Evaluation of the Antimicrobial Effect of Thymoquinone against Different Dental Pathogens: An In Vitro Study

This study aimed to evaluate the antimicrobial effect of Thymoquinone (TQ) on four different oral microorganisms. Minimum Bactericidal Concentration (MBC), Minimum Inhibition Concentration (MIC), Broth microdilution, and Well diffusion tests were used to determine the optimum antimicrobial concentrations of TQ against Streptococcus salivarius, Streptococcus oralis, Streptococcus mutans, and Staphylococcus aureus over 1, 3, 6, 12 and 24 h. Chlorhexidine 0.12% was selected as a positive control. The inhibitory effect of TQ on bacterial growth was most noticeable with S. salivarius, while the least affected was S. aureus. TQ’s MBC and MIC for S. oralis and S. aureus were comparable 2 mg/mL and 3 mg/mL, respectively. S. salivarius was most resistant to TQ and displayed a value of 5 mg/mL and 4 mg/mL for MIC and MBC, respectively. The viable count of different strains after exposure to TQ’s MBC values was most noticeable with S. aureus followed by S. oralis and S. mutans, while S. salivarius was least affected. This study emphasized the promising antimicrobial effect of TQ against the four main oral microorganisms. It has a potential preventive effect against dental caries as well as other oral diseases.     

Synthesis and evaluation of antiproliferative activity of substituted N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamides

Several novel N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamide derivatives were prepared as potential antiproliferative agents. The in vitro antiproliferative activity of the synthesized compounds was investigated against a panel of tumor cell lines including breast cancer cell lines (MDA-MB-231, T-47D) and neuroblastoma cell line (SK-N-MC) using MTT colorimetric assay. Etoposide, a well-known anticancer drug, was used as a positive standard drug. Among synthesized compounds, 4-methoxy-N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamide (5i) showed the highest antiproliferative activity against MDA-MB-231, T-47D, and SK-N-MC cells. Furthermore, pentafluoro derivatives 5a and 6a exhibited higher antiproliferative activity than doxorubicin against human leukemia cell line (CCRF-CEM) and breast adenocarcinoma (MDA-MB-468) cells. Structure–activity relationship studies revealed that xanthone benzenesulfonamide hybrid compounds can be used for the development of new lead anticancer agents.     

Synthesis and investigation of cytotoxicity of new N- and S,S-substituted-1,4-naphthoquinone (1,4-NQ) derivatives on selected cancer lines

1,4-Naphthoquinones (1,4-NQ) have been reported to possess a variety of pharma-cological properties including antibacterial, antifungal, antiviral, anti-inflammatory, anti-artherosclerotic, and anticancer effects. In this study, new N- and S,S-substituted-1,4-NQ derivatives were synthesized in excellent yields and were completely characterized by spectroscopic analysis IR, NMR (¹H and ¹³C), MS and microanalysis. The cytotoxic activities of 1,4-NQ derivatives were examined against to A-549, DU145, HCT-116 and MDA-MB-231 cancer cells. Among these compounds, 2-[4-(2-furoyl)piperazine-1-yl]-3-chloro-1,4-NQ 5 and 2,3-bis(cyclobuthylsulfanyl)-1,4-NQ 17 were identified as the most potent anticancer agents with cytotoxic activity against three cell lines (breast (MDA-MB-231), prostate (DU145), colorectal (HCT-116).     

Synthesis and Biological Evaluation of Amino Chalcone Derivatives as Antiproliferative Agents

