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Human aldo-keto reductases (AKRs) catalyze the NADPH-dependent reduction of carbonyl groups to alcohols for conjugation reactions to proceed. They are implicated in resistance to cancer chemotherapeutic agents either because they are directly involved in their metabolism or help eradicate the cellular stress created by these agents (e.g., reactive oxygen species and lipid peroxides). Furthermore, this cellular stress activates the Nuclear factor-erythroid 2 p45-related factor 2 (NRF2)-Kelch-like ECH-associated protein 1 pathway. As many human AKR genes are upregulated by the NRF2 transcription factor, this leads to a feed-forward mechanism to enhance drug resistance. Resistance to major classes of chemotherapeutic agents (anthracyclines, mitomycin, cis-platin, antitubulin agents, vinca alkaloids, and cyclophosphamide) occurs by this mechanism. Human AKRs also catalyze the synthesis of androgens and estrogens and the elimination of progestogens and are involved in hormonal-dependent malignancies. They are upregulated by antihormonal therapy providing a second mechanism for cancer drug resistance. Inhibitors of the NRF2 system or pan-AKR1C inhibitors offer promise to surmount cancer drug resistance and/or synergize the effects of existing drugs. Significance Statement Aldo-keto reductases (AKRs) are overexpressed in a large number of human tumors and mediate resistance to cancer chemotherapeutics and antihormonal therapies. Existing drugs and new agents in development may surmount this resistance by acting as specific AKR isoforms or AKR pan-inhibitors to improve clinical outcome.

A novel nitrogen mustard CBISC has been synthesized and evaluated as an anticancer agent. CBISC has been shown to exhibit enhanced cell proliferation inhibition properties against mutant p53 cell lines colorectal cancer WiDr, pancreatic cancer (MIAPaCa-2 and PANC-1), and triple negative breast cancer (MDA-MB-231 and MDA-MB-468). In vitro mechanism of action studies revealed perturbations in the p53 pathway and increased cell death as evidenced by western blotting, immunofluorescent microscopy and MTT assay. Further, in vivo studies revealed that CBISC is well tolerated in healthy mice and exhibited significant in vivo tumor growth inhibition properties in WiDr and MIAPaCa-2 xenograft models. These studies illustrate the potential utility of CBISC as an anticancer agent.

Epidemiological studies suggest suppression of the lymphocytes function through cholinergic stimulation due to organophosphorus pesticide exposure. The study aimed to assess the alteration in the levels of immune cell phenotypes among farm women (FW) and farm children (FC) who were occupationally exposed to pesticides and age/gender-matched control subjects belonging to Rangareddy district (Telangana, India). A total of 129 FW, 129 FC and 268 age/gender-matched controls were recruited. Blood samples were collected from the selected subjects to estimate the levels of nine organophosphorus pesticide residues and CD (CD3+, CD4+, CD8+, CD16+ and CD19+) cell markers using LC-MS/MS and flow cytometry, respectively. Independent t-test analysis was conducted to compare the immune cell phenotypes between exposed and control groups. Spearman's rank correlation test was further carried out to identify any possible correlation between the pesticide residues and CD markers. The mean percentage for CD4+, CD8+ and CD16+ was found to be significantly low, while for CD19 + itwas significantly high in the FW as compared to the CW group (p < 0.01). Further, the residues of chlorpyrifos and monocrotophos among FW were found to be significantly correlating with the mean percentages of CD19+ and CD8+ markers, respectively. The cell marker subsets of CD4+ and CD8+ were significantly low in FC children 9-12 years and 13-15 years age groups, respectively (p < 0.05). Also, these levels were significantly correlating with the residues of malathion and monocrotophos. The present study could indicate an alteration in the lymphocytes' subpopulations, which may thereby infer the toxicity in the first phase assessment of immunotoxicity. Therefore, further studies may be conducted to understand the suspected pesticides' mechanism along with various other factors in causing immune suppression coupled with nutritional and other related disorders.

