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Current Organic Synthesis 2024Compounds containing triazole have many significant applications in the dye and ink industry, corrosion inhibitors, polymers, and pharmaceutical industries. These... (Review)
Review
Compounds containing triazole have many significant applications in the dye and ink industry, corrosion inhibitors, polymers, and pharmaceutical industries. These compounds possess many antimicrobial, antioxidant, anticancer, antiviral, anti-HIV, antitubercular, and anticancer activities. Several synthetic methods have been reported for reducing time, minimizing synthetic steps, and utilizing less hazardous and toxic solvents and reagents to improve the yield of triazoles and their analogues synthesis. Among the improvement in methods, green approaches towards triazole forming biologically active compounds, especially anticancer compounds, would be very important for pharmaceutical industries as well as global research community. In this article, we have reviewed the last five years of green chemistry approaches on click reaction between alkyl azide and alkynes to install 1,2,3-triazole moiety in natural products and synthetic drug-like molecules, such as in colchicine, flavanone cardanol, bisphosphonates, thiabendazoles, piperazine, prostanoid, flavonoid, quinoxalines, C-azanucleoside, dibenzylamine, and aryl-azotriazole. The cytotoxicity of triazole hybrid analogues was evaluated against a panel of cancer cell lines, including multidrug-resistant cell lines.
Topics: Triazoles; Antineoplastic Agents; Humans; Green Chemistry Technology; Click Chemistry; Alkynes; Azides; Cell Line, Tumor
PubMed: 37157212
DOI: 10.2174/1570179420666230508125144 -
Cancer Science Mar 2024Pancreatic cancer (PC) is a highly aggressive and deadly malignancy with limited treatment options and poor prognosis. Identifying new therapeutic targets and developing...
Pancreatic cancer (PC) is a highly aggressive and deadly malignancy with limited treatment options and poor prognosis. Identifying new therapeutic targets and developing effective strategies for PC treatment is of utmost importance. Here, we revealed that SHCBP1 is significantly overexpressed in PC and negatively correlated with patient prognosis. Knockout of SHCBP1 inhibits the proliferation and migration of PC cells in vitro, and suppresses the tumor growth in vivo. In addition, we identified AZD5582 as a novel inhibitor of SHCBP1, which efficiently restrains the growth of PC in cell lines, organoids, and patient-derived xenografts. Mechanistically, we found that AZD5582 induced the apoptosis of PC cells by inhibiting the activity of PI3K/AKT signaling and preventing the degradation of TP53. Collectively, our study highlights SHCBP1 as a potential therapeutic target and its inhibitor AZD5582 as a viable agent for PC treatment strategies.
Topics: Humans; Phosphatidylinositol 3-Kinases; Prognosis; Signal Transduction; Pancreatic Neoplasms; Cell Line, Tumor; Cell Proliferation; Shc Signaling Adaptor Proteins; Alkynes; Oligopeptides
PubMed: 38151993
DOI: 10.1111/cas.16059 -
Phytomedicine : International Journal... Dec 2023Accumulating evidence suggested increasing energy expenditure is a feasible strategy for combating obesity, and browning of white adipose tissue (WAT) to promote...
BACKGROUND
Accumulating evidence suggested increasing energy expenditure is a feasible strategy for combating obesity, and browning of white adipose tissue (WAT) to promote thermogenesis might be one of the attractive ways. Hydroxy-α-sanshool (HAS), a natural amide alkaloid extracted from the fruits of Zanthoxylum bungeanum Maxim, possesses lots of benefits in lipid metabolism regulation.
METHODS
The anti-obesity effect of HAS was investigated by establishing an animal model of obesity and a 3T3-L1 differentiation cell model. Effects of HAS on the whole-body fat and liver of obese mice, and the role of HAS in inducing browning of white fat were studied by Micro CT, Metabolic cage detection, Cell mitochondrial pressure detection, transmission electron microscopy and cold exposure assays. Furthermore, the Real-time PCR (qPCR), digital PCR (dPCR), western blot, Co-immunoprecipitation (Co-IP), molecular docking, drug affinity responsive target stability (DARTS), Cellular thermal shift assay (CETSA) and other methods were used to investigate the target and mechanisms of HAS.