Chalcone is a common scaffold found in many biologically active compounds. The chalcone scaffold was also frequently utilized to design novel anticancer agents with potent biological efficacy. Aiming to continue the research of effective chalcone derivatives to treat cancers with potent anticancer activity, fourteen amino chalcone derivatives were designed and synthesized. The antiproliferative activity of amino chalcone derivatives was studied in vitro and 5-Fu as a control group. Some of the compounds showed moderate to good activity against three human cancer cells (MGC-803, HCT-116 and MCF-7 cells) and compound 13e displayed the best antiproliferative activity against MGC-803 cells, HCT-116 cells and MCF-7 cells with IC₅₀ values of 1.52 μM (MGC-803), 1.83 μM (HCT-116) and 2.54 μM (MCF-7), respectively which was more potent than the positive control (5-Fu). Further mechanism studies were explored. The results of cell colony formatting assay suggested compound 10e inhibited the colony formation of MGC-803 cells. DAPI fluorescent staining and flow cytometry assay showed compound 13e induced MGC-803 cells apoptosis. Western blotting experiment indicated compound 13e induced cell apoptosis via the extrinsic/intrinsic apoptosis pathway in MGC-803 cells. Therefore, compound 13e might be a valuable lead compound as antiproliferative agents and amino chalcone derivatives worth further effort to improve amino chalcone derivatives’ potency.     

Two new asterosaponins from the Far Eastern starfish Lethasterias fusca

Two new asterosaponins, lethasteriosides A (1) and B (2), were isolated along with previously known thornasteroside A (3), anasteroside A (4), and luidiaquinoside (5) from the ethanolic extract of the Far Eastern starfish Lethasterias fusca. The structures of the new compounds were elucidated by extensive NMR and ESIMS techniques, and chemical transformations. Compounds 1 and 3-5 did not show any apparent cytotoxicity against cancer cell lines T-47D, RPMI-7951, and HCT-116, but glycoside 1, at concentration of 20 microM, demonstrated considerable inhibition of the T-47D (97%), RPMI-795I (90%) and HCT-116 (90%) cell colony formations in a soft agar clonogenic assay.     

Synthesis and antitumor activity of novel pyridino[2,3-d]pyrimidine urea derivatives

A series of novel N-(3-((6-bromopyrido[2,3-d]pyrimidin-4-yl)oxy)phenyl)pyrrolidine-1-carboxamide and 1-(3-((6-bromopyrido[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3-propylurea derivatives were synthesized. Their antitumor activities against human breast carcinoma cells (MCF-7) and human colon cancer cells (HCT-116) in vitro were evaluated, using sorafenib as a positive control drug. Anticancer bioassays indicated that several compounds exhibited appreciable anticancer activity against MCF-7 and HCT-116 cells. Particularly, compounds 9g and 8b demonstrated the most significant inhibitory effect against HCT-116 and MCF-7 cells, with inhibition ratios of 25.56% and 26.46%, respectively. Additionally, the synthesized pyridine[2,3-d]pyrimidine derivatives containing a urea group moieties exhibited antitumor activities against MCF-7 and HCT-116 cells in vitro.     

Design and Synthesis of Hydrazine and Oxadiazole-containing Derivatives of Sorafenib as Antitumor Agents

A series of hydrazine and oxadiazole analogs of Sorafenib was designed, synthesized and characterized by proton nuclear magnetic resonance(¹H NMR) spectrometry and high resolution mass spectrometry(HRMS). The antiproliferative activities of these compounds against human colorectal carcinoma(HCT-116) and human breast cancer (MDA-MB-231) tumor cell lines were evaluated in vitro by MTT method[MTT=3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide]. The bioassay results suggest that most of the synthesized compounds have antitumor potential to HCT-116 cell line compared with MDA-MB-231 cell line. Compounds 8a,8b,8d, 8e,9f and 9j competitive with Sorafenib demonstrated antiproliferative activities on HCT-116 cell line.     

Design,Synthesis, and Anticancer Activity Studies of Novel Quinoline-Chalcone Derivatives

