Tested Cancer Cell Research Articles

Synthesis and in vitro anticancer activity of 4H-pyrano[2,3-d]pyrimidine−1H-1,2,3-triazole hybrid compounds bearing D-glucose moiety with dual EGFR/HER2 inhibitory activity and induced fit docking study

• 4 H -Pyrano[2,3- d ]pyrimidine−1,2,3-triazole− d -glucose hybrid compoundssynthesized • Some compounds inhibited for MCF7, HepG2, HeLa cell lines with IC 50 < 4 μM • Compounds 8v,8z,8zc , and 8zf exhibited against EGFR and HER2 tyrosine kinases • Induced fit docking and MM-GBSA simulations for 8zc on EGFR enzyme. The polysubstituted 4 H -pyrano[2,3- d ]pyrimidines 6a-zj containing propargyl group on nitrogen atom 3 of ring have been synthesized by ring-closing reaction of corresponding 2-amino-3-cyano-4 H -pyrans 4a-zj with acetic anhydride and trifluoroacetic acid as catalyst, followed by alkylation with propargyl bromide under ultrasound conditions. A series of 36 analogs of 4 H -pyrano[2,3- d ]pyrimidine 8a-zj bearing d -glucose moiety tethered 1,2,3-triazole derivatives, including eighteen new ones, were synthesized by click chemistry between these N -propargyl derivatives and peracetylated d -glucopyaranosyl azide, with using CuNPs@Montmorillonite as a catalyst under ultrasound condition in the presence of DIPEA in t -BuOH/H 2 O at 25°C for 20 min. These compounds exhibited potent anticancer activity against tested cancer cells, including MCF-7, HepG2, and HeLa. Amongst tested compounds, some compounds exhibited strong activity against tested cancer cell lines with IC 50 < 4 μM, such as 8v,8x,8z,8zc,8zf and 8zg against MCF-7, 8s,8t,8w,8zh , and 8zi against HepG2, 8h,8j,8zf and 8zh against HeLa cancer cell lines. Compounds 8v,8z,8zc , and 8zf exhibited remarkable inhibitory activity against EGFR and HER2 tyrosine kinases in comparison with Lapatinib. The resulted docking studies showed that compound 8zc displayed binding mode like Erlotinib on EGFR enzyme and showed good binding energies. Induced fit docking, MM-GBSA calculation, and molecular dynamics simulations were carried out to elucidate the inhibitory potential of compound 8zc against tested enzyme 4HJO. Docking analysis showed that amongst the hydrophilic and hydrophobic interactions at the active site of EGFR enzyme, the hydrogen-bond bindings between acetate function and appropriate amino acid residues displayed the most important contribution in intensifying their potency against this enzyme.

Synthesis and Biological Evaluation of Indole-2-Carboxamides with Potent Apoptotic Antiproliferative Activity as EGFR/CDK2 Dual Inhibitors.

The apoptotic antiproliferative actions of our previously reported CB1 allosteric modulators 5-chlorobenzofuran-2-carboxamide derivatives VIIa–j prompted us to develop and synthesise a novel series of indole-2-carboxamide derivatives 5a–k, 6a–c, and 7. Different spectroscopic methods of analysis were used to validate the novel compounds. Using the MTT assay method, the novel compounds were examined for antiproliferative activity against four distinct cancer cell lines. Compounds 5a–k, 6a–c, and 7 demonstrated greater antiproliferative activity against the breast cancer cell line (MCF-7) than other tested cancer cell lines, and 5a–k (which contain the phenethyl moiety in their backbone structure) demonstrated greater potency than 6a–c and 7, indicating the importance of the phenethyl moiety for antiproliferative action. Compared to reference doxorubicin (GI50 = 1.10 µM), compounds 5d, 5e, 5h, 5i, 5j, and 5k were the most effective of the synthesised derivatives, with GI50 ranging from 0.95 µM to 1.50 µM. Compounds 5d, 5e, 5h, 5i, 5j, and 5k were tested for their inhibitory impact on EGFR and CDK2, and the results indicated that the compounds tested had strong antiproliferative activity and are effective at suppressing both CDK2 and EGFR. Moreover, the studied compounds induced apoptosis with high potency, as evidenced by their effects on apoptotic markers such as Caspases 3, 8, 9, Cytochrome C, Bax, Bcl2, and p53.

