Search

Context Tuberculosis is one of the major infectious diseases, with people of reproductive age group having a high risk of infection. Aims The present study was designed to understand the consequences of anti-tuberculosis drugs (ATDs) used in DOTS (directly observed treatment short course) schedule on ovarian function. Methods Adult female Swiss albino mice were orally administered with combinations of ATDs used in the DOTS schedule every day for 4 weeks. At 2 weeks after the cessation of ATDs administration, the endocrine changes and ovarian function were assessed in mice. Key results Administration of ATDs to mice resulted in a prolonged estrous cycle, reduced ovarian follicle reserve, alteration in FSH, LH, and progesterone level, and decreased the number of ovulated oocytes. Further, the degree of fragmentation, degeneration, abnormal distribution of cytoplasmic organelles, abnormal spindle organisation, and chromosomal misalignment were higher in oocytes that were ovulated following superovulation. Blastocysts derived from ATDs treated mice had significantly lower total cell numbers and greater DNA damage. A marginal increase in the number of resorbed fetuses was observed in all the ATDs treated groups except in the multidrug resistance treatment group. Male progeny of ATDs treated mice had decreased sperm count and lower progressive motility, while female progeny exhibited a non-significant reduction in the number of oocytes ovulated. Conclusions The results of this study suggest that ATDs can have significant adverse effects on the ovarian reserve, cytoplasmic organisation of oocytes, and can potentially cause transgenerational changes. Implications The findings of the present study indicate ovarian toxicity of ATDs and warrant further research in the direction of identifying alternate drugs with minimal toxicity, and strategies to mitigate the ovarian toxicity induced by these drugs.

Protein kinases are the family of attractive enzyme targets for drug design with relevance to cancer biology. Serine arginine protein kinase 1 (SRPK1) is responsible for the phosphorylation of serine/arginine (SR)-rich proteins. Alternative Splicing Factor/Splicing Factor 2 (ASF/SF2) involved in mRNA editing. ASF/SF2 is over expressed in many cancers and plays crucial roles in the cell survival. Phosphorylation of ASF/SF2 is decisive for its functions in cancer. In search of potential anticancer therapeutic agents for attenuating phosphorylation of ASF/SF2, we have explored specific and potential inhibitors of SRPK1 from natural and drug like compounds databases using in-silico methods. Compound ZINC02154892 (C02) was found to be the most potent inhibitor for SRPK1. In-vitro molecular and cell biology studies have shown C02 as a potent and specific inhibitor of phosphorylation of ASF/SF2 and cell survival in leukemic cell line. Structural analysis of SRPK1 with compound C02 revealed a unique pattern of binding targeting ATP binding site along with inhibiting recruitment of ASF/SF2 by SRPK1. The possibilities of compound C02 to be used as a lead compound paving way for the development of potent and specific inhibitors of SRPK1 for designing of novel potential anticancer inhibitor is inferred from the current studies.

Spermatozoon is a motile cell with a special ability to travel through the woman’s reproductive tract and fertilize an oocyte. To reach and penetrate the oocyte, spermatozoa should possess progressive motility. Therefore, motility is an important parameter during both natural and assisted conception. The global trend of progressive reduction in the number and motility of healthy spermatozoa in the ejaculate is associated with increased risk of infertility. Therefore, developing approaches for maintaining or enhancing human sperm motility has been an important area of investigation. In this review we discuss the physiology of sperm, molecular pathways regulating sperm motility, risk factors affecting sperm motility, and the role of sperm motility in fertility outcomes. In addition, we discuss various pharmacological agents and biomolecules that can enhance sperm motility in vitro and in vivo conditions to improve assisted reproductive technology (ART) outcomes. This article opens dialogs to help toxicologists, clinicians, andrologists, and embryologists in understanding the mechanism of factors influencing sperm motility and various management strategies to improve treatment outcomes.