The chalcone and quinoline scaffolds are frequently utilized to design novel anticancer agents. As the continuation of our work on effective anticancer agents, we assumed that linking chalcone fragment to the quinoline scaffold through the principle of molecular hybridization strategy could produce novel compounds with potential anticancer activity. Therefore, quinoline-chalcone derivatives were designed and synthesized, and we explored their antiproliferative activity against MGC-803, HCT-116, and MCF-7 cells. Among these compounds, compound 12e exhibited a most excellent inhibitory potency against MGC-803, HCT-116, and MCF-7 cells with IC₅₀ values of 1.38, 5.34, and 5.21 µM, respectively. The structure–activity relationship of quinoline-chalcone derivatives was preliminarily explored in this report. Further mechanism studies suggested that compound 12e inhibited MGC-803 cells in a dose-dependent manner and the cell colony formation activity of MGC-803 cells, arrested MGC-803 cells at the G2/M phase and significantly upregulated the levels of apoptosis-related proteins (Caspase3/9 and cleaved-PARP) in MGC-803 cells. In addition, compound 12e could significantly induce ROS generation, and was dependent on ROS production to exert inhibitory effects on gastric cancer cells. Taken together, all the results suggested that directly linking chalcone fragment to the quinoline scaffold could produce novel anticancer molecules, and compound 12e might be a valuable lead compound for the development of anticancer agents.     

Antiproliferative effect of 2-Hydroxy-6-tridecylbenzoic acid from ginkgo biloba sarcotestas through the aryl hydrocarbon receptor pathway in triple-negative breast cancer cells

Abstract

This study aims to isolate the potential antiproliferative and cytotoxic compounds from ginkgo biloba sarcotestas (GBS) and investigates the underlying mechanism in human MDA-MB-231 and mouse 4T-1 triple-negative breast cancer cells. Our results showed that 2-Hydroxy-6-tridecylbenzoic acid was isolated by cytotoxicity-guided fractionation where different fractions were assessed using MTT assay against MDA-MB-231 and 4T-1 cells. Colony formation assay showed that 2-Hydroxy-6-tridecylbenzoic acid significantly inhibited cell proliferation. The inhibition was associated with the enhancement of cytochrome P450 (CYP) 1B1 expression in a dose- and time-dependent manner and no significant change of CYP1A1 expression by qPCR and Western blot assays in MDA-MB-231 and 4T-1 cells. The mechanism was further demonstrated by the activation of aryl hydrocarbon receptor (AhR) pathway with the upregulation of AhR, AhR nuclear translocator (ARNT) and AhR-dependent xenobiotic response elements (XRE) activity. These findings may have implications for development of anticancer agents containing 2-Hydroxy-6-tridecylbenzoic acid as functional additives.     

The Antiproliferative and Apoptotic Effect of a Novel Synthesized S-Triazine Dipeptide Series,and Toxicity Screening in Zebrafish Embryos

Several derivatives containing morpholine/piperidine, anilines, and dipeptides as pending moieties were prepared using s-triazine as a scaffold. These compounds were evaluated for their anticancer activity against two human breast cancer cell lines (MCF-7 and MDA-MB-231), a colon cancer cell line (HCT-116), and a non-tumorigenic cell line (HEK 293). Tamoxifen was used as a reference. Animal toxicity tests were carried out in zebrafish embryos. Most of these compounds showed a higher activity against breast cancer than colon cancer. Compound 3a—which contains morpholine, aniline, and glycylglycinate methyl ester—showed a high level of cytotoxicity against MCF-7 cells with IC₅₀ values of less than 1 µM. This compound showed a much lower level of toxicity against the non-tumorigenic HEK-293 cell line, and in the in vivo studies using zebrafish embryos. Furthermore, it induced cell cycle arrest at the G2/M phase, and apoptosis in MCF-7 cells. On the basis of our results, 3a emerges as a potential candidate for further development as a therapeutic drug to treat hormone receptor-positive breast cancer.     