New thiazole-based derivatives as EGFR/HER2 and DHFR inhibitors: Synthesis, molecular modeling simulations and anticancer activity

New series of thiazole and imidazo[2,1-b]thiazole derivatives were synthesized and tested for their in vitro anticancer activity. Compounds 27, 34, 39 and 42–44 showed the best anticancer activity against the tested cancer cell lines with high safety profile and selectivity indices, especially MCF-7 breast cancer, compared to sorafenib. As an attempt to reveal their mode of cytotoxicity, EGFR, HER2 kinase and DHFR inhibition assays were performed. Compounds 39 and 43 were the most potent dual EGFR/HER2 kinase inhibitors, with IC50 values of 0.153 (EGFR), 0.108 (HER2) and 0.122 (EGFR), 0.078 (HER2) μM, respectively. 39 and 42 were the best DHFR inhibitors showing IC50 0.291 and 0.123 μM, respectively. 39 and 43 induced their cytotoxicity via cell cycle arrest at G1/S and G1 phases, respectively, and apoptosis rather than necrosis in the MCF-7 breast cancer cell line. In vivo anti-breast cancer assay of 39 and 43 showed significant tumor volume reduction with recovered caspase-3 immunoexpression. Modeling study results proved the importance of the 5-(4-substituted phenyl)-imidazo[2,1-b]thiazole moiety and the hydrazide side chain for the anticancer activity. The most potent compounds showed good drug-likeness features and could be used as prototypes for further optimization. 39 could be an example of a multi-targeting anticancer agent that acts by inhibiting EGFR/HER2 kinase, DHFR enzymes and cellular apoptosis.

Synthesis of silver nanoparticles using Alpinia officinarum rhizome extract induces apoptosis through down-regulating Bcl-2 in human cancer cells.

In this study, silver nanoparticles were synthesized using Alpinia officinarum rhizome extract via an eco-friendly green synthesis method. The silver nanoparticles (AO-AgNPs) were characterized by UV-Vis spectrometry, scanning electron microscopy, energy-dispersive X-ray spectroscopy, and dynamic light scattering. Further, the cytotoxic and apoptotic effects of AO-AgNPs were investigated in human cancer cells with different tissue origins via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and flow cytometric analyses, respectively. The expression levels of anti-apoptotic Bcl-2 protein were evaluated via a real-time polymerase chain reaction. The synthesized AO-AgNPs induced a significant cytotoxic effect in all tested cancer cells but not in normal cells. AO-AgNPs induced the percentage of apoptotic cells and reduced the levels of anti-apoptotic Bcl-2 mRNA levels in cancer cells. These results demonstrate the potential application of AO-AgNPs in cancer treatment.

Synthesis and in vitro anticancer evaluation of 8b-hydroxy-1-(6-substitutedbenzo[d]thiazol-2-yl)-3-(3-substitutedphenyl)-1,8b-dihydroindeno[1,2-c]pyrazol-4(3aH)-ones

A series of 1,8b-dihydroindeno[1,2-c]pyrazol-4(3aH)-ones has been efficiently synthesized on reaction of 2-(3-substitutedbenzoyl)-(1H)-indene-1,3(2H)-diones 1 and 2-hydrazinylbenzo[d]thiazole/2-hydrazinyl-6-substitutedbenzo[d]thiazoles 2 in presence of dry ethanol under reflux conditions in good yields. The structures of all the synthesized derivatives were elucidated by using different physical and spectral techniques (FTIR, 1H NMR, 13C NMR, 2D NMR and HRMS). The synthesized hydroxypyrazolones were assayed for their anticancer activity against two human cancer cell lines (i) lung carcinoma (A549) and (ii) breast carcinoma (MCF7) using MTT assay. Among all the tested compounds, 3d and 3k with IC50 values in the range of 30.68 ± 0.57 µM to 34.87 ± 0.76 µM exhibited moderate inhibitory ability against both the tested cancer cell lines in comparison to the standard drug Doxorubicin (0.95 ± 0.10 µM for A549 and 1.09 ± 0.11 µM for MCF7). The moderately active compounds of the series i.e.3d and 3k were further tested against normal human embryonic kidney cell line (HEK 293T) to examine their toxicity against normal cell lines. Selectivity Index (S.I.) of the most active compounds 3d and 3k was calculated for both the cancer cell lines which revealed that these derivatives i.e. 3d (S.I = 2.82 for A549 and 2.90 for MCF7) and 3k (S.I = 2.78 for A549 and 2.95 for MCF7) are safer anticancer agents.