An easily adaptable protocol for the synthesis of 3,5-bis(het)aryl-2-carboxylate/nitrile pyrroles and the related 2,3,5-tri(het)aryl-pyrroles with complementary regioselectivity from the corresponding 1,3-bis(het)aryl-1,3-monothio diketones or β-enaminone precursors has been reported. Initially, regioselective base catalyzed condensation of glycine ethyl/methyl esters or aminoacetonitrile with 1,3-bis(het)aryl-1,3-monothio diketones give β-enaminones, which then in-situ undergoes cyclization to form 3,5-bis(het)aryl-2-carboxylate/nitrile pyrroles. The synthesis of 2,3,5 tri substituted pyrroles with full control over 3rd & 5th position on pyrrole ring is the noteworthy feature of this protocol. Although the product yields are moderate to good, the method offers a facile regioselective entry to 2,3,5 trisubstituted pyrroles without the aid of transition metal.

Pyrazole moiety represents an important category of heterocyclic compound in pharmaceutical and medicinal chemistry. The novel 1-aryl-3, 5-bis (het) aryl pyrazole derivatives were synthesized with complementary regioselectivity. The chemical structures were confirmed by IR, 1H NMR, 13C NMR, and mass spectral analysis. The chemical entities were screened in various cancer cell lines to assess their cell viability activity. Results showed that the compound 3-(1-(4-bromophenyl)-5-phenyl-1H-pyrazol-3-yl) pyridine (5d) possessed maximum cytotoxic effect against breast cancer and leukemic cells. The cytotoxicity was confirmed by live–dead cell assay and cell cycle analysis. Mitochondrial membrane potential, Annexin V-FITC staining, DNA fragmentation, Hoechst staining, and western blot assays revealed the ability of compound 5d to induce cell death by activating apoptosis in cancer cells. Thus, the present study demonstrates that compound 5d could be an attractive chemical entity for the development of small molecule inhibitors for treatment of leukemia and breast cancer.

A series of curcumin pyrazole derivatives (3a–e) were synthesized. The chemical structures were determined by 1H and 13C NMR spectroscopic techniques and their purity was confirmed by LC–MS and melting point determination. The compounds were screened for anticancer effects on different cancer cell lines by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay. The analogs demonstrated growth inhibitory effect on MCF-7, HeLa, and K562 cell lines with significant IC50 values. Compound 3b exhibited a high degree of cytotoxicity against cancer cells and minimum growth inhibitory effects against normal cells HEK293T and hence further, cell cycle analysis and mitochondrial membrane potential studies (JC-1 assay) were conducted by utilizing flow cytometry against K562 cells. This compound effectively arrested cell cycle progression at SubG1 phase and cells exhibited decreased membrane potential in a concentration-dependent manner with fluorescence shifting from red to green. Our findings suggest that compound 3b could be a promising anticancer agent since it effectively inhibited cell proliferation and can be selected for further in vitro and in vivo investigations.

International audience; Nonhomologous DNA end joining (NHEJ) is the major DNA double-strand break (DSB) repair pathway in mammals. Previously, we have described a small molecule inhibitor, SCR7, which can inhibit NHEJ in a Ligase IV-dependent manner. Administration of SCR7 within the cells resulted in the accumulation of DNA breaks, cell death, and inhibition of tumor growth in mice. In the present study, we report that parental SCR7, which is unstable, can be autocyclized into a stable form. Both parental SCR7 and cyclized SCR7 possess the same molecular weight (334.09) and molecular formula (C18H14N4OS), whereas its oxidized form, SCR7-pyrazine, possesses a different molecular formula (C18H12N4OS), molecular weight (332.07), and structure. While cyclized form of SCR7 showed robust inhibition of NHEJ in vitro, both forms exhibited efficient cytotoxicity. Cyclized and oxidized forms of SCR7 inhibited DNA end joining catalyzed by Ligase IV, whereas their impact was minimal on Ligase III, Ligase I, and T4 DNA Ligase-mediated joining. Importantly, both forms inhibited V(D)J recombination, although the effect was more pronounced for SCR7-cyclized. Both forms blocked NHEJ in a Ligase IV-dependent manner leading to the accumulation of DSBs within the cells. Although cytotoxicity due to SCR7-cyclized was Ligase IV specific, the pyrazine form exhibited nonspecific cytotoxicity at higher concentrations in Ligase IV-null cells. Finally, we demonstrate that both forms can potentiate the effect of radiation. Thus, we report that cyclized and oxidized forms of SCR7 can inhibit NHEJ in a Ligase IV-dependent manner, although SCR7-pyrazine is less specific to Ligase IV inside the cell.

