Tested Cancer Cell Lines Research Articles

Pyrene aroylhydrazone-based Pd(II) complexes for DNA/protein binding, cellular imaging and in vitro anticancer activity via ROS production

A novel class of Pd(II) pyrene aroylhydrazone complexes (Pd1–Pd4) of general formula [Pd(L)(PPh3)Cl] (L = pyrene aroylhydrazones) was synthesized and their solid-state structures were determined by single-crystal XRD study. In vitro cytotoxicity of Pd1–Pd4 were examined against two cancer cell lines, HeLa and MCF-7 and two non-cancerous cell line, HEK 293T and 3T3-L1 to assess their selectivity. Among these, Pd2 and Pd3 had the most significant cytotoxic effects in comparison to cisplatin, a traditional anticancer medication featuring undesirable side effects, in tested cancer cell lines. Moreover, they showed noticeably less toxicity towards non-cancerous cell lines. Their interactions with serum albumin were confirmed experimentally as well as with molecular docking. Pd3 was also found to effectively interact with DNA as revealed by DNA interactions studies. Pd3-treated HeLa cells exhibited nuclear apoptotic features such as chromatin condensation and nuclear fragmentation and was also found to induce ROS which further led to decrease in mitochondrial membrane potential in cancer cells. Further, Pd3 was efficiently internalized by HeLa cells as evident from cellular imaging using confocal microscopy. Taken together, we report a novel class of Pd(II) pyrene aroylhydrazone complexes displaying strong protein/DNA binding and anti-cancer activity via ROS generation under in vitro circumstances.

Physicochemical characterization and anticancer activity of the new imipramine based Co(II), Pd(II) and Mn(II) compounds

Three new imipramine-based compounds, namely: (HIMP)2CoCl4, (HIMP)2Pd2Cl6 and (HIMP)2MnCl4 (HIMP = protonated imipramine) were synthesized in a single-step reaction between imipramine hydrochloride and metal(II) chlorides. The physicochemical properties of all three compounds were thoroughly investigated using appropriate analytical techniques: single crystal and powder X-Ray diffraction analysis, elemental analysis, UV–Vis and FTIR spectroscopies, fluorescence measurements, quantum mechanical calculations, TG-DTG thermogravimetric analysis and magnetic studies. The investigations proved the high purity of the compounds and the isostructurality of (HIMP)2CoCl4 and (HIMP)2MnCl4 compounds. Of all compounds, only (HIMP)2MnCl4 exhibited fluorescent properties. When heated, all three compounds decompose, yielding the appropriate metal(II) oxides in the case of (HIMP)2CoCl4 and (HIMP)2MnCl4 compounds or metallic palladium in the case of (HIMP)2Pd2Cl6. In the last step, the anticancer activity of all three compounds was evaluated against MKN-74, PANC-1, SCOV-3, MDA-MB-231, MDA-MB-468, A-375 and SK-MEL-28 cell lines. Cytotoxicity evaluation revealed that the incorporation of the active metal ions significantly increased the imipramine activity against all tested cancer cell lines without significant toxicity against normal fibroblasts.

In vitro and in vivo anticancer activity of novel Rh(III) and Pd(II) complexes with pyrazolopyrimidine derivatives

Six pyrazolopyrimidine rhodium(III) or palladium(II) complexes, [Rh(L1)(H2O)Cl3] (1), [Rh(L2)(CH3OH)Cl3] (2), [Rh(L3)(H2O)Cl3] (3), [Rh2(L4)Cl6]·CH3OH (4), [Rh(L5)(CH3CN)Cl3]·0.5CH3CN (5), and [Pd(L5)Cl2] (6), were synthesized and characterized. These complexes showed high cytotoxicity against six tested cancer cell lines. Most of the complexes showed higher cytotoxicity to T-24 cells in vitro than cisplatin. Mechanism studies indicated that complexes 5 and 6 induced G2/M phase cell cycle arrest through DNA damage, and induced apoptosis via endoplasmic reticulum stress response. In addition, complex 5 also induced cell apoptosis via mitochondrial dysfunction. Complexes 5 and 6 showed low in vivo toxicity and high tumor growth inhibitory activity in mouse tumor models. The inhibitory effect of rhodium complex 5 on tumor growth in vivo was more pronounced than that of palladium complex 6.