The study on biological activity and molecular docking of secondary metabolites from Bacillus sp. isolated from the mangrove plant Rhizophora apiculata Blume

Five known secondary metabolites, namely 2-(2-heptenyl)-3-methyl-4-quinolinone (1), 3-methyl-2-(2-nonenyl)-4-quinolinone (2), 2-phenylacetic acid (3), 4-hydroxybenzoic acid (4), and (-)-jasmonic acid (5) were isolated and identified from the crude extract of an endophytic bacterium Bacillus sp. RAR_M1_45 from the mangrove plant Rhizophora apiculata Blume. Cytotoxic assays showed that compounds 1 and 2 exhibited cytotoxicity against the tested cancer cell lines A549 (human lung carcinoma), MCF7 (human breast carcinoma) and KB (human mouth epidermal carcinoma) with IC50 values from 65.09 ± 2.06 to 97.88 ±4.16μg/mL, whereas antimicrobial assays showed that compounds 1–3 exhibited selective antimicrobial activity against plant pathogens with MICs of 16–64 μg/mL. Additionally, compounds 1–5 exhibited α-amylase and α-glucosidase inhibitory effects with IC50 values from 63.87 ± 4.23 to 649.9 ±17.5μg/mL and from 163.3 ± 10.66 to 960.4 ±8.62μg/mL, respectively. Experimental bioassays also revealed that the α-amylase and α-glucosidase inhibitory activities of the isolated compounds were consistent with computational docking results. Regarding ligand-7TAA systems, the potential stability of the complexes by molecular docking simulation was high consistence on the order of α-amylase inhibitory assays: 5 (DS -11.9 kcal.mol−1) >4 (DS -11.3 kcal.mol−1) >3 (DS -10.7 kcal.mol−1) >2 (DS -9.9 kcal.mol−1) >1 (DS -9.0 kcal.mol−1). Regarding ligand-3W37 systems, the potential stability of the complexes by molecular docking simulation was high consistence on the order of α-glucosidase inhibitory assays: 5 (DS -12.8 kcal.mol−1) >4 (DS -12.1 kcal.mol−1) >3 (DS -11.7 kcal.mol−1) >2 (DS -10.0 kcal.mol−1) >1 (DS -9.8 kcal.mol−1).

Cancer Spheroid Proliferation Is Suppressed by a Novel Low-toxicity Compound, Pyra-Metho-Carnil, in a Context-independent Manner.

In a screen of compounds to selectively suppress the growth of cancer spheroids, which contained mutant (mt) KRAS, NPD10621 was discovered and associated derivatives were investigated. Spheroid areas from HCT116-derived HKe3 spheroids expressing wild type (wt) KRAS (HKe3-wtKRAS) and mtKRAS (HKe3-mtKRAS) were treated with 12 NPD10621 derivatives and measured in three-dimensional floating (3DF) cultures. Several cancers were treated with NPD1018 (pyra-metho-carnil: PMC) in 3DF cultures. In a nude mouse assay, 50% cell growth inhibition (GI50) values were determined. From these 12 derivatives, PMC was the most effective inhibitor of HKe3-mtKRAS spheroid growth with the least toxicity. Furthermore, PMC-mediated growth suppression was observed in all tested cancer cell lines, independent of tissue context, driver gene mutations, and drug resistance, suggesting that the PMC target(s) was crucial for cancer growth in a context-independent manner. The GI50 value of PMC in nude mice assay was 7.7 mg/kg and nude mice that were administered 40 mg/kg PMC for 7 days did not show any abnormal blood cell count values. PMC is a low-toxicity compound that inhibits the growth of different tumor cell types.

