Synthesis of novel pyrimido[4,5-b]quinoline derivatives as dual EGFR/HER2 inhibitors as anticancer agents.

A series of novel N-aryl-5-aryl-6,7,8,9-tetrahydropyrimido[4,5-b]quinolin-4-amines 4a-4l was synthesized as potential anticancer agents through Dimroth rearrangement reaction of intermediates 3a-3c. Pyrimido[4,5-b]quinolines 4a-4l showed promising activity against the Michigan Cancer Foundation-7 (MCF-7) cell line, compared with lapatinib as the reference drug. Compounds 4d, 4h, 4i, and 4l demonstrated higher cytotoxic activity than lapatinib, with IC50 values of 2.67, 6.82, 4.31, and 1.62 µM, respectively. Compounds 4d, 4i, and 4l showed promising epidermal growth factor receptor (EGFR) inhibition with IC50 values of 0.065, 0.116, and 0.052 µM, respectively. These compounds were subjected to human epidermal growth factor receptor 2 (HER2) inhibition and showed IC50 values of 0.09, 0.164, and 0.055 µM, respectively. Compounds 4d, 4i, and 4l are good candidates as dual EGFR/HER2 inhibitors. The most active compound, 4l, was subjected to cell-cycle analysis and induced cell-cycle arrest at the S phase. Compound 4l induced apoptosis 60-fold compared with control untreated MCF-7 cells. 4l can inhibit cancer metastasis. It reduced MCF-7 cell infiltration and metastasis by 45% compared with control untreated cells.

Synthesis of novel pyrimido[4,5-b]quinolines as potential anticancer agents and HER2 inhibitors.

A series of N-arylpyrimido[4,5-b]quinolines 3a-e and 2-aryl-2,3-dihydropyrimido[4,5-b]quinoline-4(1H)-ones 5a-e was designed and synthesized as potential anticancer agents against breast cancer. Compounds 3e, 5a, 5b, 5d, and 5e showed promising activity against the MCF-7 cell line. Among them, compound 5b was the most active with IC50 of 1.67 µM. Compound 5b promoted apoptosis and induced cell cycle arrest at S phase. 5b increased the level of pro-apoptotic proteins p53, Bax, and caspase-7 and inhibited the anti-apoptotic protein Bcl-2. Furthermore, all the synthesized compounds were docked into the crystal structure of HER2 (PBD: 3 pp0). Compounds 3e, 5a, 5b, 5d, and 5e showed good energy scores and binding modes. Finally, Compound 5b was evaluated on the HER2 assay and revealed good inhibition with IC50 of 0.073 µM.

New benzothienopyran and benzothienopyranopyrimidine derivatives as topoisomerase I inhibitors: Design, synthesis, anticancer screening, apoptosis induction and molecular modeling studies.

New benzothienopyran and benzothienopyranopyrimidine derivatives were synthesized based on the structural requirements of topoisomerase I inhibitors. All target compounds exhibited strong cytotoxic activity with GI50 range of 70.62 %-87.29 % in one dose NCI (USA) screening against 60 human tumor cell lines. Among the tested derivatives, eight compounds namely 4d, 4e, 4f, 5b, 5e, 6b, 6d, and 6f demonstrated broad spectrum and potent anticancer efficacy in five dose screening against all tested panels. DNA relaxation assay for the latter compounds showed that 4d, 5b, and 6f exhibited excellent inhibitory activity with IC50 range of 2.553-4.495 µM as compared to indenoisoquinoline reference drug (IC50 = 3.911 ± 0.21 µM). Moreover, the most active compounds were investigated for being topoisomerase poisons or catalytic inhibitors using DNA nicking assay. Compounds 4d and 6f were found to be potential Topo I poisons, whereas compound 5b has acted as Topo I suppressor. Analyzing cell cycle and induction of apoptosis for the most active compound 4d, revealed growth arrest at the S phase in MDA-MB-435 cells similarly to indenoisoquinoline reference drug. Additionally, in silico molecular modeling study for eight most active cytotoxic compounds in five dose screening demonstrated interaction with DNA as well as distinctive binding pattern similar to the reference indenoisoquinoline, indicating that the newly discovered targets are supposed to be promising candidates as Topo I inhibitors.