Derivatives Incorporating Acridine, Pyrrole, and Thiazolidine Rings as Promising Antitumor Agents.

Derivatives combining acridine, pyrrole, and thiazolidine rings have emerged as promising candidates in the field of antitumor drug discovery. This paper aims to highlight the importance of these three structural motifs in developing potent and selective anticancer agents. The integration of these rings within a single molecule offers the potential for synergistic effects, targeting multiple pathways involved in tumor growth and progression. Spiro derivatives were efficiently synthesized in a two-step process starting from isothiocyanates and 2-cyanoacetohydrazide. The thiourea side chain in spiro derivatives was utilized as a key component for the construction of the thiazolidine-4-one ring through regioselective reactions with bifunctional reagents, namely methyl-bromoacetate, dietyl-acetylenedicarboxylate, ethyl-2-bromopropionate, and ethyl-2-bromovalerate. These reactions resulted in the formation of a single regioisomeric product for each derivative. Advanced spectroscopic techniques, including 1D and 2D NMR, FT-IR, HRMS, and single-crystal analysis, were employed to meticulously characterize the chemical structures of the synthesized derivatives. Furthermore, the influence of these derivatives on the metabolic activity of various cancer cell lines was assessed, with IC50 values determined via MTT assays. Notably, derivatives containing ester functional groups exhibited exceptional activity against all tested cancer cell lines, boasting IC50 values below 10 μM. Particularly striking were the spiro derivatives with methoxy groups at position 3 and nitro groups at position 4 of the phenyl ring. These compounds displayed remarkable selectivity and exhibited heightened activity against HCT-116 and Jurkat cell lines. Additionally, 4-oxo-1,3-thiazolidin-2-ylidene derivatives demonstrated a significant activity against MCF-7 and HCT-116 cancer cell lines.

Binuclear Biphenyl Organogold(III) Complexes: Synthesis, Photophysical and Theoretical Investigation, and Anticancer Activity.

A series of four binuclear complexes of general formula [(C^C)Au(Cl)(L^L)(Cl)Au(C^C)], where C^C is 4,4'-diterbutylbiphenyl and L^L is either a bridging diphosphine or 4,4'-bipyridine, are synthetized with 52 to 72 % yield and structurally characterized by X-ray diffraction. The use of the chelating 1,2-diphenylphosphinoethane ligand in a 1 : 2 (P^P):Au stoichiometry leads to the near quantitative formation of a gold double-complex salt of general formula [(C^C)Au(P^P)][(C^C^)AuCl2 ]. The compounds display long-lived yellow-green phosphorescence with λem in the range of 525 to 585 nm in the solid state with photoluminescence quantum yields (PLQY) up to 10 %. These AuIII complexes are tested for their antiproliferative activity against lung adenocarcinoma cells A549 and results show that compounds 2 and 5 are the most promising candidates. The digold salt 5 shows anticancer activity between 66 and 200 nM on the tested cancer cell lines, whereas derivative 2 displays concentration values required to reduce by 50 % the cell viability (IC50 ) between 7 and 11 μM. Reactivity studies of compound 5 reveal that the [(C^C)Au(P^P)]+ cation is stable in the presence of relevant biomolecules including glutathione suggesting a structural mechanism of action.

Synthesis, Characterization, and Anticancer Activity of Phosphanegold(i) Complexes of 3-Thiosemicarbano-butan-2-one Oxime.