Green synthesis of multicolour fluorescence carbon quantum dots from sugarcane waste: Investigation of mercury (II) ion sensing, and bio-imaging applications

Initial identification is important in the predictive strategy of many life-threatening ailments, such as infectious diseases and cancer. These diseases' mortality rates could be significantly reduced if they were detected in the early stages of disease development. Natural carbon quantum dots (NCQDs) a new type of carbon-based nanomaterial have sparked the interest of researchers for many years in biomedical applications. The eco-friendly and cost-effective hydrothermal synthesis of fluorescent CQDs utilizing sugarcane baggage as a carbon source is discussed in this study. The RAMAN and XRD analysis confirmed the graphitic nature of CQDs. The FTIR, and XPS demonstrate the presence of functional groups such as CO, CC, and CN, hence it's regarded as CQDs. High-resolution transmission electron microscopy (HR-TEM) findings exhibiting that the synthesized CQDs are predominantly monodispersed spherical in shape, with particle sizes ranging from 2 to 8 nm. It is used to develop a more environmentally friendly and cost-effective fluorescent probe for detecting Hg2+ ions. MCF-7 cells were used to test cancer cell lines, which showed significant bio-labeling capacity and low cytotoxicity. The cell viabilities of the MCF-7 cells were assessed. As a result of their low cytotoxicity and good biocompatibility, we used the synthesized CQDs as an efficient fluorescent probe for multicolour live-cell imaging.

A Novel Late-Stage Autophagy Inhibitor That Efficiently Targets Lysosomes Inducing Potent Cytotoxic and Sensitizing Effects in Lung Cancer.

Simple SummaryLung cancer is the main cause of cancer-related deaths worldwide, mainly due to treatment resistance. For that reason, it is necessary to develop novel therapeutic strategies to overcome this phenomenon. The aim of our study was to design and characterize a synthetic anionophore, LAI-1, that would be able to efficiently disrupt lysosomal activity, leading to autophagy blockage, one of the most important resistance mechanisms in cancer cells. We confirmed that LAI-1 selectively localized in lysosomes, deacidifying them. This effect produced a blockage of autophagy, characterized by an abrogation of autophagosomes and lysosomes fusion. Moreover, LAI-1 produced cell death in lung cancer cells from different histological subtypes, inducing cytotoxicity more efficiently than other known autophagy inhibitors. Finally, LAI-1 was evaluated in combination therapy, showing sensitization to the first-line chemotherapeutic agent cisplatin. Altogether, LAI-1 is a novel late-stage autophagy inhibitor with potential therapeutic applications in tumors with cytoprotective autophagy.Overcoming resistance is one of the most challenging features in current anticancer therapy. Autophagy is a cellular process that confers resistance in some advanced tumors, since it enables cancer cells to adapt to stressful situations, such as anticancer treatments. Hence, the inhibition of this cytoprotective autophagy leads to tumor cells sensitization and death. In this regard, we designed a novel potent anionophore compound that specifically targets lysosomes, called LAI-1 (late-stage autophagy inhibitor-1), and evaluated its role in blocking autophagy and its potential anticancer effects in three lung cancer cell lines from different histological subtypes. Compared to other autophagy inhibitors, such as chloroquine and 3-Methyladenine, the LAI-1 treatment induced more potent anticancer effects in all tested cancer cells. LAI-1 was able to efficiently target and deacidify lysosomes, while acidifying cytoplasmic pH. Consequently, LAI-1 efficiently blocked autophagy, indicated by the increased LC3-II/I ratio and p62/SQSTM1 levels. Moreover, no colocalization was observed between autophagosomes, marked with LC3 or p62/SQSTM1, and lysosomes, stained with LAMP-1, after the LAI-1 treatment, indicating the blockage of autophagolysosome formation. Furthermore, LAI-1 induced cell death by activating apoptosis (enhancing the cleavage of caspase-3 and PARP) or necrosis, depending on the cancer cell line. Finally, LAI-1 sensitized cancer cells to the first-line chemotherapeutic agent cisplatin. Altogether, LAI-1 is a new late-stage autophagy inhibitor that causes lysosomal dysfunction and the blockage of autophagolysosome formation, as well as potently induces cancer cell death and sensitization to conventional treatments at lower concentrations than other known autophagy inhibitors, appearing as a potential new therapeutic approach to overcome cancer resistance.