Background & Objective: A facile and efficient method for the synthesis of novel derivatives of FQ citrate conjugates with 1,2,4-triazoles and 1,3,4-oxadiazole scaffolds 8-11 using conventional, as well as microwave irradiation methods, was reported. Based on these original building blocks, the new derivatives of 3, 7-disubstituted fluoroquinolones bearing the oxadiazolyl-triazole groups were obtained. These invaluable derivatives are of great interest in medicinal and pharmaceutical studies because of their important biological properties. Methods: All the reactions were examined under conventional as well as microwave mediated conditions. The structures of obtained compounds were confirmed by 1H NMR, 13C NMR, IR HRMS spectroscopy, and elemental analysis. The antibacterial and antifungal activities of these compounds were screened against Gram-positive, Gram-negative bacteria, and fungal stains by the agar well diffusion method. Cytotoxic assay of the title compounds was evaluated against cervical carcinoma cell line (HeLa) by using the MTT assay. The crystal structure of the Quinolone-DNA cleavage complex of type IV topoisomerase from S. pneumoniae (PDB ID: 3RAE) complex was obtained from the Protein Database (PDB, http:// www.rcsb.org). Molecular properties prediction-drug likeness was studied by Molinspiration and Molsoft software, while lipophilicity and solubility parameters were studied using the Osiris program. Results: A novel approach for the synthesis of benzylthio-1,2,4-triazole and 1,3,4-oxadiazoles core with regioisomeric norfloxacin citrate conjugates was developed. Among the title compounds, 11b, 10a reveal pronounced activity against S. pneumoniae with minimum inhibitory concentrations of 0.89, 0.96 mg/mL and MBCs of 2.95, 2.80 mg/mL, respectively. Minimum Fungicidal Concentration (MFC) has been determined for each compound against two fungal strains. Compound 11b showed maximum anti-cancer activity against HeLa cell line with IC50 value 11.3 ± 0.41 comparable to standard drug DXN. For binding mode, active site residues and docking energies (ΔG =-7.9 Kcal/mol) for ligand 9b exhibited the highest hydrogen bonding (3.59274 A˚), Pi– Alkyl (5.14468 A˚) interactions with amino acid LEU479 of 3RAE protein. The compounds following the Lipinski ‘Rule of five’ were synthesized for antimicrobial and anti-cancer screening as oral bioavailable drugs/leads. Maximum drug likeness model score 1.52, 1.41 was found for compounds 10d, 11b. Conclusion: The present work, through simple synthetic approaches, led to the development of novel hybrids of fluoroquinolone containing citrate-triazole-oxadiazole pharmacophores that exhibited remarkable biological activities against different microorganisms and cell lines. The compounds showed suitable druglike properties and are expected to present good bioavailability profile. An efficient combination of molecular modeling and biological activity provided an insight into QSAR guidelines that could aid in further development and optimization of the norfloxacin derivatives.

An efficient protocol is developed for the synthesis of Rilpivirine intermediate 4-[(4-chloro-2-pyrimidinyl) amino]benzonitrile hydrochloride via a simple two-step approach. Initially 1-(4-cyanophe...

The thermal unfolding of the copper redox protein azurin was studied in the presence of four different amino acid-based ionic liquids (ILs), all of which have tetramethylguanidium as cation. The anionic amino acid includes two with alcohol side chains, serine and threonine, and two with carboxylic acids, aspartate and glutamate. Control experiments showed that amino acids alone do not significantly change protein stability and pH changes anticipated by the amino acid nature have only minor effects on the protein. With the ILs, the protein is destabilized and the melting temperature is decreased. The two ILs with alcohol side chains strongly destabilize the protein while the two ILs with acid side chains have weaker effects. Unfolding enthalpy (ΔHunf°) and entropy (ΔSunf°) values, derived from fits of the unfolding data, show that some ILs increase ΔHunf°while others do not significantly change this value. All ILs, however, increase ΔSunf°. MD simulations of both the folded and unfolded protein conformations in the presence of the ILs provide insight into the different IL-protein interactions and how they affect the ΔHunf° values. The simulations also confirm that the ILs increase the unfolded state entropies which can explain the increased ΔSunf° values.