Four novel phosphanegold(I) complexes of the type [Au(PR3)(DMT)].PF6 (1-4) were synthesized from 3-Thiosemicarbano-butan-2-one oxime ligand (TBO) and precursors [Au(PR3)Cl], (where R = methyl (1), ethyl (2), tert-butyl (3), and phenyl (4)). The resulting complexes were characterized by elemental analyses and melting point as well as various spectroscopic techniques, including FTIR and (1H, 13C, and 31P) NMR spectroscopy. The spectroscopic data confirmed the coordination of TBO ligands to phosphanegold(I) moiety. The solution chemistry of complexes 1-4 indicated their stability in both dimethyl sulfoxide (DMSO) and a mixture of EtOH:H2O (1:1). In vitro cytotoxicity of the complexes was evaluated relative to cisplatin using an MTT assay against three different cancer cell lines: HCT116 (human colon cancer), MDA-MB-231 (human breast cancer), and B16 (murine skin cancer). Complexes 2, 3, and 4 exhibited significant cytotoxic effects against all tested cancer cell lines and showed significantly higher activity than cisplatin. To elucidate the mechanism underlying the cytotoxic effects of the phosphanegold(I) TBO complexes, various assays were employed, including mitochondrial membrane potential, ROS production, and gene expression analyses. The data obtained suggest that complex 2 exerts potent anticancer activity against breast cancer cells (MDA-MB-231) through the induction of oxidative stress, mitochondrial dysfunction, and apoptosis. Gene expression analyses showed an increase in the activity of the proapoptotic gene caspase-3 and a reduction in the activity of the antiapoptotic gene BCL-xL, which supported the findings that apoptosis had occurred.

Formulation of Silymarin-β Cyclodextrin-TPGS Inclusion Complex: Physicochemical Characterization, Molecular Docking, and Cell Viability Assessment against Breast Cancer Cell Lines.

Silymarin (SIL) is a poorly water-soluble flavonoid reported for different pharmacological properties. Its therapeutic applications are limited due to poor water solubility. In this study, the solubility of silymarin has been enhanced by preparing freeze-dried binary and ternary complexes using beta cyclodextrin (βCD) and d-α-tocopherol polyethylene glycol 1000 succinate (TPGS). The stoichiometry of the drug and the carrier was selected from the phase solubility study. The dissolution study was performed to assess the effect of complexation on the release pattern of SIL. The formation of inclusion complexes was confirmed by different physicochemical studies. Finally, a cell viability assay (MCF 7; breast cancer cell line) was performed to compare the activity with free SIL. The phase solubilization results revealed the formation of a stable complex (binary) with a stability constant and complexation efficiency (CE) value of 288 mol L-1 and 0.045%. The ternary sample depicted a significantly enhanced stability constant and CE value (890 mol L-1 and 0.14%). The release study results showed a marked increase in the release pattern after addition of βCD (alone) in the binary mixture (49.4 ± 3.1%) as well as inclusion complex (66.2 ± 3.2%) compared to free SIL (32.7 ± 1.85%). Furthermore, with the addition of TPGS in SIL-βCD (ternary), the SIL release was found to be significantly enhanced from the SIL ternary mixture (79.2 ± 2.13%) in 120 min. However, fast SIL release was achieved with 99.2 ± 1.7% in 45 min for the SIL ternary complex. IR and NMR spectral analysis results revealed the formation of a stable complex with no drug-polymer interaction. The formation of complexes was also confirmed by the molecular docking study (docking scores of 4.1 and -6.4 kcal/mol). The in vitro cell viability result showed a concentration-dependent activity. The IC50 value of the SIL ternary complex was found to be significantly lower than that of free SIL. The findings of the study concluded that the prepared SIL inclusion complex can be used as an alternative oral delivery system to enhance solubility, dissolution, and biological activity against the tested cancer cell line.

Attenuation of Oxidative Damage via Upregulating Nrf2/HO-1 Signaling Pathway by Protease SH21 with Exerting Anti-Inflammatory and Anticancer Properties In Vitro.

Oxidative damage and inflammation are among the very significant aspects interrelated with cancer and other degenerative diseases. In this study, we investigated the biological activities of a 25 kDa protease (SH21) that was purified from Bacillus siamensis. SH21 exhibited very powerful antioxidant and reactive oxygen species (ROS) generation inhibition activity in a dose-dependent approach. The mRNA and protein levels of antioxidant enzymes such as superoxide dismutase 1 (SOD1), catalase (CAT), and glutathione peroxidase 1 (GPx-1) were enhanced in the SH21-treated sample. SH21 also increased the transcriptional and translational activities of NF-E2-related factor 2 (Nrf2) with the subsequent development of detoxifying enzyme heme oxygenase-1 (HO-1). In addition, SH21 showed potential anti-inflammatory activity via inhibition of nitric oxide (NO) and proinflammatory cytokines, such as TNF-α, IL-6, and IL-1β, production in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. At concentrations of 60, 80, and 100 μg/mL, SH21 potentially suppressed nitric oxide synthase (iNOS) and cytokine gene expressions. Furthermore, SH21 significantly released lactate dehydrogenase (LDH) enzyme in cancer cell supernatant in a concentration-dependent manner and showed strong activity against three tested cancer cell lines, including HL-60, A549, and Hela. Our results suggest that SH21 has effective antioxidant, anti-inflammatory, and anticancer effects and could be an excellent therapeutic agent against inflammation-related diseases.

