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An efficient synthesis of aryl enopyranones via an oxidative Heck-type coupling reaction between ether protected D/L-glycals and different aryl halides is developed. This one-step method attaches an aryl group at the C-1 position keeping the C-1/C-2 double bond intact via the Saegusa-Ito type oxidation, thus facilitating the synthesis of medicinally important 2-deoxy-ß-aryl-C-glycosides after Pd/C reduction.
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An efficient regioselective method to attach thiocyanato groups at the ß-position of enol double bonds in sugar enol ethers using KSCN and potassium persulfate has been developed. The highly regioselective addition of the resulting sugar thiocyanate to electron rich species like terminal alkynes and benzynes under Pd catalysis generated C-2-thio acrylo/aryl nitrile glycals via simultaneous introduction of thio and cyano groups into carbon-carbon triple bonds.
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In this study, we synthesized a new-generation library of colchicine derivatives via cycloaddition of colchicine utilizing position C-8 and C-12 diene system regioselectivity with aryne precursor to generate a small, focused library of derivatives. We assessed their anticancer activity against various cancer cell lines like MCF-7, MDA-MB-231, MDA-MB-453, and PC-3. Normal human embryonic kidney cell line HEK-293 was used to determine the toxicity. Among these derivatives, silicon-tethered compound B-4a demonstrated the highest potency against breast cancer cells. Subsequent mechanistic studies revealed that B-4a effectively modulates cell cycle regulatory kinases (CDK-2 and CDK-4) and their associated cyclins (cyclin-B1, cyclin-D1), inducing apoptosis. Additionally, B-4a displayed a noteworthy impact on tubulin polymerization, compared to positive control flavopiridol hydrochloride in a dose-dependent manner, and significantly disrupted the vimentin cytoskeleton, contributing to G1 arrest in breast cancer cells. Moreover, B-4a exhibited substantial anti-metastatic properties by inhibiting breast cancer cell migration and invasion. These effects are attributed to the down-regulation of major epithelial to mesenchymal transition (EMT) factors, including vimentin and Twist-1, and the upregulation of the epithelial marker E-cadherin in an apoptosis-dependent manner.
Assuntos
Antineoplásicos , Neoplasias da Mama , Proliferação de Células , Colchicina , Quinase 2 Dependente de Ciclina , Quinase 4 Dependente de Ciclina , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Transição Epitelial-Mesenquimal , Humanos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Quinase 2 Dependente de Ciclina/metabolismo , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Relação Estrutura-Atividade , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Colchicina/farmacologia , Colchicina/química , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/metabolismo , Descoberta de Drogas , Feminino , Apoptose/efeitos dos fármacos , Reação de Cicloadição , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacosRESUMO
EIDD-1931 is the active form of molnupiravir, an orally effective drug approved by the United States Food and Drug Administration (USFDA) against COVID-19. Pharmacokinetic alteration can cause untoward drug interaction (drug-drug/disease-drug), but hardly any information is known about this recently approved drug. Therefore, we first investigated the impact of the arthritis state on the oral pharmacokinetics of EIDD-1931 using a widely accepted complete Freund's adjuvant (CFA)-induced rat model of rheumatoid arthritis (RA) after ascertaining the disease occurrence by paw swelling measurement and X-ray examination. Comparative oral pharmacokinetic assessment of EIDD-1931 (normal state vs arthritis state) showed that overall plasma exposure was augmented (1.7-fold) with reduced clearance (0.54-fold), suggesting its likelihood of dose adjustment in arthritis conditions. In order to elucidate the effect of EIDD-1931 treatment at a therapeutic regime (normal state vs arthritis state) on USFDA-recommended panel of cytochrome P450 (CYP) enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) for drug interaction using the same disease model, we monitored protein and mRNA expressions (rat homologs) in liver tissue by western blotting (WB) and real time-polymerase chain reaction (RT-PCR), respectively. Results reveal that EIDD-1931 treatment could strongly influence CYP3A4 and CYP2C8 among experimental proteins/mRNAs. Although CYP2C8 regulation upon EIDD-1931 treatment resembles similar behavior under the arthritis state, results dictate a potentially reverse phenomenon for CYP3A4. Moreover, the lack of any CYP inhibitory effect by EIDD-1931 in human/rat liver microsomes (HLM/RLM) helps to ascertain EIDD-1931 treatment-mediated disease-drug interaction and the possibility of drug-drug interaction with disease-modifying antirheumatic drugs (DMARDs) upon coadministration. As elevated proinflammatory cytokine levels are prevalent in RA and nuclear factor-kappa B (NF-kB) and nuclear receptors control CYP expressions, further studies should focus on understanding the regulation of affected CYPs to subside unexpected drug interaction.
