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A mild photoredox approach enabling the first one-step synthesis of thiolated 2-aminothiazoles has been reported. Notably, the incorporation of thio group on electron-rich heteroarenes such as aminothiazoles via conventional nucleophilic aromatic substitution (SsubN/subAr) presents a significant challenge owing to polarity mismatch. Herein, we present a remarkable site-selective installation of thio group at the C-5 position of the electron-rich aminothiazole skeleton and successfully used them for the postfunctionalization of drugs and natural products.

[Image: see text] PMBA (2-Pyridin-4-yl-methylene-beta-boswellic acid), screened from among the 21 novel series of semisynthetic analogues of β-boswellic acid, is being presented as a lead compound for integrative management of KRAS mutant colorectal cancer (CRC), upon testing and analysis for its anticancerous activity on a panel of NCI-60 cancer cell lines and in vivo models of the disease. PMBA (1.7–29 μM) exhibited potent proliferation inhibition on the cell lines and showed sensitivity in microsatellite instability and microsatellite stable (GSE39582 and GSE92921) subsets of KRAS gene (Kirsten rat sarcoma viral oncogene homolog)-mutated colon cell lines, as revealed via flow cytometry analysis. A considerable decrease in mitogen-activated protein kinase pathway downstream effectors was observed in the treated cell lines via the western blot and STRING (Search tool for the retrieval of interacting genes/proteins) analysis. PMBA was further found to target KRAS at its guanosine diphosphate site. Treatment of the cell lines with PMBA showed significant reduction in MGMT promoter methylation but restored MGMT (O(6)-methylguanine-DNA methyltransferase) messenger ribonucleic acid expression via significant demethylation of the hypermethylated CpG (Cytosine phosphate guanine) sites in the MGMT promoter. A significant decrease in dimethylated H3K9 (Dimethylation of lysine 9 on histone 3) levels in the MGMT promoter in DNA hypo- and hypermethylated HCT-116(G13D) and SW-620(G12V) cells was observed after treatment. In the MNU (N-methyl-N-nitrosourea)-induced CRC in vivo model, PMBA instillation restricted and repressed polyp formation, suppressed tumor proliferation marker Ki67 (Marker of proliferation), ablated KRAS-associated cytokine signaling, and decreased mortality. Clinical trial data for the parent molecule revealed its effectiveness against the disease, oral bioavailability, and system tolerance. Comprehensively, PMBA represents a new class of KRAS inhibitors having a therapeutic window in the scope of a drug candidate. The findings suggest that the PMBA analogue could inhibit the growth of human CRC in vivo through downregulation of cancer-associated biomarkers as well as reactivate expression of the MGMT gene associated with increased H3K9 acetylation and H3K4 methylation with facilitated transcriptional activation, which might be important in silencing of genes associated with upregulation in the activity of KRAS.

Supplementary Figure 1. Molecular structure and cytotoxic profile of secalonic acid D (SAD). Colony morphology, Neighbor-joining rooted tree and sequencing of fungal endophyte (EF-VR2).

Supplementary Material 1. DETAILS OF ANTIBODIES USED IN THE STUDY

Supplementary Figure 2. Schematic presentation of mechanism of action of SAD.

Supplementary Material 2. DETAILS OF PRIMERS USED IN THE STUDY

A photoredox approach enabling one-step synthesis of oxazetidines with a free –NH group via the combined use of alkyne, thiophenol, and azide has been reported.

A visible light-mediated approach enabling the use of alcohols as nucleophiles in a one-step synthesis of α-alkoxy/hydroxy diarylacetaldehydes is reported.