Discovery of Novel Naphthoquinone-Chalcone Hybrids as Potent FGFR1 Tyrosine Kinase Inhibitors: Synthesis, Biological Evaluation, and Molecular Modeling.

This work presents a flexible synthesis of 10 novel naphthoquinone-chalcone derivatives (1-10) by nucleophilic substitution of readily accessible aminochalcones and 2,3-dichloro-1,4-naphthoquinone. All compounds displayed broad-spectrum cytotoxic activities against all the tested cancer cell lines (i.e., HuCCA-1, HepG2, A549, MOLT-3, T47D, and MDA-MB-231) with IC50 values in the range of 0.81-62.06 μM, especially the four most potent compounds 1, 3, 8, and 9. The in vitro investigation on the fibroblast growth factor receptor 1 (FGFR1) inhibitory effect indicated that eight derivatives (1-2, 4-5, and 7-10) were active FGFR1 inhibitors (IC50 = 0.33-3.13 nM) with more potency than that of the known FGFR1 inhibitor, AZD4547 (IC50 = 12.17 nM). Promisingly, compounds 5 (IC50 = 0.33 ± 0.01 nM), 9 (IC50 = 0.50 ± 0.04 nM), and 7 (IC50 = 0.85 ± 0.08 nM) were the three most potent FGFR1 inhibitors. Molecular docking, molecular dynamics simulations, and MM/GBSA-based free energy calculation revealed that the key amino acid residues involved in the binding of the compounds 5, 7, and 9 and the target FGFR1 protein were similar with those of the AZD4547 (i.e., Val492, Lys514, Ile545, Val561, Ala640, and Asp641). These findings revealed that the newly synthesized naphthoquinone-chalcone scaffold is a promising structural feature for an efficient inhibition of FGFR1.

Molecular and biological characterization of pyocyanin from clinical and environmental Pseudomonas aeruginosa

BackgroundPyocyanin is a secondary metabolite secreted by P. aeruginosa. It is a redox-active blue/green phenazine pigment that has various beneficial applications. The present study aims at screening the production of pyocyanin among clinical and environmental P. aeruginosa isolates in Dakahlya governorate, Egypt. Thereafter, large-scale production, purification, structure elucidation, and assessment of the biological activity of the highest pyocyanin producers were targeted.ResultsPyocyanin from the highest clinical (PsC05) and environmental (PsE02) producers were subjected to large-scale production, followed by purification using silica gel column. Pyocyanin was characterized using TLC, UV-Vis, 1 H NMR, and FTIR spectroscopy to confirm its structure and purity. Purified pyocyanin showed remarkable antimicrobial efficacy against all tested food-borne pathogens, MDR/XDR clinically isolated bacteria and C. albicans. Furthermore, it showed a substantial effect on biofilm inhibition and eradication of pre-formed biofilm against strong biofilm producing bacterial pathogens. However, it had limited antibiofilm activity against C. albicans. Pyocyanin from PsC05 had higher antioxidant and radicals scavenging activity than that from PsE02 as determined by FRAP, DPPH, and ABTS assays. Likewise, pyocyanin from PsC05 was more active against tested cancer cell lines, especially human Breast Cancer (MCF-7) and Colorectal Carcinoma (HCT-116), than that from PsE02. More importantly, it showed minimal cytotoxicity to normal cells.ConclusionsP. aeruginosa clinical and environmental isolates produce pyocyanin pigment in varying amounts. Pyocyanin exhibits substantial anti-bacterial, and anti-fungal activity; thus, enhancing its medical applicability. It could be used to inhibit and/or eradicate biofilm from the surfaces of medical devices which is a chief source of nosocomial infections. Its antioxidant along with cytotoxic activity against cancer cell lines, make it a promising contender for use as a substitute for synthetic agents in cancer treatment.