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The novel heteronuclear complexes [{cis-PtCl (NH₃)(μ-pyrazine)ZnCl (terpy)}](ClO₄)₂ (Pt-L1-Zn) and [{cis-PtCl (NH₃)(μ-4,4′-bipyridyl)ZnCl (terpy)}](ClO₄)₂ (Pt-L2-Zn) (where terpy = 2,2′:6′,2′′-terpyridine, L1 = pyrazine, L2 = 4,4′-bipyridyl) were synthesized and characterized. The pK_a values were determined, and based on them it was established that the π-acceptor ability of the pyrazine bridging ligand is more affective on lower pK_a values. The kinetic measurements of the substitution reactions with biologically relevant ligands, such as guanosine-5′-monophosphate (5′-GMP), inosine-5′-monophosphate (5′-IMP) and glutathione (GSH), were studied at pH 7.4. The reactions were followed under pseudo-first-order conditions by UV–Vis spectrophotometry. The order of reactivity of the investigated biomolecules for the first reaction is 5′-GMP > 5′-IMP > GSH, while for the second is 5′-IMP > GSH. Pt-L1-Zn complex is more reactive than Pt-L2-Zn. The cytotoxic activity of heteronuclear Pt-L1-Zn and Pt-L2-Zn complexes was determined on human colorectal cancer cell line (HCT-116) and human breast cancer cell line (MDA-MB-231). Both complexes significantly reduced cell viability on tested cell lines and exerted significant cytotoxic effects, with better effect on HCT-116 cells than cisplatin, especially after 72 hr (IC₅₀ < 0.52 μM). The Pt-L2-Zn complex showed higher activity against human breast cancer cells (MDA-MB-231) than cisplatin after 72 hr. The higher reactivity toward DNA constituent and significant cytotoxic activity may be attributed to the different geometry, Lewis acidity of different metal centers, as well as, to choice of bridging ligands.     

Design,Synthesis and Anticancer Evaluation of Substituted Cinnamic Acid Bearing 2-Quinolone Hybrid Derivatives

A new series of hybrid molecules containing cinnamic acid and 2-quinolinone derivatives were designed and synthesized. Their structures were confirmed by ¹H-NMR, ¹³C-NMR and mass analyses. All the synthesized hybrid molecules were assessed for their in vitro antiproliferative activity against more than one cancer cell lines. Compound 3-(3,5-dibromo-7,8-dihydroxy-4-methyl-2-oxoquinolin-1(2H)-ylamino)-3-phenylacrylic acid (5a) with IC₅₀ = 1.89 μM against HCT-116 was proved to the most potent compound in this study, as compared to standard drug staurosporin. DNA flow cytometry assay of compound 5a revealed G2/M phase arrest and pre-G1 apoptosis. Annexin V-FITC showed that the percentage of early and late apoptosis was increased. The results of topoisomerase enzyme inhibition activity showed that the hybrid molecule 5a displays potent inhibitory activity compared with control.     

Study of the structure,prooxidative, and cytotoxic activity of some chelate copper(II) complexes

The six chelate N,O-copper(II) complexes were synthesised starting from salicylaldehyde anil Schiff bases, as ligands. Their structure is elucidated using experimental and theoretical tools. In vitro biological activities, i.e. cytotoxic and prooxidative effects against human epithelial mammary gland/breast metastatic carcinoma MDA-MB-231, epithelial colorectal carcinoma HCT-116, and foetal lung fibroblast healthy MRC-5 cell lines of investigated compounds are also determined. Complexes Cu-1, Cu-6, and especially Cu-7 showed significant cytotoxic effects, with IC₅₀ values comparable with effects of positive control CisPt. In addition, investigated complexes induced extreme oxidative and nitrosative stress in all treated cell lines. The most prominent effect is observed on HCT-116 cells, and on MRC-5 cells, while MDA-MB-231 cells showed higher resistance to the investigated cell lines, giving us direction towards the substances with more specific selectivity.     

New Polyenes from the Marine-Derived Fungus Talaromyces cyanescens with Anti-Neuroinflammatory and Cytotoxic Activities

Three new polyene compounds, talacyanols A–C (1–3), along with two known compounds, ramulosin (4) and eurothiocin A (5), were isolated from the marine fungus Talaromyces cyanescens derived from a seaweed Caulerpa sp. Structures of 1–5 were established by one-dimensional and two-dimensional (1D/2D) NMR, HR-ESIMS, and the modified Mosher’s methods, as well as comparison with previously reported literature data. All the compounds (1–5) were tested for their in vitro cytotoxic and anti-neuroinflammatory activities. Among them, 1 showed moderate cytotoxic activity against a panel of cancer cell lines (HCT-15, NUGC-3, NCI-H23, ACHN, PC-3, and MDA-MB-231) with GI₅₀ values ranging from 44.4 to 91.6 μM, whereas compounds 2 and 5 exhibited anti-neuroinflammatory effect without cytotoxicity against all the tested cell lines.     