Recent green approaches for the synthesis of pyrazolo[3,4-d]pyrimidines: A mini review.

Pyrazolo[3,4-d]pyrimidine as a bioisostere of purine has drawn considerable attention as a privileged scaffold for the design and discovery of novel drugs. Green synthesis is an emerging area in the field of chemistry that provides economic and environmental benefits as an alternative to traditional methods. The present mini review reflects recent advances in the green synthesis of pyrazolo[3,4-d]pyrimidines, published in the time frame from 2006 to 2019.

New benzothieno[2,3-c]pyridines as non-steroidal CYP17 inhibitors: design, synthesis, anticancer screening, apoptosis induction, and in silico ADME profile studies.

A series of [1]benzothieno[2,3-c]pyridines was synthesised. Most compounds were chosen by NCI-USA to evaluate their anticancer activity. Compounds 5a-c showed prominent growth inhibition against most cell lines. 5c was selected at five dose concentration levels. It exhibited potent broad-spectrum anticancer activity with a GI50 of 4 nM-37 µM. Cytotoxicity of 5a-c was further evaluated against prostate, renal, and breast cancer cell lines. 5c showed double and quadruple the activity of staurosporine and abiraterone, respectively, against the PC-3 cell line with IC50 2.08 µM. The possible mechanism of anti-prostate cancer was explored via measuring the CYP17 enzyme activity in mice prostate cancer models compared to abiraterone. The results revealed that 5c suppressed the CYP17 enzyme to 15.80 nM. Moreover, it was found to be equipotent to abiraterone in testosterone production. Cell cycle analysis and apoptosis were performed. Additionally, the ADME profile of compound 5c demonstrated both good oral bioavailability and metabolic stability.

Synthesis, molecular modeling and biological evaluation of new benzo[4,5]thieno[3,2-b]pyran derivatives as topoisomerase I-DNA binary complex poisons.

A series of new benzo[b]thiophenes 2a-f and benzo[4,5]thieno[3,2-b]pyran derivatives 3a-f and 4a-f were synthesized and their structures were confirmed by elemental analyses and spectral data. All synthesized compounds were evaluated by the National Cancer Institute (NCI, USA) against 60 human tumor cell lines. Compounds 3a-f and 4a-f showed potent cytotoxic effects in one dose assay with mean growth inhibition ranging from 62% to 80%. Six compounds 3a, 3d, 3e, 3f, 4d and 4e were selected by NCI, USA for five dose evaluation against 60 human tumor cell lines. Compounds 3a, 3d, 3e and 3f exhibited very potent and broad spectrum cytotoxicity against almost all cancer cell lines with mean concentration that yield 50% growth inhibition (MG-MID GI50) of 0.1-0.58 µM and mean concentration that produce 100% growth inhibition (MG-MID TGI) of 6.03-10.00 µM. Compounds 4d and 4e exhibited very potent and selective cytotoxic activity against MDA-MB-435 subpanel (melanoma cancer) with GI50 of 0.45 µM and 0.59 µM, respectively. The mechanism of antiproliferative activity was determined for the most active compounds 3a, 3d, 3e, 3f, 4d, and 4evia measuring their half maximal inhibitory concentration (IC50) against topoisomerase I enzyme at different concentrations. Compounds 3a and 3e exhibited excellent activity compared with reference drugs with IC50 of 0.295 µM and 0.219 µM, respectively. Plasmid DNA nicking assay verified that these compounds are topoisomerase I poisons not suppressors. The active compound 3e induced a significant disruption in the cell cycle profile parallel to its effect on apoptosis induction.