Synthesis, X-ray Structure, and Hirshfeld Analysis of [Ag(3-amino-5,6-dimethyl-1,2,4-triazine)(NO3)]n: A Potent Anticancer and Antimicrobial Agent

The [Ag(3ADMT)(NO3)]n complex was synthesized by the self-assembly of 3-amino-5,6-dimethyl-1,2,4-triazine (3ADMT) and AgNO3. Its molecular structure was analyzed utilizing FTIR spectra, elemental analysis, and single crystal X-ray diffraction (SC-XRD). There is one crystallographically independent Ag atom, which is tetra-coordinated by two nitrogen atoms from two 3ADMT and two oxygen atoms from two nitrate anions where all ligand groups are acting as connectors between the Ag1 sites. The geometry around the Ag(I) center is a distorted tetrahedron with a AgN2O2 coordination sphere augmented by strong argentophilic interactions between Ag atoms, which assist the aggregation of the complex units in a wavy-like and coplanar pattern to form a one-dimensional polymeric chain. The O...H (37.2%) and N...H (18.8%) intermolecular interactions contributed significantly to the molecular packing based on Hirshfeld surface analysis. The [Ag(3ADMT)(NO3)]n complex demonstrates promising cytotoxicity against lung (IC50 = 2.96 ± 0.31 μg/mL) and breast (IC50 = 1.97 ± 0.18 μg/mL) carcinoma. This remarkable cytotoxicity exceeds those of 3ADMT, AgNO3, and the anticancer medication cis-platin towards the tested cancer cell lines. In addition, the complex has a wide-spectrum antimicrobial action where the high antibacterial potency of the [Ag(3ADMT)(NO3)]n complex against P. vulgaris (MIC = 6.1 µg/mL) and B. subtilis (MIC = 17.2 µg/mL) could be comparable to the commonly used drug Gentamycin (MIC = 4.8 µg/mL). These results confirm that the components of the [Ag(3ADMT)(NO3)]n complex work together synergistically, forming a powerful multifunctional agent that could be exploited as an effective antimicrobial and anticancer agent.

Design, synthesis and anticancer activity of N-aryl indolylsulfoximines: Identification of potent and selective anticancer agents

A facile and efficient approach utilizing copper-mediated cross-coupling reaction of N-boc-3-indolylsulfoximines with aryl iodides was developed to synthesize a diverse range of N-arylated indolylsulfoximines 11a-m in excellent yields (up to 91%). The key precursors, free NH sulfoximines 9 were readily prepared by the treatment of N-boc-3-methylthioindoles 8 with a combination of IBD and ammonium carbamate. Under similar conditions NH-free indolylsulfoximine 9a was successfully prepared in gram-scale quantities. The reaction is highly chemoselective and tolerant of a wide range of functional groups. The process is environmentally friendly and is amenable to scale-up. Among the prepared N-arylated indolylsulfoximines 11a-m, compounds 11i-j (2.68–2.76 μM), 11f-g (1.9–3.7 μM) and 11k (1.28 μM) showed potent and selective cytotoxicity against 22Rv1, C4-2 and MCF7 cells, respectively. Indolylsulfoximine derivative 11l displayed a broad spectrum of activity (1.7–8.2 μM) against the tested cancer cell lines. These compounds were found to be non-cytotoxic to normal HEK293 cells, indicating their potential selectivity for cancer cells. We analysed the impact of 11l on various cellular assays to uncover its mechanism of action. Cellular assay shows that 11l increases the endogenous level of ROS, leading to the increased level of p-53 and c-jun inducing apoptosis. 11l also induced mitochondrial dysfunction, further promoting apoptotic pathways. Besides, 11l also restricts cell invasiveness, indicating that it could serve as an effective anti-metastatic agent. As oxidative stress severe F actin causing tubulin depolymerization, we examined the impact of 11l on tubulin dynamics. Accordingly, 11l treatment decreased the levels of polymerized tubulin in 22Rv1 and C4-2 cells. Although future studies are needed to determine their exact molecular target(s), our data shows that N-aryl indolylsulfoximines could serve as effective anti-cancer agents.