RESULTS
We found that treatment with HAS helped mice combat obesity caused by a high fat diet (HFD) and improve metabolic characteristics. In addition, our results suggested that the anti-obesity effect of HAS is related to increase energy consumption and thermogenesis via induction of browning of WAT. The further investigations uncovered that HAS can up-regulate UCP-1 expression, increase mitochondria number, and elevate the cellular oxygen consumption rates (OCRs) of white adipocytes. Importantly, the results indicated that browning effects of HAS is closely associated with SIRT1-dependent PPAR-γ deacetylation through activating the TRPV1/AMPK pathway, and TRPV1 is the potential drug target of HAS for the browning effects of WAT.
CONCLUSIONS
Our results suggested the HAS can promote browning of WAT via regulating AMPK/SIRT-1/PPARγ signaling, and the potential drug target of HAS is the membrane receptor of TRPV1.
Topics: Mice; Animals; PPAR gamma; Zanthoxylum; Fruit; Molecular Docking Simulation; AMP-Activated Protein Kinases; Adipose Tissue, White; Obesity; Polyunsaturated Alkamides; Diet, High-Fat; 3T3-L1 Cells; TRPV Cation Channels
PubMed: 37748388
DOI: 10.1016/j.phymed.2023.155113 -
Nature Chemical Biology Feb 2024The anthraquinone-fused enediynes (AFEs) combine an anthraquinone moiety and a ten-membered enediyne core capable of generating a cytotoxic diradical species. AFE...
The anthraquinone-fused enediynes (AFEs) combine an anthraquinone moiety and a ten-membered enediyne core capable of generating a cytotoxic diradical species. AFE cyclization is triggered by opening the F-ring epoxide, which is also the site of the most structural diversity. Previous studies of tiancimycin A, a heavily modified AFE, have revealed a cryptic aldehyde blocking installation of the epoxide, and no unassigned oxidases could be predicted within the tnm biosynthetic gene cluster. Here we identify two consecutively acting cofactorless oxygenases derived from methyltransferase and α/β-hydrolase protein folds, TnmJ and TnmK2, respectively, that are responsible for F-ring tailoring in tiancimycin biosynthesis by comparative genomics. Further biochemical and structural characterizations reveal that the electron-rich AFE anthraquinone moiety assists in catalyzing deformylation, epoxidation and oxidative ring cleavage without exogenous cofactors. These enzymes therefore fill important knowledge gaps for the biosynthesis of this class of molecules and the underappreciated family of cofactorless oxygenases.
Topics: Oxygenases; Antineoplastic Agents; Anthraquinones; Enediynes; Epoxy Compounds
PubMed: 37945897
DOI: 10.1038/s41589-023-01476-2 -
International Journal of Pharmaceutics Apr 2024Calicheamicin is a potent, cell-cycle independent enediyne antibiotic that binds and cleaves DNA. Toxicity has led to its use in a targeted form, as an antibody-drug...
Calicheamicin is a potent, cell-cycle independent enediyne antibiotic that binds and cleaves DNA. Toxicity has led to its use in a targeted form, as an antibody-drug conjugate approved for the treatment of liquid tumors. We used a reduced calicheamicin to conjugate it to a single cysteine residue at the membrane-inserting end of a pH Low Insertion Peptide (pHLIP) that targets imaging and therapeutic agents to tumors. The cytoplasmic reduction of the disulfide releases the calicheamicin, and activation, DNA binding, and strand scission ensue. We studied the interaction of pHLIP-calicheamicin with liposomal and cellular membranes and demonstrated that the agent exhibits cytotoxic activity both in highly proliferative cancer cells and in non-proliferative immune cells, such as polarized M2 macrophages. In vivo, the agent was effective in inhibiting tumor growth in mice with no signs of toxicity. Biodistribution studies confirmed tumor targeting with no accumulation of the agent in organs and tissues. The agent was found within the tumor mass and tumor-stroma interface. Treatment of tumors led to the depletion of CD206 M2- tumor-associated macrophages within the tumor core. pHLIP-calicheamicin could be pursued as an effective therapeutic for the treatment of solid tumors.