To augment sustainable tanning, less chrome input, high functional quality leather processed via no restricted substance in processing, and ease to treat the inevitable protein waste generated are the key challenge, and currently, they have become the active part of leather research. Our work covers the synthesis of a formaldehyde-free chromium-incorporated polymeric tanning agent (FF-CIPTA) and its application in a reformed leather processing route which ensures near zero discharge of chromium containing solid waste. The preliminary characterization of FF-CIPTA reveals that the developed product is stable up to pH 5.2, and the particle size distribution ranges from 955 to 1450 nm with 12% Cr2O3 content. The present work significantly reduces the tanning agent input without compromising the thermal stability (103 °C) of the leather because of its multicrosslinking nature. Since the product exhibits a polymeric character, it provides tanning-cum-filling action which in turn reduces the retanning agent consumption in subsequent processes. Scanning electron microscopic study, porosity analysis, and hand assessment results clearly indicate the significant improvement in organoleptic properties. In addition, the process also enjoys the benefits of zero chromium containing solid waste generation, 71.4% reduction in chromium input, and high chromium transfer efficiency (92%) than the conventional process (36%), and 74.4% reduction in total dissolved solids generation. Furthermore, the water consumption and chemical input are reduced by 51.6 and 17%, respectively. Reduction in wastewater treatment cost and a high economic value of chromium-free leather scraps leads to a cumulative gain of US$ 39.84 per ton of raw material processing. Overall, a potential and practical applicability for cleaner and sustainable tanning is well established.

Nitrogen, oxygen and sulfur-containing fused heterocycles are of great importance because of their exciting and diverse biological activities. The construction of the carbonnitrogen and carbon-oxygen through a multicomponent reaction approach by using ecofriendly reusable heterogeneous catalysts are of significant importance as it opens avenues for the introduction of nitrogen and oxygen in organic molecules. Thus, green methodologies have gained particular significance in this field; today, green chemistry is considered a tool for introducing sustainable concepts at the fundamental level. This review emphasizes and discusses the current progress on the applications of eco-friendly, recyclable heterogeneous catalysts for the synthesis of different heterocyclic fused systems and their green protocols. We paid particular attention to the specific integration of carbon-nitrogen, and carbon-oxygen bond-forming fused heterocycles by a one-pot approach by evaluating the literature between 2012 and the middle of 2020. The efficiency of the catalyst is assessed in terms of reaction time, yield and possible reusability. The MCR and heterogeneous catalyst strategies have demonstrated broader scope, economical and viability for the green and sustainable processes in the field of synthetic organic chemistry.

A highly efficient green protocol is described for the development of novel benzo[4,5]thiazolo[3,2-a]pyrimidine analogues through the one-pot fusion of the 2-amino-benzothiazole with different chos...

We report expedient methods to analyze the inactive and active ingredients and other impurities in Fulvestrant injection, using gas chromatography and high-performance liquid chromatography. The levels (LOQ to 150%) of Fulvestrant and related impurities were quantified using HPLC. A gradient temperature program was employed to reduce the analysis time and improve the peaks' resolution in the present study. The separation of impurities was achieved on the symmetry C8 column and maintained temp at 35 °C. The injection volume was 10 µL, and detection was made at 225 nm. For GC method used the DB-Wax column. Helium as a carrier with a flow rate of 5.0 mL min−1. The injector inlet temperature and FID temperature were maintained at 220 °C and 280 °C, respectively. Both methods exhibited excellent intra- and inter-day precision, with RSD 0.999. The methods were validated for linearity, precision, specificity, accuracy, and robustness for their intended purpose as per the current ICH guidelines. Finally, both the techniques were used in the quality control lab to estimate the solvents and impurities of reference listed drug and in house samples.