A photoredox thioformylation of terminal alkynes using nitromethane as a formyl anion equivalent, thereby leading to the synthesis of (

Effectively controlling the accumulation of adipose tissue can be a therapeutic strategy for treating obesity, which is a global problem. The present study was designed for comparative assessment ofAntilipase as well as antiadipogenesis activity was displayed by both the DCME and the compounds. Maximum antilipase property was recorded in DCME (26.02 ± .041%) at 100 The present study highlights the antiobesity potential of

Visible light mediated functionalizations have significantly expanded the scope of alkynes by unraveling new mechanistic pathways and enabling their transformation to diverse structural entities. The photoredox reactions on alkynes rely on their innate capability to generate myriad carbon-centred radicals via single electron transfer (SET), thereby, allowing the introduction of new radical precursors. Moreover, an array of methods have been developed facilitating transformations such as vicinal or gem-difunctionalization, annulation, cycloaddition and oxidative reactions to construct numerous key building blocks of natural and pharmaceutically important molecules. In addition, the introduction of photoredox chemistry has successfully been used to deal with the challenges associated with alkyne functionalization such as stereoselective and regioselective control. This article accounts for several visible light mediated functionalization reactions of alkynes, wherein they have been transformed into α-oxo compounds, β-keto sulfoxides, substituted olefins, N-heterocycles, internal alkynes and sulfur containing compounds. The article has been primarily categorized into various sections based on the reaction type with particular attention being paid to mechanistic details, advancement and future applications.

Background: Acute promyelocytic leukemia (APL) and acute lymphoblastic leukaemia (ALL) are often presented with loss of H4K16 monoacetylation (ac) and H4K20 trimethylation (3Me) due to increased activity of Class I HDAC’s. In the current study we explored the efficacy and mechanistic basis of a novel Class I HDAC inhibitor SBAK-GHA across different leukemic cell lines and characterised the distinct acetylation pattern on histone H3 and H4.Methods: We initially performed general and class specific HDAC enzyme activity assays to establish the effect of our lead molecule SBAK-GHA. Following, we have probed various acetylation sites to understand a thorough acetylation profile of various leukemic cell lines by immunoblotting. Next, to understand the effect of various Class 1 HDAC isoforms on acetylation levels of hallmark proteins in leukaemia; lentiviral knockdown approach was carried out. In addition, cell cycle analysis was also done to distinguish the pattern of cell cycle phase arrest, followed by Chip-qPCR studies of various cyclins and their relationship with cell cycle arrest. Finally, an in vivo study was performed to confirm the anti-leukemic activity of SBAK-GHA by using specific leukaemia models.Results: SBAK-GHA showed class I HDAC inhibitor activity specifically targeting HDAC 2. SBAK-GHA treatment upregulates H4K16 ac and H4K20 me3 in variety of leukemic cell lines. Similar results were found during knock down of HDAC2 in leukemic cell lines. Moreover, we also observed a coherence of events like cell cycle arrest across different cell types of leukemias and modulation in the levels of acetylation across different cyclin promoters. Further on, studies in various in vivo cancer models demonstrated SBAK-GHA to be highly selective towards lymphocytic leukaemia.Conclusion: Our data provided a basic overview of relationship between different class I HDAC isoforms and their possible roles in regulation of histone acetylation in pathogenesis of leukaemia. Our study here presented multiple evidences regarding SBAK-GHA as a novel HDAC2 inhibitor. SBAK-GHA resist leukemogenesis mainly by inducing the repressed H4K16 ac and H4K20 me3. Further, the results in present study had established a relationship between class I HDAC isoforms and their possible roles in regulation of histone acetylation in pathogenesis of leukaemia.

A photoredox-mediated protocol for the synthesis of α-alkoxy-β-ketosulfoxides and α,β-dialkoxysulfoxides using alkynes, thiol, and alcohols is reported. This work presents a rare single-step synthesis of α-substituted sulfoxides, involving tandem introduction of a thiol and alcohol as a key enabling advancement. Furthermore, the method can be easily employed to access vinyl sulfoxides and β-ketosulfoxides.

This work studied the enantioselective resolution of 2-arylpropionic acid derivatives employing immobilization of lipase produced by Bacillus subtilis strain Kakrayal_1 (BSK-L). The efficient immobilization of lipase on modified silica gel was confirmed by Fourier transform infrared spectroscopy. Tethering of lipase facilitated the enhancement of physiochemical properties and stability of enzyme. Covalently immobilized enzyme retained 85% of residual activity even on reuse after 10th reaction cycle. Validation of immobilized lipase for enantioselective resolution of 2-arylpropionic acid derivatives led to 47.8% conversion efficiency with 87% enantiomeric excess (ee) for ketoprofen, and 27.3% conversion efficiency with 75% ee for flurbiprofen. The enantioselective resolution using immobilized lipase (BSK-L) was superior to free and commercially procured lipase, which suggest a potential application of immobilized lipase in the pharmaceutical/chemical industry.