Aberrant expression of estrogen receptor alpha (ER-α) is observed in many pathological complications like breast cancer, endometrial cancer, and in osteoporosis. ER-α plays a vital role in the initiation and progression of breast cancer and confers chemo and radioresistance to the cancer cells by upregulating expression of anti-apoptotic proteins. The synthetic pyrazole derivative 3-(1-(4-bromophenyl)-5-phenyl-1H-pyrazol-3-yl)pyridine (compound 5d) displays significant cytotoxicity against mammary carcinoma cells. Molecular docking studies revealed that compound 5d binds to ligand binding domain of (ER-α). In vivo studies were carried out to investigate ER-α expression by immunohistochemistry and quantitative RT-PCR, which revealed reduction of ER-α in tumor cells upon treatment with compound 5d indicating its ER-α antagonistic effect. Our study ascertains compound 5d as a potent inhibitor of mammary carcinoma cells.

DNA minor groove binders are an important class of chemotherapeutic agents. These small molecule inhibitors interfere with various cellular processes like DNA replication and transcription. Several benzimidazole derivatives showed affinity towards the DNA minor groove. In this study we show the synthesis and biological studies of a novel benzimidazole derivative (MH1), that inhibits topoisomerase II activity and in vitro transcription. UV-visible and fluorescence spectroscopic methods in conjunction with Hoechst displacement assay demonstrate that MH1 binds to DNA at the minor groove. Cytotoxic studies showed that leukemic cells are more sensitive to MH1 compared to cancer cells of epithelial origin. Further, we find that MH1 treatment leads to cell cycle arrest at G2/M, at early time points in Molt4 cells. Finally multiple cellular assays demonstrate that MH1 treatment leads to reduction in MMP, induction of apoptosis by activating CASPASE 9 and CASPASE 3. Thus our study shows MH1, a novel DNA minor groove binder, induces cytotoxicity efficiently in leukemic cells by activating the intrinsic pathway of apoptosis.

One step synthesis of 2,3-dihydroquinazolin-4(1H)-ones from gem-dibromomethylarenes using 2-aminobenzamide is described. Gem-dibromomethylarenes are used as aldehyde equivalent for the efficient synthesis of 2,3-dihydroquinazolin-4(1H)-ones, this synthesis takes shorter reaction time with quick isolation and excellent product yield.

Chemically synthesized small molecules play important role in anticancer therapy. Several chemical compounds have been reported to damage the DNA, either directly or indirectly slowing down the cancer cell progression by causing a cell cycle arrest. Direct or indirect reactive oxygen species formation causes DNA damage leading to cell cycle arrest and subsequent cell death. Therefore, identification of chemically synthesized compounds with anticancer potential is important. Here we investigate the effect of benzothiazole derivative (5g) for its ability to inhibit cell proliferation in different cancer models. Interestingly, 5g interfered with cell proliferation in both, cell lines and tumor cells leading to significant G2/M arrest. 5g treatment resulted in elevated levels of ROS and subsequently, DNA double-strand breaks (DSBs) explaining observed G2/M arrest. Consistently, we observed deregulation of many cell cycle associated proteins such as CDK1, BCL2 and their phosphorylated form, CyclinB1, CDC25c etc. Besides, 5g treatment led to decreased levels of mitochondrial membrane potential and activation of apoptosis. Interestingly, 5g administration inhibited tumor growth in mice without significant side effects. Thus, our study identifies 5g as a potent biochemical inhibitor to induce G2/M phase arrest of the cell cycle, and demonstrates its anticancer properties both ex vivo and in vivo.