Silica nanoparticles have attracted a huge bioaudience as these are biosafe materials for targeted delivery applications due to their ease of functionalisation, less toxicity, and bio-compatibility. However, poor knowledge of the interaction mechanism between silica nanoparticles and protein causes less development of silica-based fluorescent probes for practical applications. Hence, in this work, the interaction mechanism and structural changes in BSA caused by silica nanoparticles with different functional groups have been studied. First dye-supported silica nanoparticles with hydroxyl terminal (DSN) and amine terminal (DSFN) were synthesized by a modified Stober process. The dye supported on silica nanoparticles resulted in improving the photostability, with less toxicity when compared to the bare dye system. To improve the bioavailability, BSA was conjugated with both hydroxyl (BSA–DSN) and amine functionalised dye supported silica nanoparticles (BSA–DSFN). To understand the structural modification induced by silica with different terminals, nanoparticles were incubated with BSA (Bovine Serum Albumin) for 48 h. Then, the structural changes caused by BSA interacting with silica nanoparticles were evaluated using various techniques such as UV-VIS spectroscopy, fluorescence spectroscopy, CD (circular dichroism), and lifetime measurements. Longer lifetime emphasized the stable photophysical properties of BSA conjugated dye supported silica nanoparticles for live-cell imaging. These interaction studies generated knowledge on structural modification induced by BSA adsorption on silica nanoparticles and its bioavailability for cell imaging. The circular dichroism measurement divulges that the stabilisation of the secondary structure and improved thermal stability of BSA were attained after conjugating with silica nanoparticles. Cell toxicity and imaging results showed that BSA conjugated with amine-functionalised silica nanoparticles BSA@DSFN proved to be an ideal candidate for long-life fluorescent probes for cellular imaging application.

The Knoevenagel condensation is a powerful tool to build carbon-carbon bonds. Knoevenagel synthesis of cyanoacrylates has received considerable attention, mainly because the compounds possess wide-...

Herein, we report the synthesis and application of a smart polymeric acrylic syntan (synthetic tanning material), which can respond to temperature and pH. Behavior of polymer at different pH (1-10) at room temperature (28°C) was studied. Also interactions with collagen were ascertained in order to understand the polymers’ response towards secondary structures of collagen. Leather made using the experimental syntan demonstrated higher temperature resistance of 3±0.5°C compared to control syntan treated leathers (1±0.5°C) when exposed to heat under artificial simulation. Experimental leathers exhibited better strength and organoleptic properties. These smart leathers find its application in extreme climatic conditions of heat or cold.

Severe water deficit and highly polluting effluent generation from leather industries have constantly been pressurizing the tanners to adopt cleaner leather processing systems. The present study aims to minimize the use of water by substituting it with non-aqueous green solvents and also to enhance the enzyme action in alpha-amylase based fiber opening process. The activity of alpha-amylase in select non-aqueous green solvents namely, heptane, polyethylene glycol 200 and propylene glycol is considerably higher by 62, 38 and 31% than in water, respectively. Comparable results are obtained for the catalytic efficiency of alpha-amylase and hence it is further validated in collagen fiber opening trials as well. Scanning electron micrographs, histological images and proteoglycan estimation supported the above findings at 1% alpha-amylase dosage. The final quality of the experimental leathers in terms of physical and bulk properties is comparable to that of control leathers. Recycling studies indicate that it is possible to replace water with green solvents for enzymatic fiber opening with the feasibility to recover more than 85% solvent-enzyme mixture and reuse without any additional alpha-amylase usage. Reduction in pollution load coupled with the efficient catalytic action of enzyme in non-aqueous media favors the present protocol for industrial applications.

A series of nitric oxide (NO) donor furoxan conjugates of N, N-dialkylcarboxy coumarins have been synthesized as potential anticancer agents. The synthesized compounds have been tested for their in vitro antiproliferative activities on various cancer and noncancerous cell lines. The candidate derivatives exhibit selectivity towards cancer cells with excellent activities in low nM to µM concentrations. In vitro mechanistic studies indicate that the candidate compounds generate substantial NO, inhibit colony formation, and cause apoptosis in cancer cells. A preliminary in vivo tolerance study of the lead candidate 10 in mice indicates that it is well-tolerated, evidenced by zero mortality and normal body weight gains in treated mice. Further translation of the lead derivative 10 using MDA-MB-231 based tumor xenograft model shows good tumor growth reduction.

