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Novel fused chromenes ( 4 , 7 ⁻ 11 ) and pyrimidines ( 12 ⁻ 16 ) were designed, synthesized, and evaluated for their mammary gland breast cancer (MCF-7), human colon cancer (HCT-116), and liver cancer (HepG-2) activities. The structural identity of the synthesized compounds was established according to their spectroscopic analysis, such as FT-IR, NMR, and mass spectroscopy. The preliminary results of the bioassay disclosed that some of the target compounds were proven to have a significant antiproliferative effect against the three cell lines, as compared to Doxorubicin, Vinblastine, and Colchicine, used as reference drugs. Particularly, compounds 7 and 14 exerted promising anticancer activity towards all cell lines and were chosen for further studies, such as cell cycle analysis, cell apoptosis, caspase 3/7 activity, DNA fragmentation, cell invasion, and migration. We found that these potent cytotoxic compounds induced cell cycle arrest at the S and G2/M phases, prompting apoptosis. Furthermore, these compounds significantly inhibit the invasion and migration of the different tested cancer cells. The structure-activity relationship (SAR) survey highlights that the antitumor activity of the desired compounds was affected by the hydrophobic or hydrophilic nature of the substituent at different positions.

A series of 1H-benzo[f]chromene moieties (4a–z) were synthesised under Ultrasonic irradiation and confirmed with spectral analyses. Derivative 4i solely possessed an X-ray single crystal. The anti-proliferative efficacy of the desired molecules has been explored against three cancer cells: MCF-7, HCT-116, and HepG-2 with the cytotoxically active derivatives screened against MCF-7/ADR and normal cells HFL-1 and WI-38. Furthermore, compounds 4b–d, 4k, 4n, 4q, and 4w, which possessed good potency against MCF-7/ADR, were tested as permeability glycoprotein (P-glycoprotein [P-gp]) expression inhibitors. The attained data confirmed that 4b–d, 4q, and 4w exhibited strong expression inhibition against the P-gp alongside its cytotoxic effect on MCF-7/ADR. The western blot results and Rho123 accumulation assays showed that compounds 4b–d, 4q, and 4w effectively inhibited the P-gp expression and efflux function. Meanwhile, 4b–d, 4q, and 4w induced apoptosis and accumulation of the treated MCF-7/ADR cells in the G1 phase and 4k and 4n in the S phase of the cell cycle. [ABSTRACT FROM AUTHOR]

β-Enaminonitriles bearing 9-hydroxy-1H-benzo[f]chromene moiety was synthesized. The targeted compounds were evaluated for their anti-proliferative activity against three human tumor cell lines, PC-3, SKOV-3 and HeLa, and the active cytotoxic compounds were further evaluated against cancer cells, MCF-7/ADR, and two normal cell lines, HFL-1 and WI-38. Few compounds were assigned to be the most potent derivatives against PC-3, SKOV-3 and HeLa cell lines in comparison with Vinblastine and Doxorubicin. Several compounds possessed a relatively good potency against MCF-7/ADR cells as compared with Doxorubicin and were tested as a P-gp inhibitor. Moreover, the halogenated substituents, 2,4-F2, 2,3-Cl2, 2,5-Cl2 and 3,4-Cl2; have good potency against P-gp-mediated MDR in MCF-7/ADR as compared with Doxorubicin. Meanwhile, Rho123 accumulation assays revealed that few compounds effectively inhibited P-pg and efflux function. In addition, certain derivatives induced apoptosis and an accumulation of the treated MCF-7/ADR cells in the G1, S and G1/S phases. [ABSTRACT FROM AUTHOR]