Isoxazole derivatives are an important group of chemotherapeutic prototypes. In the current study, we have synthesized few isoxazole derivatives and tested them for their antiproliferative properties in cancer cell lines such as MCF7 and HeLa. The lead compound, 3-(3,4-dimethoxyphenyl)-5-(thiophen-2-yl)isoxazole (2b), showed considerable inhibition of proliferation of MCF7 and HeLa cells with the IC50 values of 19.5 and 39.2 µM, respectively. Cell cycle analyses and annexin-FITC staining in 2b-treated breast adenocarcinoma cells (MCF7) showed increased sub-G1 population and apoptosis. Furthermore, we tested the tumor inhibitory effect of 2b and estrogen receptor expression profile in DMBA-induced mammary tumors in Sprague–Dawley rats. The gross morphology of tumor studies was investigated by histopathology and ERα protein expression was evaluated by immunohistochemistry, which showed tumor regression and downregulation of ERα in tumor cells. The present results implicate that compound 2b could be used for the further derivatization for the treatment of breast cancer.

In search of synthetic chemotherapeutic substances capable of inhibiting, retarding, or reversing the process of multistage carcinogenesis, we synthesised a series of novel 1-(4-methoxybenzyl)-3-cyclopropyl-1H-pyrazol-5-amine derivatives 9(a-h) by a nucleophilic substitution reaction and characterized by (1)H and (13)C nuclear magnetic resonance (NMR), liquid chromatography mass spectrometry (LC/MS), Fourier-transform infrared (FTIR), and elemental analysis. These novel compounds were evaluated for their efficacy in inhibiting VERO normal and MCF-7 breast cancer cells proliferation by trypan blue exclusion assay, MTT assay, [(3)H] thymidine incorporation assay and DNA fragmentation analysis. Among the series, some compounds exhibited interesting growth inhibitory effects against cell lines. From the Structure-Activity Relationship studies, it has been revealed that, both novel patented compounds and therapeutic protocols of N-terminal pyrazole ring structures play key role in the antiproliferative activity.

In search of synthetic chemotherapeutic substances capable of inhibiting, retarding, or reversing the process of multi-stage carcinogenesis, we synthesized a series of novel 5-amino pyrazole derivatives 11(a-h) by a nucleophilic substitution reaction and characterized by 1H nuclear magnetic resonance (NMR), liquid chromatography mass spectrometry (LC/MS), Fourier-transform infrared (FTIR), and elemental analysis. These novel compounds were evaluated for their efficacy in inhibiting Ehrlich ascites tumor [EAT] cells in-vivo. In the present study we designed, synthesized, characterized and investigate the anti-angiogenic effects of these compounds, on Ehrlich ascites tumor [EAT] cells in-vivo. The compounds were subsequently tested for their ability to inhibit neovascularisation in chorio allantoin membrane (CAM) model. From the Structure Activity Relationship (SAR) studies, it reveals that, the substitution at N-terminal in pyrazole ring plays key role in the antitumor and anti-angiogenic effects.

Condensed-bicyclic triazolo-thiadiazoles were synthesized via an efficient “green” catalyst strategy and identified as effective inhibitors of PTP1B in vitro. The lead compound, 6-(2-benzylphenyl)-3-phenyl-[1,2,4]triazolo[3][1,3,4]thiadiazole (BPTT) was most effective against human hepatoma cells, inhibits cell invasion and decreases neovasculature in HUVEC and also tumor volume in EAT mouse models. This report describes an experimentally unidentified class of condensed-bicyclic triazolo-thiadiazoles targeting PTP1B and its analogs could be the therapeutic drug-seeds.