Background Endophytes have proven to be an invaluable resource of chemically diverse secondary metabolites that act as excellent lead compounds for anticancer drug discovery. Here we report the promising cytotoxic effects of Cladosporol A (HPLC purified >98%) isolated from endophytic fungus Cladosporium cladosporioides collected from Datura innoxia. Cladosporol A was subjected to in vitro cytotoxicity assay against NCI60 panel of human cancer cells using MTT assay. We further investigated the molecular mechanism(s) of Cladosporol A induced cell death in human breast (MCF-7) cancer cells. Mechanistically early events of cell death were studied using DAPI, Annexin V-FITC staining assay. Furthermore, immunofluorescence studies were carried to see the involvement of intrinsic pathway leading to mitochondrial dysfunction, cytochrome c release, Bax/Bcl-2 regulation and flowcytometrically measured membrane potential loss of mitochondria in human breast (MCF-7) cancer cells after Cladosporol A treatment. The interplay between apoptosis and autophagy was studied by microtubule dynamics, expression of pro-apoptotic protein p21 and autophagic markers monodansylcadaverine staining and LC3b expression. Results Among NCI60 human cancer cell line panel Cladosporol A showed least IC50 value against human breast (MCF-7) cancer cells. The early events of apoptosis were characterized by phosphatidylserine exposure. It disrupts microtubule dynamics and also induces expression of pro-apoptotic protein p21. Moreover treatment of Cladosporol A significantly induced MMP loss, release of cytochrome c, Bcl-2 down regulation, Bax upregulation as well as increased monodansylcadaverine (MDC) staining and leads to LC3-I to LC3-II conversion. Conclusion Our experimental data suggests that Cladosporol A depolymerize microtubules, sensitize programmed cell death via ROS mediated autophagic flux leading to mitophagic cell death. Graphical abstract The proposed mechanism of Cladosporol A -triggered apoptotic as well as autophagic death of human breast cancer (MCF-7) cells. The figure shows that Cladosporol A induced apoptosis through ROS mediated mitochondrial pathway and increased p21 protein expression in MCF-7 cells in vitro.

l-Vasicine is a quinazoline alkaloid with an electron dense ring and additional functionalities in its structure. Employing target oriented synthesis (TOS) based on in silico studies, molecules with significant docking scores containing different derivatives of l-vasicine as caps were synthesized. Interestingly, one molecule, i.e., 4a, which contained 3-hyroxypyrrolidine as a cap group and a six carbon long aliphatic chain as a linker was found to inhibit HDACs. 4a showed more specificity toward class I HDAC isoforms. Also 4a was found to be less cytotoxic toward normal cell lines as compared to cancer cell lines. 4a inhibited cancer cell growth and induced cell death by various mechanisms. However, 4a was found to induce cell death independent of ROS generation, and unlike many natural product based HDAC inhibitors, 4a was found to be nontoxic under in vivo conditions. Importantly, we for the first time report the possibility of using a 3-hydroxypyrrolidine cap for the synthesis of HDAC inhibitors with good potency.

A first procedure on the synthesis of dibenzo-1,7-naphthyrdine carboxylate via photoredox catalysis has been developed. The reaction features an umpolung reaction of C-3 keto group and entrapment of decarbonylation prone C-2 of isatin. Additionally, the method showcases chemo-divergent behaviour of isatins in aprotic solvents leading to synthesis of tryptanthrin derivatives via photoredox catalysis. The reaction is easy to set up and scalable to gram levels.

A single-step synthesis of 4-hydroxy-functionalized bi-aryl and aryl/alkyl ketones via oxidative coupling of terminal alkynes with benzoquinones is reported. Furthermore, with naphthoquinones, owing to the cross-resonance of carbonyl with the aromatic ring, alkene-alkyne cycloaddition is more favored to give four-membered carbocyclic adducts, thereby precluding the requirement of preactivated alkynes.