Synthesis and Evaluation of Cytotoxic Activity of New Analogues of 4‐Substituted 1,2,4‐Benzothiadiazine‐1,1‐dioxide

AbstractA new series of 4‐benzyl analogues of 1,2,4‐benzothiadiazine‐1,1‐dioxide was synthesized. All these compounds were subsequently tested for in vitro anti‐cancer activity against cancer cell lines selected by National Cancer Institute using one dose (10−5 M), following their standard screening procedure. The new compounds were characterized by 1H NMR, 13C NMR, LCMS, and IR techniques. All the synthesized compounds showed sensitivity against tested cancer cell lines. Notably, the compound having 3‐fluoro‐4‐methoxybenzyl group on 1,2,4‐benzothiadiazine‐1,1‐dioxide ring exhibited the most promising cytotoxicity effect. It displayed a growth percentage oscillating between −32.82 % and 93.85 % on Melanoma and Breast cancer cell lines, respectively. Additionally, this compound demonstrated a significant antiproliferative effect on Leukaemia and CNS cancer cell lines. The most affected cell lines were MDA‐MB‐468 (Breast Cancer, lethality is 32.82 %) and MDA‐MB‐435 (Melanoma, −15.62 %). Other compounds in the series also demonstrated considerable antiproliferative effects on Breast cancer cell line.

Design, Synthesis, and Biological Evaluation of New Potential Unusual Modified Anticancer Immunomodulators for Possible Non-Teratogenic Quinazoline-Based Thalidomide Analogs.

Sixteen new thalidomide analogs were synthesized. The new candidates showed potent in vitro antiproliferative activities against three human cancer cell lines, namely hepatocellular carcinoma (HepG-2), prostate cancer (PC3), and breast cancer (MCF-7). It was found that compounds XII, XIIIa, XIIIb, XIIIc, XIIId, XIVa, XIVb, and XIVc showed IC50 values ranging from 2.03 to 13.39 µg/mL, exhibiting higher activities than thalidomide against all tested cancer cell lines. Compound XIIIa was the most potent candidate, with an IC50 of 2.03 ± 0.11, 2.51 ± 0.2, and 0.82 ± 0.02 µg/mL compared to 11.26 ± 0.54, 14.58 ± 0.57, and 16.87 ± 0.7 µg/mL for thalidomide against HepG-2, PC3, and MCF-7 cells, respectively. Furthermore, compound XIVc reduced the expression of NFκB P65 levels in HepG-2 cells from 278.1 pg/mL to 63.1 pg/mL compared to 110.5 pg/mL for thalidomide. Moreover, compound XIVc induced an eightfold increase in caspase-8 levels with a simultaneous decrease in TNF-α and VEGF levels in HepG-2 cells. Additionally, compound XIVc induced apoptosis and cell cycle arrest. Our results reveal that the new candidates are potential anticancer candidates, particularly XIIIa and XIVc. Consequently, they should be considered for further evaluation for the development of new anticancer drugs.

Design, synthesis, anticancer activity and molecular docking of novel 1H-benzo[d]imidazole derivatives as potential EGFR inhibitors

Here, we present the design, synthesis, and evaluation of a new series of 1H-benzo[d]imidazole derivatives (10a–j) to determine their anticancer efficacy. The MCF-7 and HCT116 cancer cell lines were used to test the synthesized compounds anticancer effects. Most of the newly synthesized benzimidazole compounds had a cytotoxic impact, in some cases much more potent than the reference medication. When compared to the reference drug erlotinib, compounds 10g, 10i, and 10j in particular shown strong anticancer efficacy against the tested cancer cell lines with good safety and selectivity indices. All newly synthesized compounds relative inhibitory potency against EGFR wild type (WT) and mutant EGFR L858R/T790M was evaluated in comparison to erlotinib, a standard drug. Comparing compound 10i to other members of the series, it showed the most inhibitory effect against EGFR WT and L858R/T790M with IC50 values of 4.38 and 5.69 nM, respectively. Synthetic compounds revealed substantial EGFR WT and L858R/T790M inhibition with selectivity of over 3.09 and 13.29-folds greater activity than reference medication erlotinib. One such example is compound 10i. The mode of action mechanisms between the potent molecules and the matching EGFR kinase protein were explained by molecular docking investigations. Additionally, predicting the drug-likeness of molecules were promising, indicating the compounds’ drug-like characteristics. Compounds 10g, 10i, and 10j have been shown to be good candidates and deserving further exploration.