Novel Tdp1 Inhibitors Based on Adamantane Connected with Monoterpene Moieties via Heterocyclic Fragments

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a promising target for anticancer therapy due to its ability to counter the effects topoisomerase 1 (Top1) poison, such as topotecan, thus, decreasing their efficacy. Compounds containing adamantane and monoterpenoid residues connected via 1,2,4-triazole or 1,3,4-thiadiazole linkers were synthesized and tested against Tdp1. All the derivatives exhibited inhibition at low micromolar or nanomolar concentrations with the most potent inhibitors having IC₅₀ values in the 0.35–0.57 µM range. The cytotoxicity was determined in the HeLa, HCT-116 and SW837 cancer cell lines; moderate CC₅₀ (µM) values were seen from the mid-teens to no effect at 100 µM. Furthermore, citral derivative 20c, α-pinene-derived compounds 20f, 20g and 25c, and the citronellic acid derivative 25b were found to have a sensitizing effect in conjunction with topotecan in the HeLa cervical cancer and colon adenocarcinoma HCT-116 cell lines. The ligands are predicted to bind in the catalytic pocket of Tdp1 and have favorable physicochemical properties for further development as a potential adjunct therapy with Top1 poisons.     

Design,Synthesis, and Antipoliferative Activities of Novel Substituted Imidazole-Thione Linked Benzotriazole Derivatives

A new series of benzotriazole moiety bearing substituted imidazol-2-thiones at N1 has been designed, synthesized and evaluated for in vitro anticancer activity against the different cancer cell lines MCF-7(breast cancer), HL-60 (Human promyelocytic leukemia), and HCT-116 (colon cancer). Most of the benzotriazole analogues exhibited promising antiproliferative activity against tested cancer cell lines. Among all the synthesized compounds, BI9 showed potent activity against the cancer cell lines such as MCF-7, HL-60 and HCT-116 with IC₅₀ 3.57, 0.40 and 2.63 µM, respectively. Compound BI9 was taken up for elaborate biological studies and the HL-60 cells in the cell cycle were arrested in G₂/M phase. Compound BI9 showed remarkable inhibition of tubulin polymerization with the colchicine binding site of tubulin. In addition, compound BI9 promoted apoptosis by regulating the expression of pro-apoptotic protein BAX and anti-apoptotic proteins Bcl-2. These results provide guidance for further rational development of potent tubulin polymerization inhibitors for the treatment of cancer.     

Triangulene C, a new cubitane-based diterpenoid from the soft coral Sinularia triangula

A new cubitane-based diterpenoid, triangulene C (1), was isolated from the soft coral Sinularia triangula and its structure was elucidated on the basis of spectroscopic data. Compound 1 was not cytotoxic (IC50 > 20 microg/mL) toward the four human cancer cell lines tested (HL60, MDA-MB-231, HCT-116 and DLD-1).     

Sea Anemone Heteractis crispa Actinoporin Demonstrates In Vitro Anticancer Activities and Prevents HT-29 Colorectal Cancer Cell Migration