Synthesis of certain benzothieno[3,2-d]pyrimidine derivatives as a selective SIRT2 inhibitors.

A series of new benzothieno[3,2-d]pyrimidine derivatives were designed and synthesized. The National Cancer Institute (NCI, USA) evaluated all synthesized compounds against 60 human tumor cell lines. Most of the compounds showed good cytotoxicity against MCF-7 breast cancer cell line and UO-31 renal cancer cell line (growth inhibitory range: 17.88%-68.65%). IC50 of twelve most active compounds was determined against MCF-7 and UO-31 cell lines. Compounds 7, 10, 13, 16 and 17 proved a prominent anticancer activity against tested cell lines (IC50 range 0.23-26.25 µg/mL). IC50 against SIRT2 enzyme was evaluated for the most active compounds to explore the mechanism of antiproliferative activity. The best activity was displayed by compound 7 (IC50 = 2.10 µg/mL), which is 6.6 more potent than cambinol as a reference. Moreover, compound 7 displayed high selectivity against SIRT1 and SIRT2 over SIRT3 in the selectivity studies and displayed twice activity of cambinol in hyperacetylation of α-tubulin protein with IC50 = 32.05 µg/mL. Molecular docking study of the synthesized compounds into SIRT2 active site was performed to rationalize the remarkable SIRT2 inhibitory activity.

Novel Pyrazolo[3,4-d]pyrimidines as Potential Cytotoxic Agents: Design, Synthesis, Molecular Docking and CDK2 Inhibition.

BACKGROUND: Pyrazolo[3,4-d]pyrimidine scaffold was reported to possess potent cytotoxic and CDK2 inhibitory activity as analogue of roscovitine. OBJECTIVE: To design and synthesize novel 1-(4-flourophenyl)pyrazolo[3,4-d]pyrimidine derivatives as bioisosters of roscovitine with potential cytotoxic and CDK2 inhibitory activity. METHODS: A series of novel 1-(4-flourophenyl)pyrazolo[3,4-d]pyrimidines were designed and synthesized. Structural elucidation for all the newly synthesized compounds was achieved through performing MS, 1H NMR, 13C NMR and IR spectral techniques. Eight compounds were screened for their cytotoxic activity by National Cancer Institute (USA) against 60 different human cancer cell lines. Compounds 2a, 4, 6, 7b, 8a and 8b were further studied through the determination of their IC50 values against the most sensitive cell lines. The inhibitory activities of compounds 2a and 4 were evaluated against CDK2 enzyme. RESULTS: Compound 4 exhibited the most prominent broad-spectrum cytotoxic activity against 42 cell lines representing all human cancer types showing growth inhibition percentages from 53.19 to 99.39. Compound 2a showed promising selectivity against several cell lines. Moreover, all the test compounds exhibited potent cytotoxic activity in nanomolar to micromolar range with IC50 values ranging from 0.58 to 8.32µM. Compound 2a showed significant cytotoxic activity against CNS (SNB-75), lung (NCI-H460) and ovarian (OVCAR-4) cancer cell lines with IC50 values 0.64, 0.78 and 1.9µM, respectively. Compound 4 showed promising potency against leukemia (HL-60) and CNS (SNB-75) cell lines (IC50 = 0.58 and 0.94µM, sequentially). Moreover, the antiproliferative activities of compounds 2a and 4 appeared to correlate well with their ability to inhibit CDK2 at sub-micromolar level (IC50 = 0.69 and 0.67µM, respectively) that were comparable to roscovitine (IC50=0.44µM). The Molecular docking results revealed that compound 4 interacted with the same key amino acids as roscovitine in the active site of CDK2 enzyme with a marked docking score (-14.1031 kcal/mol). CONCLUSION: 1-(4-Flourophenyl)pyrazolo[3,4-d]pyrimidine is a promising scaffold for the design and synthesis of potent cytotoxic leads.