A photoredox-mediated gem-difunctionalization of alkynes leading to the synthesis of α,α-aminothio-substituted carbonyl compounds is reported. The work presents concomitant introduction of α-C-N and C-S bonds as a key enabling advance. Furthermore, the low bond dissociation energy of the C-S bond compared to that of C-N or C-C bonds has been exploited for selective functionalization using different nucleophiles to build diverse α,α-disubstituted carbonyl scaffolds. Mild reaction conditions, broad substrate scope, and good yields are some of the added advantages of this reaction.

An endophytic fungus, Alternaria alternata was isolated from Grewia asiatica. Upscaling of the fermentation broth led to the isolation of a new structural isomer of alternariol (3), along with alternariol (1) and alternariol 9-methyl ether (2). Additionally, an LC-ESI-MS/MS method was developed for the simultaneous detection and quantification of 1–3 through multiple reaction monitoring (MRM). The limit of quantification (LOQ) and detection (LOD) were fewer than 5.0, 2.0, 0.3 and 1.5, 0.7, 0.1 μg/ml, respectively for 1–3. Furthermore, 1 and 3 showed significant activity against gram-positive bacteria, Staphylococcus aureus and 1 displayed MIC comparable to that of ciprofloxacin against VRE and MRSA.

A method for regio-selective phosphation and phopshonation at 9-position of fluorenones has been developed. The outcome of reaction can be controlled by varying temperature viz., at low temperature phosphonate is the exclusive product, whereas at high temperature phosphate is the favoured product. The reaction is easy to set up, involves mild conditions and proceeds efficiently over a broad range of substrates with excellent functional group tolerance.

A highly chemoselective visible light mediated strategy has been developed for oxidation of benzylic alcohols. The method circumvents the use of toxic metal catalysts, high energy light source, and operates at room temperature. Furthermore reaction is easily scalable to gram levels.

Objective & design Investigation was carried out on Saponin 1 (SAP-1), a novel molecule isolated from Parthenium hysterophorus , on proinflammatory (Th1) & anti-inflammatory (Th2) cytokines in blood of arthritic balb/c mice. Methods Adjuvant induced developing inflammatory arthritis was induced in mice which were treated with SAP-1 in graded oral doses. The molecular markers were determined using Flow Cytometry which uses sensitivity of amplified fluorescence detection to measure soluble analytes in particle based immune assay. The T-helper (Th1) deviated cells produce detectable level of Tumor necrosis factor (TNF-alpha), interleukin-2 (IL-2) & interferon-gamma (IFN-gamma), while the Th2 deviated cells produce significant amount of interleukin-4 (IL-4) and interleukin-5 (IL-5). Results SAP-1 at graded oral doses inhibited expression of IFN-gamma & TNF-alpha in serum & correspondingly increased expression of IL-4 significantly. SAP-1 also inhibited IL-17 and CD4 + CD25 + cell population showing to have suppressive effect on Th-17 pathway as well as T-regulatory cells. It also suppressed the increased levels of pro-inflammatory mediators like IL-1β and NO. Inhibitors of Cox-2 and MCP-1 provide effective improvements in signs and symptoms of Rheumatoid Arthritis. SAP-1 decreased the elevated concentration of both COX-2 and MCP-1 in arthritic animals. Conclusions SAP-1 diminishes Th1 immunity activation, a primary cause of arthritis, in favour of Th2 dominance, which reduces arthritic condition in mice displaying immune-modulatory potential.

A photoredox catalyzed approach enabling use of alkynes as surrogate of 2-oxoaldehydes/1,2-diones is reported. The method overcomes the difficulty associated with application of unsubstituted aliphatic α-oxoaldehydes, which has hitherto limited their general use. Indoles, tryptamine, and tryptophan methyl ester participated in the reaction to give a variety of α-oxo based analogues. Quantum yield investigations support a radical chain mechanism.

The carbon-carbon and carbon-heteroatom bond formation reactions are considered as a fundamental tool in synthetic organic chemistry. They have been effectively utilized in the synthesis of medicinally significant molecules, agrochemicals and valuable compounds in material sciences. This has been primarily enabled by highly efficient protocols arising from divergent mechanistic pathways. In this personal account, we aim to discuss some recent advances in carbon-carbon or carbon-heteroatom bond formation reactions to which our group has actively contributed. More specifically, this record focuses on the use of unsaturated carbon compounds for the construction of C-C and C-X bonds.