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Coronaviruses are a group of enveloped viruses with non-segmented, single-stranded, and positive-sense RNA genomes. It belongs to the 'Coronaviridae family', responsible for various diseases, including the common cold, SARS, and MERS. The COVID-19 pandemic, which began in March 2020, has affected 209 countries, infected over a million people, and claimed over 50,000 lives. Significant efforts have been made by repurposing several approved drugs including antiviral, to combat the COVID-19 pandemic. Molnupiravir is found to be the first orally acting efficacious drug to treat COVID-19 cases. It was approved for medical use in the UK in November 2021 and other countries, including USFDA, which granted approval an emergency use authorization (EUA) for treating adults with mild to moderate COVID-19 patients. Considering the importance of molnupiravir, the present review deals with its various synthetic strategies, pharmacokinetics, bio-efficacy, toxicity, and safety profiles. The comprehensive information along with critical analysis will be very handy for a wide range of audience including medicinal chemists in the arena of antiviral drug discovery especially anti-viral drugs against any variant of COVID-19.
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Antivirais , Tratamento Farmacológico da COVID-19 , COVID-19 , Citidina , Hidroxilaminas , SARS-CoV-2 , Humanos , Antivirais/farmacologia , Antivirais/química , Antivirais/uso terapêutico , Antivirais/síntese química , Hidroxilaminas/uso terapêutico , Hidroxilaminas/química , Hidroxilaminas/farmacologia , COVID-19/virologia , SARS-CoV-2/efeitos dos fármacos , Citidina/análogos & derivados , Citidina/uso terapêutico , Citidina/farmacologia , Citidina/química , Citidina/síntese química , Uridina/farmacologia , Uridina/análogos & derivados , Uridina/síntese química , Uridina/química , Uridina/uso terapêutico , Pandemias , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológicoRESUMO
In an endeavour to improve the anti-cancer activity of betulinic acid (BA), a series of C-30 derivatives were envisaged and synthesized with a novel synthetic approach. All the derivatives were evaluated for cytotoxic activity by MTT assay against six different human cancer cell lines: prostate (PC3), lung (A549), human hepatocellular carcinoma (HepG2), human leukemia (Molt-4), pancreatic (Panc-1) and breast (MCF-7). The data revealed that compound 16 was observed most promising cytotoxic agent with IC50 values of 7.43 µM, 9.1 µM, and 9.64 µM against A549, MCF-7, and PC3 cancer cell lines respectively. A further mechanistic study confirmed compound 16 showed significant cell death by arresting the cell cycle in the G1 phase and inducing apoptosis in A549 cells.Communicated by Ramaswamy H. Sarma.
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Leishmaniasis, one of the neglected diseases, ranks second to malaria in the cause of parasitic mortality and morbidity. The present chemotherapeutic regimen faces the limitations of drug resistance and toxicity concerns, raising a great need to develop new chemotherapeutic leads that are orally administrable, potent, non-toxic, and cost-effective. Several research groups came forward to fill this therapeutic gap with new classes of active compounds against leishmaniasis, one such being 3,3'-diindolylmethane (DIM) derivatives. We tried to link this concept with another promising approach of glycoconjugation to study how glycosylated groups work differently from non-glycosylated ones. In the present study, a series of 3,3'-DIM derivatives have been synthesized and screened for their anti-leishmanial potency on Leishmania donovani promastigotes. Next, we synthesized the ß-N,N' glycoside of potent compound 3d using indole-indoline conversion, Fischer-type glycosylation, 2,3-dichloro-5,6-dicyano-1,4-benzoquionone (DDQ) oxidation, and molecular iodine catalyzed coupling with a suitable aldehyde in reasonable overall yield. The biological evaluation revealed that glycosides had reduced cytotoxic effects on the J774A.1 macrophage cell line. The enzyme inhibition study confirms that the glycoside derivatives have significant inhibitory activity against the leishmanial topoisomerase IB enzyme. Molecular docking further displayed the better binding efficiency of glycoside 13 with the target enzyme, suggesting the involvement of more H-bond interactions in the case of glycosides as compared to free drugs. Therefore, this work helps in proposing the fact that the addition of sugar moieties adds some favorable characteristics to free inhibitors, making it a promising approach for future clinical diagnostic and therapeutic applications, which can prove to be a valuable arsenal in combating such neglected diseases.
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We have developed a synthesis of 1-3 and 1-1 disaccharides from 2-benzoyl glycal and anomeric thiol and/or hydroxy sugar acceptors under mild conditions at room temperature. The regio and stereo-selectivity of the newly formed inter-glycosidic linkages are dependent on the nature of the glycal donor (D or L) and anomeric acceptor.