The discovery of a non-competitive GOT1 inhibitor, hydralazine hydrochloride, via a coupling reaction-based high-throughput screening assay

Glutamate oxaloacetate transaminase 1 (GOT1) plays a key role in aberrant glutamine metabolism. GOT1 suppression can arrest tumor growth and prevent the development of cancer, indicating GOT1 as a potential anticancer target. Reported GOT1 inhibitors, on the other hand, are quite restricted. Here, we developed and optimized a coupling reaction-based high-throughput screening assay for the discovery of GOT1 inhibitors. By using this screening assay, we found that the cardiovascular drug hydralazine hydrochloride inhibited GOT1 catalytic activity, with an IC50 of 26.62 ± 7.45 μM, in a non-competitive and partial-reversible manner. In addition, we determined the binding affinity of hydralazine hydrochloride to GOT1, with a Kd of 16.54 ± 8.59 μM, using a microscale thermophoresis assay. According to structure–activity relationship analysis, the inhibitory activity of hydralazine hydrochloride is mainly derived from its hydrazine group. Furthermore, it inhibits the proliferation of cancer cells MCF-7 and MDA-MB-468 with a slight inhibitory effect compared to other tested cancer cells, highlighting GOT1 as a promising therapeutic target for the treatment of breast cancer.

In vitro and in silico cytotoxic activities of triterpenoids from the leaves of Aralia dasyphylla Miq. and the assessment of their ADMET properties

From the methanol extract of the leaves of Aralia dasyphylla Miq. (Araliaceae), ten triterpenoids including five ursane-type triterpenoids, ursolic acid (1), 3-O-α-l-arabinopyranosyl ursolic acid (2), ursolic acid 28-O-β-D-glucopyranosyl ester (3), 3-O-[β-D-glucopyranosyl (l→3)]-α-L-arabinopyranosyl ursolic acid (4), and matesaponin 1 (5), and five oleanane-type triterpenoids, elatoside E (6), elatoside F (7), 3-O-[β-D-glucopyranosyl (l→3)]-α-L-arabinopyranosyl oleanolic acid (8), 3-O-α-L-arabinopyranosyl oleanolic acid (9) and oleanolic acid 28-O-β-D-glucopyranosyl ester (10) were isolated. Their structures were elucidated based on 1D-, 2D-NMR and ESI-MS spectra as well as by comparison with those reported in the literature. All isolated compounds were evaluated in vitro for their cytotoxic activities against three human cancer cell lines (HepG2, LU-1 and RD) and in silico by molecular docking studies on human glucose transporter 1 (hGLUT1) protein. The triterpenoids 2, 4, 6, 8 and 9 exhibited good growth inhibition of HepG2 and LU-1 cancer cell lines with IC50 values in the range 1.76 − 7.21 (μM). The oleanane type triterpenoid 8 was the highest cytotoxic compound to inhibit all the tested cancer cell lines with IC50 values of 2.73 ± 0.12, 1.76 ± 0.11, 2.63 ± 0.10 μM, respectively. The in silico molecular docking study results showed that compounds 4 and 6 had the highest binding affinity. Compounds 1–10 were evaluated for their in silico ADMET of absorption, distribution, metabolism, excretion and oral toxicity parameters. Compounds 6, 8, 9 and 10 from A. dasyphylla are potential hGLUT1 inhibitors and worth of further investigation for the prevention or treatment of diabetes and cancer. Communicated by Ramaswamy H. Sarma

Cytotoxicity, acute and sub-chronic toxicities of the fruit extract of Tetrapleura tetraptera (Schumm. & Thonn.) Taub. (Fabaceae)

BackgroundTetrapleura tetraptera is a medicinal spice traditionally used to treat cancer, diabetes, and several other ailments. This study analyzed the cytotoxicity of the dichloromethane methanol extract of T. tetraptera fruits (TTF) and its constituents. The toxicity profile of the TTF extract was also evaluated in rats.MethodsThe Cytotoxicity of this extract was evaluated using the resazurin reduction assay (RRA). Acute and sub-chronic toxicity studies were performed according to the protocol described by the Organisation for Economic Cooperation, and Development (OECD). Hematological, serum, and urine biochemical parameters, as well as histological sections of the liver and kidney, were also evaluated based on standard methods.ResultsThe TTF extract, compound 5, and the reference drug doxorubicin were active in all 9 tested cancer cell lines. The recorded IC50 ranged from 18.32 μM (against B16-F1 murine melanoma cells) to 36.18 μM (against SKMel-505 BRAF wildtype melanoma cells) for TTF, from 10.02 μM (towards MaMel-80a BRAF-V600E homozygous mutant melanoma cells) to 31.73 μM (against SKMel-28 BRAF-V600E homozygous mutant melanoma cells) for compound 5, and from 0.22 μM (against B16-F1 cells) to 9.39 μM (against SKMel-505 cells) for doxorubicin. The study of acute toxicity test showed that the lethal dose (LD50) of this extract was greater than 5000 mg/kg body weight. In the sub-chronic toxicity studies, variations were observed in some biochemical parameters, especially at higher doses.ConclusionTTF and its most active compound (5) are found to be potential cytotoxic agents, meanwhile, TTF was safe when given a single oral dose of 5000 mg/kg. However, caution is necessary in case of prolonged oral administration due to potential alterations of renal function at high doses (> 1000 mg/kg).