Topics: Animals; Mice; Calicheamicins; Tissue Distribution; Antineoplastic Agents; Neoplasms; DNA; Hydrogen-Ion Concentration
PubMed: 38428548
DOI: 10.1016/j.ijpharm.2024.123954 -
The Lancet. HIV Feb 2024In two phase 3 trials for first-line therapy in adults with HIV-1, doravirine showed non-inferior efficacy, a favourable safety profile, and a superior lipid profile to... (Randomized Controlled Trial)
Randomized Controlled Trial
Safety and efficacy of doravirine as first-line therapy in adults with HIV-1: week 192 results from the open-label extensions of the DRIVE-FORWARD and DRIVE-AHEAD phase 3 trials.
BACKGROUND
In two phase 3 trials for first-line therapy in adults with HIV-1, doravirine showed non-inferior efficacy, a favourable safety profile, and a superior lipid profile to darunavir and efavirenz through to 48 and 96 weeks. Here we report 192-week results from both studies.
METHODS
DRIVE-FORWARD and DRIVE-AHEAD are multicentre, double-blind, randomised, active comparator-controlled, phase 3 trials of first-line antiretroviral treatment in adults with HIV-1. Eligible participants (aged ≥18 years) were naive to antiretroviral therapy, had plasma HIV-1 RNA 1000 copies per mL or more at screening, had no known resistance to any of the trial drugs, and had creatinine clearance 50 mL per min or more. DRIVE-FORWARD was conducted at 125 sites in 15 countries and compared doravirine (100 mg) with ritonavir-boosted darunavir (ritonavir [100 mg] and darunavir [800 mg]), each administered orally once daily with two nucleoside or nucleotide reverse transcriptase inhibitors (tenofovir disoproxil fumarate [300 mg] and emtricitabine [200 mg] or abacavir sulfate [600 mg] and lamivudine [300 mg]). DRIVE-AHEAD was conducted at 126 sites in 23 countries and compared doravirine (100 mg), lamivudine (300 mg), and tenofovir disoproxil fumarate (300 mg) with that of efavirenz (600 mg), emtricitabine (200 mg), and tenofovir disoproxil fumarate (300 mg), all administered orally once daily. DRIVE-FORWARD enrolment was between Dec 1, 2014, and June 1, 2020, and DRIVE-AHEAD enrolment was between June 10, 2015, and Aug 10, 2020. After the 96-week double-blind phase, eligible participants could enter an open-label extension and either continue doravirine or switch from comparator to doravirine for an additional 96 weeks. Efficacy (HIV-1 RNA <50 copies per mL) and safety assessments (adverse events and changes in laboratory parameters) were pooled. The DRIVE-FORWARD and DRIVE-AHEAD trials were registered with ClinicalTrials.gov, NCT02275780 and NCT02403674.
FINDINGS
Of 1494 participants treated in the double-blind phase (1261 [84%] male and 233 [16%] female), 550 continued doravirine and 502 switched to doravirine in the extension. Using the FDA snapshot approach, HIV-1 RNA less than 50 copies per mL was maintained in 457 (83%) of 550 participants who continued doravirine and 404 (80%) of 502 participants who switched to doravirine. Protocol-defined virological failure and development of resistance were low, occurring mainly before week 96. Two (<1%) of 550 participants who continued doravirine reported serious drug-related adverse events, and three (1%) who continued doravirine and one (<1%) of 502 who switched to doravirine discontinued due to drug-related adverse events. Participants continuing or switching to doravirine showed generally favourable lipid profiles, little weight gain, and small decreases in estimated glomerular filtration rates, with no discontinuations due to increased creatinine or renal adverse events.
