomerase I are common target enzymes for the majority of the anticancer agents. In contrast to quinazolines and quinolines, kinase inhibitors and topoisomerase inhibitors incorporating cinnoline scaffold are relatively infrequent. Thus the aim of this work was to replace the former scaffolds with the latter one. Eighteen novel cinnoline derivatives were designed, synthesized and characterized using both microanalytical and spectral data. METHODS: The cytotoxic activity of the new compounds was screened in vitro against both human breast cancer cells and normal breast cells. RESULTS: The enzymatic inhibition activity of promising candidates against both epidermal growth factor receptor tyrosine kinase and topoisomerase I was accomplished. CONCLUSIONS: Cell cycle profiles were observed at IC50 doses of representative biologically active compounds. Compound 7 represented a new scaffold incorporating triazepinocinnoline ring system and showed outstanding cytotoxic activity against MCF-7 (0.049 µM), tyrosine kinase inhibition (0.22 µM), apoptosis percentage and the highest selectivity index.

Design, synthesis and cytotoxic activity of certain novel chalcone analogous compounds.

A series of chalcone analogous compounds were designed and synthesized. Replacing/substituting the enone or ethylenic bridge of the parent chalcone with rigid heterocyclic moieties or substituted aromatic amines gave nineteen target compounds. Their cytotoxic activities were screened against both breast and liver cancer cells as well as breast and liver normal cells. Target compounds were also evaluated for their inhibition activity of tubulin beta polymerization. Target compound 2e, 3a, 3b, 3c, 4a-4d, 5a, 5b and 6 showed broad spectrum excellent anticancer activity against both MCF-7 and HepG2. Compound 4a showed the most TUBb inhibition activity.

Synthesis and evaluation of 4-anilinoquinazoline bioisosteres as potential anti-breast cancer agents.

Based on one of the four major categories of scaffold hopping theory namely hetrocycle replacements, a series of 5-arylthieno[2,3-d]pyrimidines had been prepared and evaluated as anti-breast cancer agents. Optimization by combination of different pharmacophores with the thienopyrimidine scaffold led to discovery of biologically active compounds.

Synthesis of novel chromene derivatives of expected antitumor activity.

Inhibition of tubulin polymerization is one of the important tactics in cancer therapy. Since 4-aryl-4H-chromene derivatives are found to be microtubule-binding agents via interfering with tubulin polymerization so we decide to concentrate our exploration efforts on the combination of this nucleus with 5-, 6-, and/or 7-memebered heterocyclic moieties in a novel series of compounds to explore the effect that might result from this combination. Ten novel compounds were selected for anticancer screening assay against MCF-7 breast cancer cell line in comparison to colchicine as positive control and most of them showed excellent activity.