Microwave-assisted synthesis, spectroscopic characterization, and biological evaluation of fused thieno[2,3-d]pyrimidines as potential anti-cancer agents targeting EGFRWT and EGFRT790M.

Epidermal growth factor receptor (EGFR) is a transmembrane protein tyrosine kinase that is usually overexpressed in many types of cancers. In the present study, an effort was done in synthesis of new 3,4-diaminothieno[2,3-b] thiophene-2,5-dicarbonitrile derivatives 2-8, assisted by a microwave device. Different spectroscopic instruments were used for their analysis and confirmed their chemical structures. The antimicrobial properties of the produced compounds were investigated and found to be promising. Next, they were tested for cytotoxicity against MCF-7, HepG-2, HCT-116, and A549 cell lines. Moreover, in vitro cytotoxicity evaluation against well-known standards, namely, gefitinib and erlotinib was achieved using MTT method. The obtained compounds (2-8) were found to be more effective against the two tested cancer cell lines than erlotinib. In MCF-7 and A549 cells, compound 3 was found to be 4.42 and 4.12 times more active than erlotinib, respectively. The activity of radical scavenging was inhibited by 78%. The most cytotoxic compounds were subsequently studied for their kinase inhibitory effect against EGFRWT and EGFRT790M using the HTRF assay. Compound 3 was shown to be the most powerful against both kinds of EGFR, with IC50 values of 0.28 and 5.02. Furthermore, compound 2 demonstrated the highest antioxidant activity as it has a radical scavenging activity of 78%. Compounds 2,6,7 and 8 revealed to be the most safe compounds, none hepatotoxic, none carcinogenic, none immunotoxic, none mutagenic and none cytotoxic.

Design, Synthesis and In vitroCytotoxic Evaluation of Novel Hybrids of Artemisinin and Quinazolinone

Background: In this study, two novel hybrid series of artemisinin and quinazolinones were synthesized and evaluated in vitro cytotoxicity against two human cancer cell lines, including SKLu-1 (lung cancer), MCF- 7 (breast cancer). The bio-assay results indicated that most of the target compounds exhibited cytotoxic activities against both human cancer cell lines tested and seemed to be more cytotoxic toward the breast (MCF-7) cancer cells than lung (SKLu-1) cancer cells. Among the synthesized artemisinin hybrids, the compound 13d containing a quinazolinone conjugated system exhibited the most potent cytotoxicity against the SKLu-1 and MCF-7 cell lines with IC50 values of 1.62 and 0.77 μM, respectively. Objective: This study aims at developing novel hybrids of artemisinin and quinazolinones as anticancer agents. Method: A series of novel hybrids were designed, synthesized, and evaluated for cytotoxicity against two human cancer cell lines, including SKLu-1 and MCF-7, using the SRB method. Results: All thirteen hybrids of artemisinin with quinazolinone exhibited cytotoxic activity against two tested cancer cell lines, in which the compound 13d exhibited the most potent cytotoxicity against the SKLu-1 and MCF-7 cell lines with IC50 values of 1.62 and 0.77 μM, respectively. Conclusion: The research results suggest that some compounds could be considered as leads for future design of hybrids and have the potential for further studies in the field of anti-cancer agent development.

Heteroleptic silver(I), nickel(II), and copper(II) complexes of N4‐substituted thiosemicarbazones and ciprofloxacin: Theoretical, in vitro anti‐proliferative, and in silico molecular modeling and pharmacokinetics studies