This is an effective, efficient and the easiest method of conversion of substituted 2-aminobenzamides into the corresponding dihydroquinazolinones using gem-dibromomethylarenes under mild reaction conditions.

A new, simple, and microwave-assisted, solution-phase T3P®-DMSO mediated method for the preparation of a novel class of estrogen receptor alpha (ERα) ligands based on the 2-phenylquinoline scaffold was developed. Furthermore, the novel ERα ligands were tested for their bioactivity against ERα-positive and ERα-negative cell lines. The ligand (entry 4), with amine and nitro group substitution at C4 position, displayed significant cytotoxicity against MCF-7 and HepG2 cells with an IC50 value of 6 and 11 μM, respectively. On the other hand, ERα-negative cells displayed resistance to quinolines induced cytotoxicity with an IC50 value >100 Mm and they does not induce cytotoxicity in normal breast epithelial cells. Molecular docking analyses suggest a consistent binding mode for these ERα ligands in the ligand binding domain of the human ERα and predict the ligands to occupy the hydrophobic cavity in a similar fashion as estradiol or GW2368.

Aberrant activation of nuclear factor kappa B (NF-κB) has been linked with the pathogenesis of several proinflammatory diseases including number of cancers and inflammatory bowel diseases. In the present work, we evaluated the anticancer activity of 1,2-oxazines derivatives against colorectal cancer cell lines and identified 2-((2-acetyl-6,6-dimethyl-4-phenyl-5,6-dihydro-2H-1,2-oxazin-3-yl)methyl)isoindoline-1,3-dione (API) as the lead anticancer agent among the tested compounds. The apoptosis inducing effect of API was demonstrated using flow cytometry analysis and measuring the caspase 3/7 activity in API treated cells. Based on the literature on inhibition of NF-κB by oxazines, we evaluated the effect of 1,2-oxazines against the ability of NF-κB binding to DNA, NF-κB-dependent luciferase expression and IκBα phosphorylation. We found that, API abrogate constitutive activation of NF-κB and inhibits IκBα phosphorylation in HCT116 cells. Our in silico analysis revealed the binding of oxazines to the hydrophobic cavity that present between the interface of p65 and IκBα. Given the relevance with aberrant activation of NF-κB in inflammation bowel disease (IBD), we evaluated the effect of API on dextran sulphate sodium-induced IBD mice model. The treatment of IBD induced mice with API decreased the myeloperoxidase activity in colonic extract, modulated the colon length and serum levels of pro- and anti-inflammatory cytokines such as TNF-α, IFN-γ, IL-6, IL-1β and IL-10. Furthermore, the histological analysis revealed the restoration of the distorted cryptic epithelial structure of colon in the API treated animals. In conclusion, we comprehensively validated the NF-κB inhibitory efficacy of API that targets NF-κB in in vitro colon cancer and an in vivo inflammatory bowel disease model.

A series of novel substituted 1-(4-methoxybenzyl)-3-cyclopropyl-1H-pyrazol-5-amine benzamides 9(a-h) were synthesized to determine their antibacterial and antifungal activities as well as possible structure-activity relationships (SARs) to improve therapeutic efficacy. The pyrazol-5-amine benzamides were screened for their antibacterial activity against standard strains of Gram-positive (Streptococcus pyogenes NCIM 2608, Staphylococcus aureus ATCC 29737, Bacillus subtilis NCIM 2010) and Gram-negative (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 20852, Klebsiella pneumoniae MTCC 618) bacteria by using streptomycin as positive control. They were also tested for their antifungal activities against mycotoxic strains of Fusarium verticillioides, Aspergillus ochraceous, Aspergillus flavus, Alternaria alternata, and Penicillium chrysogenum using nystatin as positive control. Among the synthesized compounds, 9d, 9g, and 9h showed potent antimicrobial activities.