The synthesis of cyclopropyl methyl ketones and highly strained fused substituted dihydrobenzopyran cyclopropyl lactones derived from coumarin carboxylates and chloroacetone in the presence of potassium carbonate is reported. One step synthetic access to the previously unknown dihydrobenzopyran cyclopropyl tricyclic ketals is achieved with wide substrate scope. Substituted coumarin carboxylates, phenylamides or a quinolin-2(1H)-one possessing alkyl electron donating (methyl, t-butyl) and electron withdrawing groups (F, Cl, Br, NO2) in the 4 or 6 positions formed the highly strained dihydrobenzopyran cyclopropyl tricyclic ketals in moderate yield alongside the expected coumarin carboxylate. Saturation or substitution at the 5-position or 6-OMe afforded no tricyclic ketal compound but solely coumarin carboxylates. The formation of both structures in selected derivatives was confirmed by X-ray crystallography. A plausible mechanism is proposed for the formation of the fused lactone; via intramolecular rearrangement of cis cyclopropyl methyl ketones with phenolic acetate via the formation of a hemiacetal.

Monocarboxylate transporters 1 and 4 (MCT1 and MCT4) are involved in tumor development and progression. Their expression levels are related to clinical disease prognosis. Accordingly, both MCTs are promising drug targets for treatment of a variety of human cancers. The noninvasive imaging of these MCTs in cancers is regarded to be advantageous for assessing MCT-mediated effects on chemotherapy and radiosensitization using specific MCT inhibitors. Herein, we describe a method for the radiosynthesis of [18 F]FACH ((E)-2-cyano-3-{4-[(3-[18 F]fluoropropyl)(propyl)amino]-2-methoxyphenyl}acrylic acid), as a novel radiolabeled MCT1/4 inhibitor for imaging with PET. A fluorinated analog of α-cyano-4-hydroxycinnamic acid (FACH) was synthesized, and the inhibition of MCT1 and MCT4 was measured via an L-[14 C]lactate uptake assay. Radiolabeling was performed by a two-step protocol comprising the radiosynthesis of the intermediate (E)/(Z)-[18 F]tert-Bu-FACH (tert-butyl (E)/(Z)-2-cyano-3-{4-[(3-[18 F]fluoropropyl)(propyl)amino]-2-methoxyphenyl}acrylate) followed by deprotection of the tert-butyl group. The radiofluorination was successfully implemented using either K[18 F]F-K2.2.2 -carbonate or [18 F]TBAF. The final deprotected product [18 F]FACH was only obtained when [18 F]tert-Bu-FACH was formed by the latter procedure. After optimization of the deprotection reaction, [18 F]FACH was obtained in high radiochemical yields (39.6 ± 8.3%, end of bombardment (EOB) and radiochemical purity (greater than 98%).

In 21st century, organic and domestic wastes and discharges from varied chemical and manufacturing industries to water bodies become a critical issue and challenge for the researchers, engineers and policy makers. Advanced oxidation processes (AOPs) are efficient, sustainable, economically viable and green techniques to elimination on-degradable organic pollutants by biological and traditional processes. A number of research articles have been published from the past two decades on the wastewater treatment using various advanced oxidation processes. The main objective of this review paper is to provide the quick view for researchers, academicians and scientists in the area of wastewater treatment using various types of AOPs, which incorporate green principles involves in the processes for removal of different pollutants and contaminants including dyes, phenols, pesticides, herbicides etc. from wastewaters, with emphasis on the degradation efficiency of various photocatalysts. The formation reactions of •OH radical and the mechanisms of degradation of various organic pollutants in the wastewater is also discussed. This review covers various types of advanced oxidation processes, viz., ozone-based processes, photocatalysis and Fenton-based reactions.