A highly efficient Cu–Mn-catalyzed process for the aminolysis of esters was developed. Also, the catalyst promoted the self- and cross-dehydrogenative coupling of anilines to generate symmetrical and unsymmetrical azobenzenes, respectively. The reactions were performed under neutral conditions with an inexpensive catalyst, gave high yields, and offered wide functional group tolerance.

A series of β-boswellic acid derivatives were synthesized and evaluated for anticancer activity. One of the lead analog 4f displayed significant anticancer activity against a panel of cancer cells as well as substantially inhibited colony formation in HCT-116 cells. Furthermore, 4f was found to be a potent inducer of apoptosis confirmed by loss of mitochondrial membrane potential, DAPI staining, Western blotting and ROS generation.

A library of boswellic acid analogues were synthesized and tested for their anti-inflammatory potential on key inflammatory mediators, TNF-α and IL-6. The study led to the identification of lead compounds showing significant inhibition of the cytokines, TNF-α and IL-6 both in vitro and in vivo.

A metal-free oxidative coupling of styrenes and benzyl alcohols with arenes has been developed for the synthesis of biaryls. The reaction features a conspicuous benzylic C-C bond cleavage of styrenes and benzyl alcohols. The reaction with both substrates proceeds through a common aldehydic intermediate formed through oxidative C-C bond cleavage of alkene and oxidation of benzyl alcohols. The reaction proceeds efficiently over a broad range of substrates with excellent functional group tolerance.

Deregulation of PI3K signalling pathway is strongly involved in pathology of cancer and development of resistance in tumour cells. Here, we report that pharmacologically active vasicinone analogue, RLX (7, 8, 9, 10-Tetrahydroazepino [2, 1-b] quinazolin-12-(6H)-on), exhibited potent anticancer activities both in vitro and in vivo. In this study, RLX treatment displayed strong inhibition of proliferation against various cancer cell lines. However, colon cancer cells were found to be the most sensitive towards RLX mediated inhibition of proliferation. The result showed that RLX treatment followed strong concentration dependent inhibition of HCT-116 cell proliferation and colony formation. RLX treatment to HCT-116 was observed to be associated with down-regulation of p110α and p85 subunits of PI3K thereby decreasing the expression of subsequent downstream effector proteins. Interestingly, silencing of PI3K gene by siRNA in combination with RLX confirmed the anti-proliferation effect of RLX against HCT-116 cells and is mediated by the PI3K pathway. We also found that RLX induced sub-G1 arrest and mitochondrial potential loss followed by pFoxO3a(Thr32) nuclear-cytoplasmic translocation inhibition. Moreover, RLX treatment in in vivo models substantially resulted in a tumour growth inhibition. Overall, our findings reveal the functional role of the PI3K/Akt/FoxO3a pathway that gets deregulated in cancer and suggests its simultaneous targeting by RLX thereby further identifying the compound as a potent inhibitor of the PI3K/Akt/FoxO3a pathway under in vitro and tumour regression in vivo.

A simple and practical method for synthesizing α-ketoamides has been developed involving Cu(OTf)2-promoted oxidative amidation-diketonization of terminal alkynes with primary/secondary amines. This method has a wide substrate scope, and atmospheric oxygen acts as the oxidant.

A novel metal-free strategy for oxidative amidation of terminal alkenes by using I2/DMSO for the synthesis of α-ketoamides has been developed. Intriguingly, the use of tert-butylhydroperoxide (TBHP) as co-oxidant can facilitate the synthesis of α-ketoamides at room temperature without any solvent, thereby making it a green protocol. The reaction with primary amines can be easily achieved by using SeO2 as an oxidizing agent. Besides, the scope of the method was also extended to the synthesis of benzothiazolines and quinazolines.