Novel pyrazolo[3,4-d]pyrimidines: design, synthesis, anticancer activity, dual EGFR/ErbB2 receptor tyrosine kinases inhibitory activity, effects on cell cycle profile and caspase-3-mediated apoptosis.

A series of novel pyrazolo[3,4-d]pyrimidines was synthesised. Twelve synthesised compounds were evaluated for their anticancer activity against 60 human tumour cell lines by NCI (USA). Compound 7d proved prominent anticancer activity. It showed 1.6-fold more potent anti-proliferative activity against OVCAR-4 cell line with IC50 = 1.74 µM. It also exhibited promising potent anticancer activity against ACHN cell line with IC50 value 5.53 µM, representing 2.2-fold more potency than Erlotinib. Regarding NCI-H460 cell line, compound 7d (IC50 = 4.44 µM) was 1.9-fold more potent than Erlotinib. It inhibited EGFR and ErbB2 kinases at sub-micromolar level (IC50 = 0.18 and 0.25 µM, respectively). Dual inhibition of EGFR and ErbB2 caused induction of apoptosis which was confirmed by a significant increase in the level of active caspase-3 (11-fold). It showed accumulation of cells in pre-G1 phase and cell cycle arrest at G2/M phase.

Synthesis of new pyrazoles and pyrozolo [3,4-b] pyridines as anti-inflammatory agents by inhibition of COX-2 enzyme.

New pyrazoles and pyrazolo[3,4-b] pyridines were synthesized and their structure was confirmed by elemental analyses as well as IR, 1H NMR, 13C NMR, and mass spectral data. All the newly synthesized derivatives were evaluated in vitro for inhibitory activity against COX-1 and COX-2 enzymes and their IC50 values were calculated, most of the derivatives showed good inhibitory activity with derivatives IVb, IVh and IVJ showing inhibitory activity better than celecoxib. Moreover, the eight most potent derivatives IVa, IVb, IVc, IVd, IVe, IVh, IVJ, and IVL were selected for in vivo assay to measure their effect on paw edema in rates and their ulcerogenic effect. Compounds IVa, IVb and IVc were found to be the most active and selective as COX-2 inhibitors and most effective in protection from edema, they were also found to have lowest ulcerogenic effect among all derivatives.

Synthesis, antitumor screening and cell cycle analysis of novel benzothieno[3,2-b]pyran derivatives.

Three series of benzothiophene derivatives were designed and synthesized as cytotoxic agents. The compounds were subjected to in vitro antitumor screening at the National Cancer Institute (NCI), Bethesda, MD. The results of the single dose screening indicated that only the benzothieno[3,2-b]pyran series 3a-f exhibited potent and broad spectrum cytotoxic activity and was subjected to five dose cytotoxic screening. The most active compound in this study was 2-amino-6-bromo-4-(4-nitrophenyl)-4H-[1]benzothieno[3,2-b]pyran-3-carbonitrile (3e) with MG-MID GI50, TGI, and LC50 values of 0.11, 7.94 and 42.66 µM, respectively. Compound 3e exhibited broad spectrum anticancer activity against a panel of 59 cell lines. To elucidate the underlying mechanism of compound 3e cytotoxic activity, we examined its effect on cell cycle progression and its ability to induce apoptosis using human colon adenocarcinoma cell line (HCT-116). The effect of compound 3e on the cell cycle progression indicated that exposure of HCT-116 cells to compound 3e for 24 and 48 h, induced a significant disruption in the cell cycle profile including time dependent decrease in cell population at G1 phase with concomitant increase in pre-G and G2/M cell population. Moreover, compound 3e induced time dependent increase in the percentage of early and late apoptotic and necrotic cell population. In conclusion, we were able to successfully design a new series of benzothieno[3,2-b]pyran derivatives with potent cytotoxic activity and their mechanism of cytotoxicity was examined.