Azilsartan (I) is an orally administered drug to control high blood pressure in adults. 1 , 4 Azilsartan medoxomil (II), a US FDA approved prodrug of Azilsartan (Figure 1), is an angiotensin II rec...

The design of an efficient photocatalytic system with a capability of effective photon conversion for hydrogen evolution is highly challenging. Herein, we report the first example of phenanthroline based ruthenium complexes (PRC1-3) embedded nanostructured hierarchical porous TiO2 composites (HPT) that showed impressive H2 evolution reaction (HER) under simulated light irradiation. The introduction of the propenyl groups in the Ru-Phen complexes reveal enhanced light response (350–550 nm) with increased charge transfer behaviour and lifetime of 77–127 ns. The composite PHPT-PRC’s endows high performance towards HER. The superior activity of PHPT-PRC3 exhibits H2 yield of 3066 μmolg−1cat with a turnover number of 123 after 4 h compared to N719 sensitized PHPT (N719-PHPT). The enhancement in HER is due to the strong photon absorption in PRC3 with 3-propenyl moieties with an extended excited state lifetime. Further, the high surface area and uniform porous structures of HPT favours better transport of irradiated light absorption and enhanced charge transfer property which synergistically improves the effective charge transfer on the photocatalytic HER. The experimental observations corroborated with computational calculations which further elucidates the high efficiency of PRC3 than 1 and 2 due to favourable HOMO-LUMO energy levels, efficient charge separation and enhanced regeneration of oxidized dye.

Purpose Nucleic acid-based therapies are a promising therapeutic tool. The major obstacle in their clinical translation is their efficient delivery to the desired tissue. We developed a novel nanosized delivery system composed of conjugates of α-tocopherol, polyethyleneimine, and polyethylene glycol (TPP) to deliver nucleic acids. Methods We synthesized a panel of TPP molecules using different molecular weights of PEG and PEI and analyzed with various analytical approaches. The optimized version of TPP (TPP111 - the 1:1:1 molecular ratio) was self-assembled in water to produce nanostructures and then evaluated in diversified in vitro and in vivo studies. Results Through a panel of synthesized molecules, TPP111 conjugate components self-assembled in water, forming globular shaped nanostructures of ~90 nm, with high nucleic acid entrapment efficiency. The polymer had low cytotoxicity in vitro and protected nucleic acids from nucleases. Using a luciferase-expressing plasmid, TPP111-plasmid nano-complexes were rapidly up-taken by cancer cells in vitro and induced strong transfection, comparable to PEI. Colocalization of the nano-complexes and endosomes/lysosomes suggested an endosome-mediated uptake. Using a subcutaneous tumor model, intravenously injected nano-complexes preferentially accumulated to the tumor area over 24 h. Conclusion These results indicate that we successfully synthesized the TPP111 nanocarrier system, which can deliver nucleic acids in vitro and in vivo and merits further evaluation.

We report the synthesis of 1, 5, 10 wt% cobalt oxide/reduced graphene oxide (CoO–RGO) composite materials by a simple solvothermal method. We assessed their catalytic activity in liquid phase epoxidation reaction without any sacrificial reductant and fully characterised the prepared catalysts by different techniques, including powder XRD, Raman spectra, scanning electron microscopy, transmission electron microscopy and ICP-MS. 5 wt% Cobalt oxide (CoO–RGO-5) promoted material showed high conversion (57%) of trans-stilbene oxide and excellent selectivity (96%) towards trans-stilbene epoxidation in DMF solvent by using the molecular oxygen as an oxidant. The conversion efficiency of trans-stilbene reaction remained the same for fresh and recycled catalysts after the 4th run.

Calcium oxide incorporated porous carbon materials were synthesized by the impregnation method to study CO2 adsorption and separation of CO2/CH4. The X-ray diffraction, Raman analysis, N2 isotherms...