Design, synthesis, and biological evaluation of a series of benzofuran[3,2-d]pyrimidine-4(3H)-one derivatives containing thiosemicarbazone analogs as novel PARP-1 inhibitors

Poly ADP ribose polymerase-1 (PARP-1), one of the most important members of the PARP protein family, plays a crucial role in DNA damage repair, gene transcription, and apoptosis of cancer cells. In this work, benzofuran[3,2-d]pyrimidine-4(3H)-one was used as a framework to design and synthesize a series of novel PARP-1 inhibitors by introducing thiosemicarbazone or its derivatives into the scafford. Among all the target compounds, 19b and 19c were found to exhibit more potent inhibitory activity and higher selectivity against PARP-1 than Olaparib, especially the latter had an IC50 value of 0.026 μM against PARP-1 enzyme and a PARP-2/PARP-1 selectivity of 85.19-fold over Olapanib. Apart from strong cytotoxicity against the tested cancer cell lines, 19c was most sensitive to SK-OV-3 cells, with an IC50 value of 4.98 μM superior to Olaparib. Anti-cancer mechanism studies revealed that 19c could inhibit DNA single-strand breakage repair and aggravate DNA double-strand breakage by inhibiting PARP-1 activity, and promote the apoptosis of cancer cells through the mitochondrial apoptosis pathway.

Efficacy and safety of glycosphingolipid SSEA-4 targeting CAR-T cells in an ovarian carcinoma model.

Chimeric antigen receptor (CAR) T-cell immunotherapies for solid tumors face critical challenges such as heterogeneous antigen expression. We characterized SSEA-4 cell-surface glycolipid as a target for CAR-T cell therapy. SSEA-4 is mainly expressed during embryogenesis but is also found in several cancer types making it an attractive tumor-associated antigen. Anti-SSEA-4 CAR-T cells were generated and assessed pre-clinically in vitro and in vivo for anti-tumor response and safety. SSEA-4 CAR-T cells effectively eliminated SSEA-4 positive cells in all the tested cancer cell lines whereas SSEA-4 negative cells lines were not targeted. In vivo efficacy and safety studies using NSG mice and the high-grade serous ovarian cancer cell line OVCAR4 demonstrated a remarkable and specific anti-tumor response at all the CAR-T cell doses used. At high T cell doses, CAR-T cell-treated mice showed signs of health deterioration after a follow-up period. However, the severity of toxicity was reduced with a delayed onset when lower CAR-T cell doses were used. Our data demonstrate the efficacy of anti-SSEA-4 CAR-T therapy; however, safety strategies, such as dose-limiting and/or equipping CAR-T cells with combinatorial antigen recognition should be implemented for its potential clinical translation.

Green approach for the synthesis of ZnO nanoparticles using Cymbopogon citratus aqueous leaf extract: characterization and evaluation of their biological activities