New pharmacophore organoselenium compound (1) was designed, synthesized and characterized by various spectroscopic methods (IR, ESI–MS, 1H, 13C and 77Se NMR) and further confirmed by X–ray crystallography. Compound 1 consists of two 3,5–bis(trifluoromethyl)phenyl units which are connected to the selenium atom via the organometallic C–Se bond. In vitro DNA binding studies of 1 was investigated by absorption and emission titration methods which revealed that 1 recognizes the minor groove of DNA in accordance with molecular docking studies with the DNA duplex. Gel electrophoretic assay demonstrates the ability of 1 to cleave pBR322 DNA through hydrolytic process which was further validated by T4 religation assay. To understand the drug–protein interaction of which ultimate molecular target was DNA, the affinity of 1 towards HSA was also investigated by the spectroscopic and molecular modeling techniques which showed hydrophobic interaction in the subdomain IIA of HSA. Furthermore, the intracellular localization of 1 was evidenced by cell imaging studies using HeLa cells.

The role of acetaldehyde as a nucleophile in various asymmetric C–C bond forming transformations is presented, with consideration given not only to the optimization of reaction parameters relevant to product formation, polymerization, by-products, purification, chirality and instability of the final products, but also to the application of the final products in the synthesis of bioactive molecules. This review is organized according to the use of acetaldehyde in different organocatalytic reactions covering the most recent reports. In the last section indirect sources of acetaldehyde are discussed from the perspective of difficult handling and its requirement of slow addition as well as being freshly distilled in some of the transformations, which is one of the most critical issues in the late exploitation of acetaldehyde as a nucleophile in synthetic chemistry.

A common protocol for the synthesis of amides, esters and α-ketoesters via cross dehydrogenative coupling of aldehydes and amines/alcohols has been developed. The method is applicable to a wide variety of alcohols and amines as well as aliphatic and aromatic aldehydes. Also, the use of acetaldehyde for acetylation and ethyl glyoxalate to access 2-oxo-amino esters is presented for the first time.

An efficient metal free self-sorting tandem protocol for stereospecific synthesis of 2-thio-1,4-enediones involving C-C double bond formation via direct coupling of terminal alkynes has been developed. The method was also extended to the first synthesis of β-thio-γ-keto-α,β-unsaturated esters via a cross coupling reaction with ethyl glyoxylate. The reaction relies on a first of its kind use of Bronsted and Lewis acids to switch selectivity for the synthesis of an E or a Z-isomer respectively.

A new metal free self-sorting tandem reaction between styrenes and anilines to access 2,4-disubstituted quinolines has been developed. The reaction relies on simultaneous C–C and C–N bond formation along with a C–C bond cleavage, under metal free conditions. The reaction proceeds efficiently over a broad range of substrates with excellent functional group tolerance. The utility of the method was also demonstrated in a first synthesis of bis-indoles from styrenes.

Natural product derivatives have proven to be cutting edge window for drug discovery and development. BA-25 (3-α-o-acetoxy-4β-amino-11-oxo-24-norurs-12-ene) an amino analogue of β-boswellic acid exhibited inhibition of TNF-α and IL-6 in THP-1 cells as demonstrated previously, however, the effect on principal inflammatory mediators such as cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and the pathways that mediate this function remains unknown. This study was designed to examine the comparative anti-inflammatory activity of BA-25 with its parent compound, β boswellic acid both in vitro and in vivo. The effect of BA and BA-25 on suppression of NO, PGE2, LTB4, COX-2 in LPS-stimulated RAW 264.7 cells was determined by ELISA, RT-PCR and ROS by flow cytometry. Phosphorylation of NF-kBp65, IKB degradation was determined by western blotting and also the nuclear localization of NF-kBp65 was assessed by immunofluorescence. Furthermore, this study was extended on Carrageenan induced paw oedema modelled BALB/c mice. A novel derivative BA-25, reported first time notably decreased the LPS (1 μg/mL) induced upregulation in the transcription of TNF-α, IL-6, iNOS and COX-2. Also the protein expression of iNOS and COX-2 as well as their downstream products NO and PGE2 respectively, were also decreased efficiently at a concentration of 10 μM than BA. Moreover, LPS upregulated NF-kB p65 expression and IκB degradation was significantly decreased after BA-25 treatment. In addition, the treatment of BA-25 also restored the paw oedema and decreased the magnitude of histopathological alterations. Our data together suggested that BA-25 might be regarded as prospective therapeutic anti-inflammatory alternative and demands further investigation in pharmacological studies.