Novel fused chromenes (4,7–11) and pyrimidines (12–16) were designed, synthesized, and evaluated for their mammary gland breast cancer (MCF-7), human colon cancer (HCT-116), and liver cancer (HepG-2) activities. The structural identity of the synthesized compounds was established according to their spectroscopic analysis, such as FT-IR, NMR, and mass spectroscopy. The preliminary results of the bioassay disclosed that some of the target compounds were proven to have a significant antiproliferative effect against the three cell lines, as compared to Doxorubicin, Vinblastine, and Colchicine, used as reference drugs. Particularly, compounds 7 and 14 exerted promising anticancer activity towards all cell lines and were chosen for further studies, such as cell cycle analysis, cell apoptosis, caspase 3/7 activity, DNA fragmentation, cell invasion, and migration. We found that these potent cytotoxic compounds induced cell cycle arrest at the S and G2/M phases, prompting apoptosis. Furthermore, these compounds significantly inhibit the invasion and migration of the different tested cancer cells. The structure-activity relationship (SAR) survey highlights that the antitumor activity of the desired compounds was affected by the hydrophobic or hydrophilic nature of the substituent at different positions. [ABSTRACT FROM AUTHOR]

[Display omitted] • Thirteen compounds of new N -sulfonylpiperidines were designed and synthesized. • Cytotoxic activities were evaluated against HCT-116, HepG-2, and MCF-7 cell lines. • In vitro VEGFR-2 inhibition was evaluated. • Cell cycle and apoptosis analyses were performed. • Molecular docking studies were carried out. A new panel of N -sulfonylpiperidine derivatives has been designed and synthesized as vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors. Anti-proliferative activities of the synthesized members were tested against colorectal carcinoma (HCT-116), hepatocellular carcinoma (HepG-2), and breast cancer (MCF-7) cell lines. Compounds 3a, 4, 8, and 9 showed the highest activities against the tested cell lines. In particular, compound 8 showed excellent activities against HCT-116, HepG-2, and MCF-7 with IC 50 values of 3.94, 3.76, and 4.43 μM, respectively. Such IC 50 values are comparable to vinblastine (IC 50 = 3.21, 7.35, 5.83 μM, respectively) and doxorubicin (IC 50 = 6.74, 7.52, 8.19 μM, respectively). In vitro VEGFR-2 inhibitory activity of the most promising molecules (3a, 4, 8, and 9) indicated that compound 8 is the highest VEGFR-2 inhibitor with an IC 50 of 0.0554 μM, compared to sorafenib (IC 50 = 0.0416 μM). The most promising candidates (3a, 4, 8, and 9) were subjected to flow cytometry analyses to assess their effects on the cell cycle behavior and the apoptotic power against the three tested cell lines (HCT-116, HepG-2, and MCF-7). The tested compound arrested the tumor cells at both the G2/M and Pre-G1 phases. In addition, compound 9 was proved as the most effective apoptotic inducer among the tested compounds against the tested cells. Molecular docking studies against VEGFR-2 (PDB ID: 2OH4) revealed good binding modes of the synthesized compound similar to that of sorafenib. Computational investigation of ADMET parameters revealed the drug-likeness of the synthesized compounds. [ABSTRACT FROM AUTHOR]

• Tricyclic 4 H -benzo[ h ]chromene and 1 H -benzo[ f ]chromene derivatives were synthesized as potential anticancer agents. • The cytotoxic activity was tested against MCF-7, HepG-2, and PC-3 cell lines. • The cell cycle analysis and apoptosis assay were reported. • The tyrosine kinase receptors EGFR and VEGFR-2 were study. A class of 4 H -benzo[ h ]chromene (4a-h) and 1 H -benzo[ f ]chromene (6a-h) derivatives linked to carboxamide/carbothioamide at the 3/2-positions were designed and synthesized with the intent of cultivating efficacious antitumor agents. The pursued benzochromenes were successfully authenticated via the employment of an array of spectral assays. Subsequently, an antiproliferative evaluation against a selected line of tumorous cells (MCF-7, HepG-2, and PC-3) were performed in-vitro for the novel benzochromenes (4a-h and 6a-g) with the superior cytotoxically-active molecules subjected to additional assessment against the non-cancerogenic cells (HFL-1 and WI-38). Compounds 4a, 6b, 6c, 6d, 6f, and 6g demonstrated high efficiency towards MCF-7, HepG-2, and PC-3 cell lines, analogous to that of Vinblastine, Doxorubicin, and feeble efficacy against normal cell lines. The inhibition activity of the selected molecules (4a, 6b, 6c, 6d, 6f, and 6g) was detected in the G2/M phase of the cell cycle, which similarly instigated the suppression of the topoisomerase I & II enzymes in order to yield this result. Additionally, the derivatives submitted for the topoisomerase inhibition appraisal were similarly subjugated to examinations regarding the inhibition of tyrosine kinase receptors EGFR and VEGFR-2, in which the results were successively contrasted against the reference kinase inhibitor Sorafenib. Lastly, the molecular docking assay of the highly potent and efficacious derivatives in correlation with the active enzymatic and kinase sites was addressed. [ABSTRACT FROM AUTHOR]