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The pharmacokinetic alteration of an antimicrobial medication leading to sub-therapeutic plasma level can aid in the emergence of resistance, a global threat nowadays. In this context, molnupiravir (prodrug of EIDD-1931) is the most efficacious orally against corona virus disease (COVID-19). In addition to drug-drug interaction, the pharmacokinetics of a drug can significantly vary during any disease state, leading to disease-drug interaction. However, no information is available for such a recently approved drug. Therefore, we aimed to explore the oral pharmacokinetics of EIDD-1931 in seven chemically induced disease states individually compared to the normal state using various rat models. Induction of any disease situation was confirmed by the disease specific study(s) prior to pharmacokinetic investigations. Compared to the normal state, substantially lowered plasma exposure (0.47- and 0.63-fold) with notably enhanced clearance (2.00- and 1.56-fold) of EIDD-1931 was observed in rats of ethanol-induced gastric injury and carbon tetrachloride-induced liver injury states. Conversely, paclitaxel-induced neuropathic pain and cisplatin-induced kidney injury states exhibited opposite outcomes on oral exposure (1.43- and 1.50-fold) and clearance (0.69- and 0.65-fold) of EIDD-1931. Although the highest plasma concentration (2.26-fold) markedly augmented in the doxorubicin-induced cardiac injury state, streptozocin-induced diabetes and lipopolysaccharide-induced lung injury state did not substantially influence the pharmacokinetics of EIDD-1931. Exploring the possible phenomenon behind the reduced or boosted plasma exposure of EIDD-1931, results suggest the need for dose adjustment in respective diseased conditions in order to achieve desired efficacy during oral therapy of EIDD-1931.
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COVID-19 , Ratos , Animais , Citidina , HidroxilaminasRESUMO
A facile synthesis of C1-C2 interlinked disaccharides is achieved from readily available iodo-glycals and unsubstituted glycals. Ester-protected donors reacted with ether-protected acceptors under Pd-Ag catalysis to access C-disaccharides bearing C-3 vinyl ether, which upon ring opening by Lewis acid furnished pi-extended conjugated orthogonally protected chiral ketones. Benzyl deprotection and reduction of the double bonds resulted in a fully saturated disaccharide stable toward acid hydrolysis.
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A simple method for the iodination of unsaturated sugars to form sugar vinyl iodides was developed under oxidant-free conditions using NaH/DMF/iodine as a reagent system at ambient temperature. 2-Iodoglycals bearing ester, ether, silicon, and acetonide protection were synthesized in good to excellent yield. 3-Vinyl iodides derived from 1,2:5,6-diacetonide glucofuranose were transformed to C-3 enofuranose and bicyclic 3,4-pyran-fused furanose via Pd-catalyzed C-3 carbonylation and intramolecular Heck reaction, respectively, as the key step.
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Iodetos , Iodo , Carboidratos , ÉsteresRESUMO
A reaction of glycals with two different types of nucleophiles in the presence of SnCl4 enabled one-pot rapid access to 2-deoxy-3-thio pyranoses and their O-glycosides. The process involves thioaryl substitution at C-3 with stereoretention and α-selective O-glycosylation at C-1 from d-glycals, thus combining two reactions with three interventions. The present methodology features an attractive three-component coupling (1:1.2:1.5 ratio) with operational simplicity at 0 °C in 10-20 min. This stereoselective one-pot 1,3-difunctionalization approach of glycals is compatible with wide range of primary and secondary alcohols affording products in good to excellent yields. This methodology was successfully extended toward disaccharide synthesis. Several control experiments suggested a plausible reaction mechanism and rationale behind regio and stereoselectivity. The reaction strategy possesses an intrinsic ability for the synthesis of various natural products and drug molecules.
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COVID-19 pandemic caused by the SARS-CoV-2 virus has led to a worldwide crisis. In view of emerging variants time to time, there is a pressing need of effective COVID-19 therapeutics. Setomimycin, a rare tetrahydroanthracene antibiotic, remained unexplored for its therapeutic uses. Herein, we report our investigations on the potential of setomimycin as COVID-19 therapeutic. Pure setomimycin was isolated from Streptomyces sp. strain RA-WS2 from NW Himalayan region followed by establishing in silico as well as in vitro anti-SARS-CoV-2 property of the compound against SARS-CoV-2 main protease (Mpro). It was found that the compound targets Mpro enzyme with an IC50 value of 12.02 ± 0.046 µM. The molecular docking study revealed that the compound targets Glu166 residue of Mpro enzyme, hence preventing dimerization of SARS-CoV-2 Mpro monomer. Additionally, the compound also exhibited anti-inflammatory and anti-oxidant property, suggesting that setomimycin may be a viable option for application against COVID-19 infections.