BackgroundThe green synthesis of metal and metal oxide nanoparticles (NPs), notably from plants, has attracted increasing attention in recent years. Although the increased popularity use of Cymbopogon citratus as a therapeutic substance, to date, there has not been any research on the chemistry of C. citratus aqueous leaf extract (ALE) or synthesis of ZnO NPs utilizing an extract from it. The ecologically safe ALE of C. citratus was employed in this study as a bio-reducing and capping agent to synthesize ZnO NPs.ResultsThe novelty of the current study is the investigation of the antioxidant, anti-inflammatory, anti-microbial, and cytotoxic potencies of biosynthesized ZnO NPs utilizing C. citratus ALE. Zinc acetate dihydrate was used as the precursor and the leaf extract serves as the reducing agent. ZnO NPs from ALE of C. citratus were characterized by the spherical in form by using high-resolution transmission electron microscopy (HR-TEM) and the Scherrer formula was used to calculate the size of the crystalline structure. The presence of numerous functional groups in both the ALE and the NPs is confirmed by FTIR analysis. The highest absorption peak is observed at 370 nm. The stability and particle size of the biosynthesized ZnO NPs are demonstrated by dynamic light scattering (DLS) analysis. The biosynthesized ZnO NPs exhibited excellent antioxidant activity with an IC50 value of 45.67 ± 0.1 μg/mL and exerted interesting anti-inflammatory activity (98.1% ± 0.04) when compared to the standard indomethacin (92.1% ± 0.07) at 1 mg/mL. They also showed anti-microbial activity for both bacterial and fungal which growth rates for both significantly decreased with the increase in ZnO NPs concentration compared to the control. The anticancer activity of biosynthesized ZnO NPs and C. citratus ALE was in vitro tested against seven human cancer cell lines (HCCL) (i.e. H1299, MDA-MB-468, HNO97, HEK, HCT116, HuH7, and HEPG2) compared to normal cells (HSF) using the sulforhodamine-B (SRB) assay. More interestingly, the biosynthesized ZnO NPs displayed remarkable selective cytotoxicity against all tested cancer cell lines without any effect on normal cells. In contrast, the cancer cell lines were not affected by the ALE of C. citratus at any concentrations tested.ConclusionsAll the findings confirm that the ZnO NPs biosynthesized in the current work are promising candidates for a variety of biological activities, and as a result, they can be helpful to the medical sector, environmental and agricultural applications.Graphical

Rhodium(III)-Picolinamide Complexes Act as Anticancer and Antimetastasis Agents via Inducing Apoptosis and Autophagy.

As a continuation of our endeavors in discovering metal-based drugs with cytotoxic and antimetastatic activities, herein, we reported the syntheses of 11 new rhodium(III)-picolinamide complexes and the exploration of their potential anticancer activities. These Rh(III) complexes showed high antiproliferative activity against the tested cancer cell lines in vitro. The mechanism study indicated that Rh1 ([Rh(3a)(CH3CN)Cl2]) and Rh2 ([Rh(3b)(CH3CN)Cl2]) inhibited cell proliferation by multiple modes of action via cell cycle arrest, apoptosis, and autophagy and inhibited cell metastasis via FAK-regulated integrin β1-mediated suppression of EGFR expression. Furthermore, Rh1 and Rh2 significantly inhibited bladder cancer growth and breast cancer metastasis in a xenograft model. These rhodium(III) complexes could be developed as potential anticancer agents with antitumor growth and antimetastasis activity.

Design, synthesis, anticancer evaluation, and in silico studies of some thieno[2,3-d]pyrimidine derivatives as EGFR inhibitors.

New series of 20 thieno[2,3-d]pyrimidine derivatives have been synthesized. The National Cancer Institute evaluated all the newly synthesized compounds for their antiproliferative activity against a panel of 60 cancer cell lines. Compound 7b exhibited a remarkable antineoplastic activity at 10 µM dose and was therefore tested at five dose concentrations. The significant and broad-spectrum antineoplastic action of compound 7b was observed against 37 of the tested cancer cell lines with a dose that inhibits 50% of the growth compared to control values in the micromolar range of 1.95-9.6 µM. The dose which inhibits the growth completely in the cytostatic range of 3.99-100 µM was also observed. Compound 7b effectively inhibited epidermal growth factor receptor (EGFR) with 50% inhibition concentration value (IC50 ) = 0.096 ± 0.004 compared to erlotinib with IC50 = 0.037 ± 0.002. Moreover, compound 7b revealed a powerful downregulation effect on total EGFR concentration and its phosphorylation. In addition, compound 7b inhibited phosphatidylinositol 3-kinase, protein kinase B, and the mammalian target of rapamycin pathway phosphorylation. Furthermore, compound 7b raised total apoptosis by 21.93-fold in the ovarian cancer cell line (OVCAR-4) and caused an arrest in the cell cycle in the G1/S phase. It also raised the level of caspase-3 by 4.72-fold. Furthermore, to determine the binding manner of the most effective derivatives and validate their capacity to comply with the pharmacophoric properties necessary for EGFR inhibition, they were docked into the active site of the EGFR.