• Design of novel fused chromene and pyrimidine derivatives as promising anticancer agents. • The cytotoxic activity of the new molecules was explored against three cancer cell lines MCF-7, HCT-116, and HepG-2. • Flow cytometric analyses also confirmed that some of the new compounds can induce apoptosis in MCF-7, HCT-116 and HepG-2 cell lines. • These compounds have significantly inhibited the invasion and migration of the different tested cancer cells. Novel β -enaminonitrile/ester compounds (4 , 6) and an imidate of 4 (9) were utilized as key scaffolds for the synthesis of newly 2-substituted 4 H -benzo[ h ]chromene (7, 8, 10, 11, 13, 14) and 7 H -benzo[ h ]chromeno[2,3– d ]pyrimidine derivatives (15 – 19). The spectral data confirmed the successful isolation of the desired compounds. The targeted compounds were assessed for their in vitro anticancer activity against mammary gland breast cancer cell line (MCF-7), human colon cancer (HCT-116), and liver cancer (HepG-2), while doxorubicin, vinblastine, and colchicine were utilized as standard references drugs. Some of the examined compounds displayed high growth inhibitory activity against the three different cell lines. For example, the aminoimino derivative (18) exhibited excellent antitumor activity versus all cancer cell lines with IC 50 values = 0.45 µg/mL, 0.7 µg/mL, and 1.7 µg/mL. Among the tested molecules, compounds 9 , 15 , and 18 were selected for further study regarding their effects on cell cycle analysis, apoptosis assay, caspase 3/7 activity, and DNA fragmentation. We found that these three potent cytotoxic compounds induce cell cycle arrest at the S and G2/M phases, which causes apoptosis. Furthermore, these compounds significantly inhibit the invasion and migration of the different tested cancer cells. Finally, the SAR survey highlighted the antitumor activity of the new molecules that was remarkably influenced by the hydrophilicity of substituent as well the fused rings at certain positions. [ABSTRACT FROM AUTHOR]

[Display omitted] • Naturally occurring chromene and benzochromene scaffolds are biologically active. • Synthesized benzochromenes induce cancer cell apoptosis in vitro and in vivo. • Halogens at meta or para positions of the phenyl ring enhance chromene cytotoxicity. Herein, a series of aryl-substituted derivatives of 3-amino-1-aryl-9-methoxy-1 H -benzo[ f ]chromene-2-carbonitriles (4a - 4q) were designed and synthesized via reaction of 7-methoxy-2-naphthol with a mixture of appropriate aromatic aldehydes and malononitrile under microwave conditions. Among the tested benzochromene, the known compound 4e and four novel compounds 4f , 4j , 4k , 4m exhibited the highest cytotoxicity towards a panel of six human cancer cell lines MDA-MB-231, A549, HeLa, MIA PaCa-2, RPMI 7951, and PC-3. Compound 4j with 2,4-dichloro substitution on the pendant phenyl ring exhibited the highest broad-spectrum cytotoxicity towards all tested cancer cell lines. Compounds 4e , 4f , 4j , 4k , 4m were further selected to study the mechanism of cellular toxicity using the triple-negative breast cancer cells MDA-MB-231. Compounds 4e , 4f , 4j , 4k , 4m induced accumulation of the treated MDA-MB-231 cells in the S phase and 4k additionally in the G 2 /M phase of the cell cycle. Compounds 4e , 4f , 4j , 4k , 4m induced dissipation of mitochondrial transmembrane potential and activation of caspase 3/7 in MDA-MB-231 cells with 4 j being one of the most active. In an in vivo model, compound 4j and less efficiently 4e and 4f inhibited growth and proliferation and triggered DNA fragmentation in MDA-MB-231 xenografts grown on chick chorioallantoic membranes. SAR study confirmed that the 2,4-dichloro substitution pattern on the pendant phenyl ring enhanced the cytotoxic activity of benzochromene. [ABSTRACT FROM AUTHOR]