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COVID-19 , Humanos , SARS-CoV-2 , Simulação de Acoplamento Molecular , Pandemias , Inibidores de Proteases , Antivirais/farmacologia , Simulação de Dinâmica MolecularRESUMO
The present study focused on the forced degradation behavior of sertraline hydrochloride (SRT), selective serotonin reuptake inhibitor (SSRI). The drug was exposed to different stressed conditions (hydrolytic, oxidative, thermal and photolytic) according to ICH Q1A (R2) guidelines. The study revealed that SRT was stable in hydrolytic (acidic, basic and neutral) and thermal degradation conditions. In contrast, five degradation products (DPs) were formed under oxidative and photolytic degradation conditions. The chromatographic separation of drug substance and its DPs was achieved on an Acquity HSS T3 column (100 × 2.1 mm, 1.7 µ) using 0.1% formic acid and acetonitrile as the mobile phase in gradient mode using a UHPLC-DAD system. The DPs were identified and characterized by high-resolution LC/MS and LC/MS/MS in ESI positive mode. Two DPs (DP-I and DP-II) were formed when SRT was exposed to oxidative degradation conditions. Three DPs formed (DP III-V) when exposed to photolytic degradation conditions. All the five major DPs were isolated using Preparative HPLC. The structures of major DPs formed were further confirmed using NMR technique (1D and 2D). The proposed mechanism for the formation of the SRT DPs via the photolytic/oxidative stress degradation pathway are discussed and outlined.
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Sertralina , Espectrometria de Massas em Tandem , Acetonitrilas/química , Cromatografia Líquida de Alta Pressão/métodos , Estabilidade de Medicamentos , Hidrólise , Oxirredução , Fotólise , Inibidores Seletivos de Recaptação de Serotonina , Espectrometria de Massas em Tandem/métodosRESUMO
Biosynthesis of bisaryl preanthraquinone antibiotics by various microorganisms differs in monomeric subunits as well as their dimerization positions leading to different configurations. The present study relates to the production of rare bisaryl anthraquinone antibiotics by a new Streptomyces strain isolated from Shivalik region of NW Himalayas. In vitro anticancer and anti-migratory effects of Setomimycin (9,9' bisanthraquinone antibiotic) was seen with a significant reduction in the expression of both MEK as well as ERK pathways in a dose dependent manner at 6.5 µM & 8 µM concentration in HCT-116 and 5.5 µM & 7 µM concentration in MCF-7 cells. In vivo studies in aggressive orthotopic mouse mammary carcinoma model (4T1) demonstrated about 76% reduction of primary tumor weight and 90.5% reduction in the tumor volume within two weeks. In vivo pharmacokinetics study of setomimycin revealed that it can be rapidly absorbed with an adequate plasma exposure and half-life which can be linked to its in vivo efficacy.
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Streptomyces , Animais , Antraquinonas/metabolismo , Antraquinonas/farmacologia , Antibacterianos , Humanos , Células MCF-7 , Camundongos , Streptomyces/metabolismoRESUMO
A Ni-catalyzed direct access to various pyrano cis-fused dihydro benzofurans and indoles from unsaturated enopyranoses and o-iodo phenols/anilines is developed. The domino synthesis of pyrano C2-C1 and C3-C2 cis-fused heteroarynes were achieved both from glycals and pseudo glycals in which heteroatoms are linked at C2 and C3 positions, respectively, with excellent chemo-selectivity.
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Benzofuranos , Iodo , Compostos de Anilina , Catálise , Indóis , Estrutura Molecular , FenóisRESUMO
[This corrects the article DOI: 10.1039/D1RA06912H.].
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Correction for 'Diastereoselective synthesis of glycopyrans 1,2-annulated with dioxazinanes from 1,2-anhydrosugars and N-substituted nitrones' by Ajaz Ahmed et al., Org. Biomol. Chem., 2022, 20, 1436-1443, DOI: 10.1039/d1ob02310a.
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Transformation of glycals to 2,3-di-substituted-3-dexoy-glycals were achieved by sequential C2 alkenylation of pseudoglycals followed by capture of nucleophiles at C3 position. Anomeric linked N-(glycosyloxy) acetamides group assisted innate C2-H activation of pseudoglycals under palladium catalysis is achieved. The synthesized C2 alkenylated products were further attacked by thio/amino nucleophiles at C3 position under basic conditions in stereo-selective fashion to generate 2,3-branched glycals with the elimination of directing groups and translocation of double bond. Different control experiments were conducted to establish the role of directing groups in C-H functionalization of pseudoglycals and reason for selectivity.