INTERPRETATION
Favourable efficacy and safety profiles for doravirine at week 96 were maintained through to week 192 in participants who continued or switched to doravirine, supporting use of doravirine for long-term first-line HIV-1 treatment and for virologically suppressed adults switching therapy.
FUNDING
Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.
Topics: Adult; Male; Humans; Female; Adolescent; HIV Infections; HIV-1; Lamivudine; Ritonavir; Darunavir; Creatinine; Tenofovir; Emtricitabine; HIV Seropositivity; RNA; Lipids; Anti-HIV Agents; Treatment Outcome; Viral Load; Triazoles; Benzoxazines; Alkynes; Pyridones; Cyclopropanes
PubMed: 38141637
DOI: 10.1016/S2352-3018(23)00258-8 -
Marine Drugs Jul 2023Four new chlorinated cycloaromatized enediyne compounds, jejucarbosides B-E (-), were discovered together with previously-identified jejucarboside A from a marine...
Four new chlorinated cycloaromatized enediyne compounds, jejucarbosides B-E (-), were discovered together with previously-identified jejucarboside A from a marine actinomycete strain. Compounds - were identified as new chlorinated cyclopenta[]indene glycosides based on 1D and 2D nuclear magnetic resonance, high-resolution mass spectrometry, and circular dichroism (CD) spectra. Jejucarbosides B and E bear a carbonate functional group whereas jejucarbosides C and D are variants possessing 1,2-diol by losing the carbonate functionality. It is proposed that the production of - occurs via Bergman cycloaromatization capturing Cl and H in the alternative positions of a -benzyne intermediate derived from a 9-membered enediyne core. Jejucarboside E () displayed significant cytotoxicity against human cancer cell lines including SNU-638, SK-HEP-1, A549, HCT116, and MDA-MB-231, with IC values of 0.31, 0.40, 0.25, 0.29, and 0.48 μM, respectively, while jejucarbosides B-D (-) showed moderate or no cytotoxic effects.
Topics: Humans; Enediynes; Streptomyces; Antineoplastic Agents; Glycosides; Cell Line; Molecular Structure
PubMed: 37504936
DOI: 10.3390/md21070405 -
European Journal of Nuclear Medicine... Apr 2024Triple-negative breast cancer (TNBC) has a poor prognosis due to the absence of effective therapeutic targets. Vascular endothelial growth factor (VEGF) family are...
PURPOSE
Triple-negative breast cancer (TNBC) has a poor prognosis due to the absence of effective therapeutic targets. Vascular endothelial growth factor (VEGF) family are expressed in 30-60% of TNBC, therefore providing potential therapeutic targets for TNBC. Aflibercept (Abe), a humanized recombinant fusion protein specifically bound to VEGF-A, B and placental growth factor (PIGF), has proven to be effective in the treatment in some cancers. Therefore, Zr/Lu-labeled Abe was investigated for its theranostic role in TNBC.
METHODS
Abe was radiolabeled with Zr and Lu via the conjugation of chelators. Flow cytometry and cell immunofluorescent staining were performed to evaluate the binding affinity of Abe. Sequential PET imaging and fluorescent imaging were conducted in TNBC tumor bearing mice following the injection of Zr-labeled Abe and Cy5.5-labeled Abe. Treatment study was performed after the administration of Lu-labeled Abe. Tumor volume and survival were monitored and SPECT imaging and biodistribution studies were conducted. Safety evaluation was performed including body weight, blood cell measurement, and hematoxylin-eosin (H&E) staining of major organs. Expression of VEGF and CD31 was tested by immunohistochemical staining. Dosimetry was estimated using the OLINDA software.