Novel Molecular Discovery of Promising Amidine-based thiazole analogues as Potent Dual Matrix Metalloproteinase-2 and 9 Inhibitors: Anticancer Activity Data with Prominent Cell Cycle Arrest and DNA Fragmentation Analysis Effects. • 2-Aminothiazoles, linked amidine moieties were synthesized as potential anticancer agents. • The cytotoxic activity was tested against (MDA-MB-231), (HCT-116) and (MCF-7) cell lines. • The thiazole-based MMP-2/9 inhibitors have significant potential for anticancer treatment. • Compounds 4a were able to induce cell cycle arrest at G2/M phase, cause intrinsic and extrinsic apoptotic cell death. Thiazole derivatives are known to possess various biological activities such as antiparasitic, antifungal, antimicrobial and antiproliferative activities. Matrix metalloproteinases (MMPs) are important protease target involved in tumor progression including angiogenesis, tissue invasion, and migration. Therefore, MMPs have also been reported as potential diagnostic and prognostic biomarkers in many types of cancer. Herein, new aryl thiazoles were synthesized and evaluated for their anticancer effects on a panel of cancer cell lines including the invasive MDA-MB-231 line. Some of these compounds showed IC 50 values in the submicromolar range in anti-proliferative assays. In order to examine the relationship between their anticancer activity and MMPs targets, the compounds were evaluated for their inhibitory effects on MMP-2 and 9. That data obtained revealed that most of these compounds were potent dual MMP-2/9 inhibitors at nanomolar concentrations. Among these, 2-(1-(2-(2-((E)-4-iodobenzylidene)hydrazineyl)-4-methylthiazol-5-yl)ethylidene)hydrazine-1-carboximidamide (4a) was the most potent non-selective dual MMP-2/9 inhibitor with inhibitory concentrations of 56 and 38 nM respectively. When compound 4a was tested in an MDA-MB-231, HCT-116, MCF-7 model, it effectively inhibited tumor growth, strongly induced cancer cell apoptosis, inhibit cell migration, and suppressed cell cycle progression leading to DNA fragmentation. Taken together, the results of our studies indicate that the newly discovered thiazole-based MMP-2/9 inhibitors have significant potential for anticancer treatment. [ABSTRACT FROM AUTHOR]

• Diverse heterocyclic compounds with a sulfonamide moiety were created. • Various compounds showed antiproliferative activity against cancer cell lines. • Compounds 17a , 21 , 24 and 30a potently induced cell cycle arrest and apoptosis. • Compound 24 exhibited a promising activity against human Topoisomerases I and II. • Molecular modeling experiments significantly supported the molecular target. A series of heterocyclic compounds with a sulfonamide moiety were synthesized from reaction of enaminone 4 with active methylene compounds, glycine derivatives, 1,4-benzoquinone, hydroxylamine hydrochloride, hydrazonyl halides and dimethylacetylenedicarboxylate. The newly synthesized sulfonamide derivatives were characterized by FT-IR, 1H NMR, 13C NMR, mass spectroscopy, elemental analysis and alternative synthetic routes. The reactions products were evaluated for their antiproliferative activity against a panel of three different human cancerous cell lines, MCF-7 (breast), HepG-2 (liver) and HCT-116 (colon) and the results were deployed to derive the structure–activity relationships (SAR). Various test compounds were potent antiproliferative to cancerous cells; reaching very low micromolar levels, as in case of 21 which showed IC 50 value of 6.2 μM against HepG-2 cell. In addition, treatment of cancerous cells with the synthesized compounds induced cell apoptosis and G2/M phase arrest evidenced by flow cytometric analysis. Furthermore, the activity of the synthesized compounds against TOP I and II were documented by DNA relaxation assays. Data revealed that compound 24 significantly interfered with TOP I- and II-mediated DNA relaxation, nicking and decatenation, with IC 50 values 27.8 and 33.6 μM, respectively. Moreover, the molecular docking studies supported the results from enzymatic assays, where compound 24 was intercalated between nucleotides flanking the DNA cleavage site via pi-pi stacking and hydrophobic interactions. In conclusion, aromatic heterocycles linked to sulfonamides are excellent molecular frameworks amenable for optimization as dual TOP I and II poisons to control various human malignancies. [ABSTRACT FROM AUTHOR]