In this study, a series of new heteroleptic silver(I), nickel(II), and copper(II) complexes of the type [M(L1–3)(Cfx)n] (1–9), where L1–3 = N4‐substituted thiosemicarbazones (TSCs), Cfx = ciprofloxacin, M = Ag(I), Ni(II), or Cu(II), and n = 1 or 2, have been synthesized and characterized by spectral methods. The spectral data of the complexes suggest bidentate behavior of the TSC ligand, which coordinate with metal ion through thione sulphur and hydrazine nitrogen atoms, and neutral bidentate behavior of the ciprofloxacin drug that coordinates with metal ion through pyridone oxygen and one of the carboxylate oxygen atoms. The structural properties of the silver(I) complexes (1–3) were studied by density functional theory calculations, which indicate the distorted tetrahedral geometry with lower energy gap for complex 3. All the heteroleptic complexes were screened for their in vitro anti‐proliferative activity against four cancerous (lung [A549], estrogen negative [MDA‐MB‐231], estrogen positive [MCF‐7] and Henrietta's cancer cells [HeLa]), and one non‐cancerous (non‐tumorigenic human breast epithelial cell line [MCF‐10a]) cell lines by MTT reduction assay. The obtained results revealed the lower activity of silver(I) complexes and higher activity of copper(II) complexes against the tested cancer cell lines. The complexes 6 and 9 induce apoptosis in MDA‐MB‐231 cells, which was evidenced by acridine orange/ethidium bromide staining method. The molecular docking studies revealed hydrogen bonding and hydrophobic interactions between the complexes and the epidermal growth factor receptor. The in silico analysis of the complexes for Lipinski's “rule of five” and absorption, distribution, metabolism, and excretion properties predicted the drug‐likeness of the synthesized complexes.

Design, synthesis and evaluation of 4-phenyl-1,2,3-triazole substituted pyrimidine derivatives as antiproliferative and tubulin polymerization inhibitors

Ligands binding to the colchicine domain of the tubulin protein act as tubulin polymerization inhibitors and arrest the cell cycle in G2/M phase. A series of 4-Phenyl-1,2,3-triazole substituted pyrimidine derivatives have been synthesized and evaluated for antiproliferative and antitubulin activities. In the series, AV-6 and AV-14 were found to be active against the three tested cancer cell lines wherein AV-6 displayed IC50 values of 1.2 µM, 5.5 µM, and 1.9 µM while AV-14 displayed IC50 values of 4.7 µM, 1.7 µM, and 1.4 µM against HCT-116, MCF-7 and HT-29 cell lines, respectively. These compounds were found to be non toxic to the normal cells (HEK-293). In the cell cycle analysis and JC-1 studies, these compounds induce mitocondria mediated apoptosis. In the tubulin polymerization inhibition studies, AV-6 displayed significant tubulin polymerization inhibition potential. In the molecular docking and simulation studies, these compounds fit well in the active site of colchicine.

In vitro cytotoxic activity-guided isolation studies on the underground parts of Valeriana speluncaria Boiss.

Two unreported neolignans, speluncarins A (1) and B (2) together with seven known compounds (3–8, 13) were isolated from the underground parts of Valeriana speluncaria Boiss through cytotoxic activity-guided fractionation method. The crude extract, subextracts, main fractions and isolates were evaluated for their in vitro cytotoxic activities against MCF-7 and U87 cancer cell lines as well as HUVEC cell line by MTS assay. Although the crude EtOH extract, CHCl3 and EtOAc subextracts as well as some fractions exhibited remarkable cytotoxic effect against tested cancer cell lines, the purified compounds did not demonstrate promising activity in the tested concentrations. Besides these studies, five known lignan glucosides (8–12) were obtained from the inactive n-BuOH subextract. The structures of the isolates were elucidated by extensive 1D and 2D NMR spectroscopy and HR-MS analysis. This is the first phytochemical and bioactivity study on V. speluncaria, an endemic species to Turkey.

Design, synthesis, and biological evaluation of a new series of pyrazole derivatives: Discovery of potent and selective JNK3 kinase inhibitors

The design, synthesis, and biological activities of a new series of pyrazole derivatives are reported. The target compounds 1a-1w were initially investigated against NCI-60 cancer cell lines. Compounds 1f, 1h, 1k, and 1v exerted the highest anti-proliferative activity over the studied panel of cancer cell lines. Compound 1f showed the most potent activity, and it is more potent than sorafenib in 29 cancer cell lines of different types and more potent than SP600125 against almost all the tested cancer cell lines. It also exerted sub-micromolar IC50 values (0.54–0.98 µM) against nine cell lines. Moreover, the 23 target compounds were tested against Hep3B and HepG2 hepatocellular carcinoma cell lines, of which compounds 1b, 1c, and 1h showed the strongest anti-proliferative activity. The most potent anticancer compounds (1b, 1c, 1f, and 1h) demonstrated a high selectivity towards cancer cells vis-à-vis normal cells. Compounds1f and 1h induced apoptosis and mild necrosis upon testing against RPMI-8226 leukemia cells. Kinase profiling of this series led to the discovery of two potent and selective JNK3 inhibitors, compounds 1c and 1f with an IC50 values of 99.0 and 97.4 nM, respectively. Both compounds showed a good inhibitory effect against JNK3 kinase in the whole-cell NanoBRET assay. This finding was further supported through molecular modeling studies with the JNK3 binding site. Moreover, compounds 1c and 1f demonstrated a very weak activity against CYP 2D6, CYP 3A4, and hERG ion channels.