RESULTS
FITC-labeled Abe showed a strong binding affinity to VEGF in TNBC 4T1 cells and HUVECs by flow cytometry and cell immunofluorescence. Tumor uptake of Zr-labeled Abe peaked at 120 h (SUVmax = 3.2 ± 0.64) and persisted before 168 h (SUVmax = 2.54 ± 0.42). The fluorescence intensity of the Cy5.5-labeled Abe group surpassed that of the Cy5.5-labeled IgG group, implying that Cy5.5-labeled Abe is a viable candidate monitoring in vivo tumor targeting and localization. Lu-labeled Abe (11.1 MBq) served well as the therapeutic component to suppress tumor growth with standardized tumor volume at 16 days, significantly smaller than PBS group (about 815.66 ± 3.58% vs 3646.52 ± 11.10%, n = 5, P < 0.01). Moreover, SPECT images confirmed high contrast between tumors and normal organs, indicating selective tumor uptake of Lu-labeled Abe. No discernible abnormalities in blood cells, and no evident histopathological abnormality observed in liver, spleen, and kidney. Immunohistochemical staining showed that Lu-labeled Abe effectively inhibited the expression of VEGF and CD31 of tumor, suggesting that angiogenesis may be suppressed by Lu-labeled Abe. The whole-body effective dose for an adult human was estimated to be 0.16 mSv/MBq.
CONCLUSION
Zr/Lu-labeled Abe could be a TNBC-specific marker with diagnostic value and provide insights into targeted therapy in the treatment of TNBC. Further clinical evaluation and translation may be of high significance for TNBC.
Topics: Female; Humans; Animals; Mice; Vascular Endothelial Growth Factor A; Triple Negative Breast Neoplasms; Precision Medicine; Tissue Distribution; Cell Line, Tumor; Placenta Growth Factor; Recombinant Fusion Proteins; Carbocyanines; Receptors, Vascular Endothelial Growth Factor
PubMed: 38135849
DOI: 10.1007/s00259-023-06575-9 -
Chemical Record (New York, N.Y.) Jul 2023Enamines are formed by reacting a carbonyl compound with an amine under dehydration conditions. A vast array of transformations has been achieved via preformed enamine... (Review)
Review
Enamines are formed by reacting a carbonyl compound with an amine under dehydration conditions. A vast array of transformations has been achieved via preformed enamine chemistry. Recently, by introducing conjugating double bonds to the enamine functionality, dienamines, and trienamines have propelled the discovery of several previously unattainable remote-site functionalization reactions of carbonyl compounds. Comparatively, alkyne-conjugating enamine analogues have recently shown high potential in multifunctionalization reactions while remaining underexplored. In this account, we systematically summarized and discussed recent advances in synthetic transformations based on ynenamine-containing compounds.
Topics: Catalysis; Stereoisomerism; Amines; Alkynes
PubMed: 37098876
DOI: 10.1002/tcr.202300099 -
Chemistry (Weinheim An Der Bergstrasse,... Jul 2023Hydrosilylation of C=C double and C≡C triple bonds is one of the most widely used processes in organosilicon chemistry, mostly catalyzed by Pt-based complexes. Herein,...
Hydrosilylation of C=C double and C≡C triple bonds is one of the most widely used processes in organosilicon chemistry, mostly catalyzed by Pt-based complexes. Herein, the synthesis of a dicationic Zn -based complex with a tripodal tris(2-pyridylmethyl)amine (TPA) ligand is reported which was found to be a highly chemoselective catalyst for hydrosilylation reactions of alkynes. Mechanistic studies revealed that unlike typical Zn-catalyzed hydrosilylation reactions where the key step is the activation of the Si-H bond, this system catalyzes the hydrosilylation reaction through the activation of C≡C triple bonds, which presumably is the reason for its high chemoselectivity. Remarkably, the hydrosilylation of alkynes could be performed in the presence of alkenes and other functional groups that remained intact in this reaction.
PubMed: 37186082
DOI: 10.1002/chem.202300798