• β -enamionitriles, linked 8-bromo-1 H -benzo[ f ]chromene moieties were synthesized as potential anticancer agents. • The cytotoxic activity was tested against (MCF-7), (HCT-116) and (HepG-2) cell lines. • Compounds 4b , d , e , i , k were able to induce cell cycle arrest at G2/M phase, increase the production of Caspases 3, 8, and 9, and finally cause intrinsic and extrinsic apoptotic cell death. • Compounds 4b , d , e , i , k prompting apoptotic cell death due to the dual inhibitory effect on the catalytic activity of topoisomerase II. In our endeavors to develop novel and powerful agents with antiproliferative activities, a series of β -enamionitriles , linked to the 8-bromo-1 H -benzo[ f ]chromene moieties (4a-m), was designed and synthesized under microwave irradiation conditions. The structures of the target compounds were established on the basis of their spectral data: IR, 1H NMR, 13C NMR, 13C NMR-DEPT/APT, 19F NMR and MS. Furthermore, the antiproliferative properties were evaluated against the human cancer cell lines MCF-7, HCT-116, and HepG-2 in comparison to the positive controls Vinblastine and Doxorubicin, employing the viability assay. The obtained results confirmed that most of the tested molecules revealed strong and selective cytotoxic activities against the three cancer cell lines. The most potent cytotoxic compounds 4b , 4d , 4e , 4i , and 4k were elected for further examination, such as the cell cycle analysis, the apoptosis assay, the Caspase production, and the DNA fragmentation. This study also revealed that the desired compounds stimulate cell cycle arrest at the G2/M phases, increase the production of Caspases 3, 8, and 9, and finally cause intrinsic and extrinsic apoptotic cell death. Moreover, these compounds suppress the action of the topoisomerase II enzyme and also disrupt the microtubule functions. The SAR study of the synthesized compounds verified that the substitution on the phenyl ring of the 1 H -benzo[ f ]chromene nucleus, accompanied with the presence of the bromine atom at the 8-position, increases the ability of these molecules against different cell lines. [ABSTRACT FROM AUTHOR]

Novel halogenated β -enaminonitriles linked 9-bromo-1 H -benzo f -chromene moieties with dual inhibition of Topoisomerase I and II. • 4 H -Benzo h chromenes were synthesized as potential anticancer agents. • The cytotoxic activity was tested against MCF-7, HCT-116 and HepG-2 cell lines. • Compounds 4c,d,h,l,m were induce cell cycle arrest at G2/M phase. • Compounds 4c,d,h,l,m prompting apoptotic cell death due to the dual inhibitory effect on the catalytic activity of topoisomerase I and II. A novel series of halogenated β -enaminonitriles (4a-m), linked 9-bromo-1 H -benzo f -hromene moieties, were synthesized via microwave irradiation and were predestined for their cytotoxic activity versus three cancer cell lines, namely: MCF-7, HCT-116, and HepG-2. Several of the tested compounds showed high growth inhibitory activities versus the tumor cell lines. Particularly, compounds 4c , 4d , 4f , 4h , 4j , 4l , and 4m demonstrated superior antitumor activities against the aforementioned cell lines. Moreover, the apoptosis process in all the tested cells was induced by compounds 4c , 4d , 4h , 4l , and 4m , as observed by the Annexin V/PI double staining flow cytometric assay. The DNA flow, cytometric analysis revealed that these compounds prompted cell cycle arrest at the G2/M phases. Furthermore, the topoisomerase catalytic activity assays indicated that these compounds inhibited both the topoisomerase I and II enzymes. [ABSTRACT FROM AUTHOR]