Nanogel-mediated drug delivery system for anticancer agent: pH stimuli responsive poly(ethylene glycol/acrylic acid) nanogel prepared by gamma irradiation

The popularity of nanogel as nano drug carrier lies in its adjustable physical properties, and the ability to encapsulate drug particles with improved properties is being developed to meet the diverse pH-sensitive nanogel for anticancer agent. Monitoring pH has been identified as an important diagnostic element during the treatment process. A pH-sensitive nanogel consisting of (PEG/PMAc) in the ratio of (50:50%) hasbeen cross-linkedby γ-irradiation techniques at an irradiation dose of 5 kGy. Compound 4 and its nanogel 5 were synthesized and assessed for their anticancer effects against HepG2, A549, MCF-7 and HCT-116 as dual VEGFR-2 and EGFR tyrosine kinases inhibitors. The molecular design was performed to investigate the binding mode of compound 4 with VEGFR-2 and EGFR receptors. Our compound 5 in nanogel showed enhanced anticancer activities against the four tested cancer cell lines and also showed higher inhibition activities against VEGFR-2 and EGFRT790M kinases than the derivative 4. Finally, our derivative 4 showed good in silico calculated ADMET profile. It was expected to show good GIT absorption in human, lower CNS side effects, no hepatotoxic actions and higher acute and oral chronic toxic doses in comparing to sorafenib and erlotinib. The obtained results showed that, our compound could be useful as a template for future design, optimization, adaptation and investigation to produce more potent and selective dual VEGFR-2/EGFRT790M inhibitors with higher anticancer activity.

The effect of novel synthetic semicarbazone- and thiosemicarbazone-linked 1,2,3-triazoles on the apoptotic markers, VEGFR-2, and cell cycle of myeloid leukemia

Vascular Endothelial Growth Factor II (VEGFR-2) has been proved as a rational target in cancer therapy. Although currently prescribed VEGFR-2 inhibitors are showing potent antitumor activity, they are often causing serious unwanted effects, restricting their extensive use as chemotherapeutics. Herein, after analyzing the structures of the effective VEGFR-2 inhibitor molecules, we report the synthesis of a new set of semicarbazone- and thiosemicarbazone-linked 1,2,3-triazoles with expected potency of inhibiting the VEGFR-2 signaling. The design of new compounds considered maintaining the essential pharmacophoric features of sorafenib for effective binding with the receptor target. All compounds have been evaluated for their growth inhibition effect against a panel of sixty cancer cells at the National Cancer Institute. Leukemia cancer cells, especially HL-60 and SR, were shown to be the most sensitive to the cytotoxic effect of new compounds. Thiosemicarbazones 21, 26, and 30 exhibited the best activity against almost all tested cancer cells. Therefore, a set of subsequent in vitro biological evaluations has been performed to understand the mechanistic effect of these compounds further. They inhibited the VEGFR-2 with IC50 values of 0.128, 0.413, and 0.067 µM respectively compared with 0.048 µM of Sorafenib. The probable mechanistic effect of 30 has been further evaluated on a number of apoptotic and antiapoptotic markers including BAX, BCL2, caspase-3, and caspase-9. Results revealed the potential of the thiosemicarbazone-linked triazole 30 to induce both the early and the late apoptosis, elevate BAX/BCL2 ratio, induce caspase-3 & caspase-9, and arrest the HL-60 cell cycle at the G2/M and G0-G1 phases. Molecular docking of new semicarbazones and thiosemicarbazones into the proposed biological target receptor has also been performed. Results of docking studies proved the potential of new semicarbazone- and thiosemicarbazone-linked 1,2,3-triazoles to effectively bind with crucial residues of the VEGFR-2 binding pocket.