Actinoporins are the most abundant group of sea anemone cytolytic toxins. Their membranolytic activity is of high interest for the development of novel anticancer drugs. However, to date the activity of actinoporins in malignant cells has been poorly studied. Here, we report on recombinant analog of Hct-S3 (rHct-S3), belonging to the combinatory library of Heteractis crispa actinoporins. rHct-S3 exhibited cytotoxic activity against breast MDA-MB-231 (IC₅₀ = 7.3 µM), colorectal HT-29 (IC₅₀ = 6.8 µM), and melanoma SK-MEL-28 (IC₅₀ = 8.3 µM) cancer cells. The actinoporin effectively prevented epidermal growth factor -induced neoplastic transformation of JB6 Cl41 cells by 34% ± 0.2 and decreased colony formation of HT-29 cells by 47% ± 0.9, MDA-MB-231 cells by 37% ± 1.2, and SK-MEL-28 cells by 34% ± 3.6. Moreover, rHct-S3 decreased proliferation and suppressed migration of colorectal carcinoma cells by 31% ± 5.0 and 99% ± 6.4, respectively. The potent anti-migratory activity was proposed to mediate by decreased matrix metalloproteinases-2 and -9 expression. In addition, rHct-S3 induced programmed cell death by cleavage of caspase-3 and poly (ADP-ribose) polymerase, as well as regulation of Bax and Bcl-2. Our results indicate rHct-S3 to be a promising anticancer drug with a high anti-migratory potential.     

Anticarcinogenic and Antioxidant Action of an Edible Aquatic Flora Jussiaea repens L. Using In Vitro Bioassays and In Vivo Zebrafish Model

Oxidative stress is the major cause of many health conditions, and regular consumption of antioxidants helped to encounter and prevent such oxidative stress-related diseases. Due to safety concerns over long-term uses of synthetic antioxidants, natural antioxidants are more preferred. The purpose of this study is to investigate the antioxidant and anticancer activities of Jussiaea repens L., a wild edible flora found in Manipur, India. The antioxidant activity was evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), Ferric reducing antioxidant power (FRAP) assay and DNA-nicking assay. The anticancer activity was tested using five cancer lines viz., SKOV3 cells (ovarian), HeLa (cervical), MDA-MB-231 (breast), PANC-1 (pancreatic), and PC3 (prostate). The toxicity, developmental effect, antiproliferative activity was further tested using zebrafish embryos. The methanolic plant extract had higher polyphenol content than flavonoids. The in vitro study demonstrated a promising antioxidant capacity and DNA protection ability of this plant. The extract also showed cytotoxic activity against SKOV3, HeLa, MDA-MB-23, and PANC-1 cancer cell lines. The in vivo studies on zebrafish embryos demonstrated the extract’s ability to suppress the developmental process and elicited more cytotoxicity to cancer cells than developing zebrafish embryos. Moreover, the in vivo studies on zebrafish embryos also indicated the antiproliferative activity of J. repens L. extract.     

Chitinase inhibits growth of human breast and colorectal cancer cells in vitro and Ehrlich ascites carcinoma cells in vivo

Trichosanthes dioica seed extract was loaded on a QA-cellulose column and the unbound fraction with the chitinase activity was run on SDS-PAGE. Multiple bands were observed and were separated by a Sephadex G-50 column. The combination of the 6 and 33 kDa masses supported the degradation of chitinase as purified earlier. Only the 33 kDa fraction contained sugar and showed chitinase activity. The chitinase was also isolated by using a chitin column. At 200 µg/ml protein concentration, the chitinase inhibited 49.1 %, 48.8 % and 38.12 % of Ehrlich ascites carcinoma, HCT-116 and MCF-7 cells growth, respectively, in a dose-dependent manner. Exactly, 46 % and 82 % EAC cell growth inhibition were observed after treating the EAC cells bearing Swiss albino mice with the chitinase at the doses of 1.0 and 2.0 mg/Kg/day respectively. EAC, HCT-116 and MCF-7 cells growth inhibitions were due to the induction of apoptosis. ROS was accumulated in HCT-116 and MCF-7 cells. After treatment of HCT-116 cells, the expression level of p53 and TNFα genes increased and PARP gene decreased. On the other hand, elevated expression was observed for PARP, MAPK, NFκB, FAS, FADD, and Caspase-8 genes in MCF-7 cells. The induction of apoptosis in HCT-116 was further confirmed by caspase protein expression. The chitinase causes ‘S’ cell cycle arrest in MCF-7 and HCT-116 cells. T. dioica seed chitinase inhibited EAC, HCT-116 and MCF-7 cells by inducing apoptosis in vitro and EAC in vivo in mice. These promising results indicated that T. dioica seed chitinase can be an anticancer agent.