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Enantiomerically pure 4-hydroxymorphan-7-ones were prepared in two steps from the natural product (R)-carvone. At first, the isopropenyl moiety of (R)-carvone was converted into the epoxide 7. A Domino reaction consisting of epoxide opening with primary amines followed by intramolecular conjugate addition of the resulting secondary amines at the α,ß-unsaturated ketone established the morphan scaffold. This novel morphan synthesis allowed the modification of the bicyclic system at three positions resulting in 26 diverse morphans. Various primary amines led to morphans 8‒13 with different N-substituents. Acylation or water elimination followed by hydrogenation led to esters 15 and 16 or the morphan 18 without a hydroxy moiety. The benzylidenemorphans 25a and 26a were prepared by condensation of the ketones 11a and 12a with benzaldehyde. Finally, the α-methylene ketone of 11a and 12a was exploited to obtain indolomorphans, quinolinomorphans, pyrimidinomorphans and pyrazolomorphans. Affinity of the novel morphans at opioid receptors MOR, DOR and KOR could not be detected. However, the indolomorphan 19 and the quinolinomorphan 22 showed nanomolar σ1 receptor affinity (Ki = 58 nM and 20 nM).

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Aim: This study explores the cytotoxic and apoptotic effects of novel thiazolidinone-1,2,3-triazole hybrids on HT-1080, A-549, and MDA-MB-231 cancer cell lines.Methods & results: The synthesized compounds underwent comprehensive characterization (NMR and HRMS) to confirm their structures and purity. Subsequent anticancer activity screening across diverse cancer cell lines revealed promising antitumor potential notably, compounds 6f and 6g. Mechanistic investigations unveiled that compound 6f triggers apoptosis through the caspase-3/7 pathway. In terms of in silico studies, the compound 6f was identified as a potent inhibitor of caspase-3 and caspase-7.Conclusion: The present study underscores the therapeutic potential of thiazolidinone-1,2,3-triazole hybrids against certain cancer cells. These findings highlight a promising avenue for the development of cancer treatment strategies utilizing these (R)-Carvone-based derivatives.

[Box: see text].

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In the present work, we describe the synthesis of new 1,3,4-thiadiazole derivatives from natural (R)-carvone in three steps including, dichloro-cyclopropanation, a condensation with thiosemicarbazide and then a 1,3-dipolar cycloaddition reaction with various nitrilimines. the targeted compounds were structurally identified by 1H & 13C NMR and HRMS analyses. The cytotoxic assay demonstrated that some synthesized novel compounds were potent on certain cancer cell lines. Molecular modeling studies were undertaken to rationalize the wet lab study results. Furthermore, molecular docking was performed to unveil the binding potential of the most active derivatives, 3a and 6c, to caspase-3 and COX-2. The stabilities of the protein-compound complexes obtained from the docking were evaluated using MD simulation. Furthermore, FMO and related parameters of the active compounds and their stereoisomers were examined through DFT studies. The docking study showed compound 6c had a higher binding potential than caspase-3. However, the binding strength of 6c was found to be less than that of the standard drug, doxorubicin, as it formed lower conventional hydrogen bonds. On the other hand, compound 3a had a higher binding potential to COX-2. However, the binding potential 3a was much lower than that of the standard COX-2 inhibitor, celecoxib. The MD simulation demonstrated that the caspase-3-6c complex was less stable than the caspase-3-doxorubicin complex. In contrast, the COX-2-3a complex was stable, and 3a was anticipated to remain inside the protein's binding pocket. The DFT study showed that 3a had higher chemical stability than 6c. The electron exchange capacity, chemical stability, and molecular orbital distributions of the stereoisomers of the active compounds were also found to be alike.

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Within the context of Molecular Electronic Density Theory (MEDT), this study investigates the Diels-Alder reaction among isoprene (2) and R-carvone (1R) applying DFT simulations, with and without Lewis acid (LA) catalysis. The results show that carvone (1R) acts as an electrophile and isoprene (2) as a nucleophile in a polar process. LA catalysis increases the electrophilicity of carvone, thereby improving the reactivity and selectivity of the reaction by reducing the activation Gibbs free energy. Parr functions reveal that the C5=C6 double bond is more reactive than the C9=C10 double bond, indicating chemoselectivity. The examination of the Electron Localization Function (ELF) reveals high regio- and stereoselectivity, indicating an asynchronous mechanism for the LA-catalyzed DA reaction. Furthermore, it is suggested that cycloadduct 3 has great anti-HIV potential because it exhibits lower binding energies than azidothymidine (AZT) in the docking studies of cycloadducts 3 and 4 amongst a primary HIV-1protein (1A8O plus 5W4Q).

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The botanical insecticide market is growing because of limitations placed on the use of certain synthetic chemical insecticides. In this sense, the lesser mealworm Alphitobius diaperius (Coleoptera: Tenebrionidae) is the main poultry pest. The insect causes weight loss and damage to the digestive system of poultry, and it is a vector and reservoir of pathogens. Consequently, this study explored the following hypotheses: (i) essential oils (EOs) derived from Mentha spp. are toxic to A. diaperius; (ii) these EOs are compatible with Beauveria bassiana, the natural enemy of the poultry pest, that parasite A. diaperinus; (iii) these EOs also exhibit activity against bacteria that are pathogenic to poultry. In topical applications and ingestion tests, EOs from Mentha arvensis, Mentha spicata, and Mentha piperita were toxic to A. diaperinus. Chromatographic analyses revealed that menthol is the predominant compound in M. arvensis and M. piperita, whereas carvone is the major compound in M. spicata. Both (-)- and (+)-menthol, along with (-)- and (+)-carvone, underwent testing with A. diaperinus. Nevertheless, their activity was not as potent as those of the EOs, suggesting a possible synergistic and/or additive effect. The EOs did not have any adverse effects on the conidial germination, vegetative growth, or conidia production per colony of the entomopathogenic fungus B. bassiana. Consequently, these EOs are compatible with this natural enemy. The EO extracted from M. spicata exhibited significant toxicity against Staphylococcus aureus (ATCC 25923), whereas the remaining EOs displayed moderate toxicity against this bacterium. The EOs derived from Mentha spp., as assessed in this study, hold promise for the development of botanical insecticides tailored for the control of A. diaperinus. These insecticides are selective in favor of the natural enemy B. bassiana and can also serve as effective sanitizers, thanks to their antibacterial properties.

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(-)-Ambrox, a highly prized and commercially significant component of ambergris, finds widespread application in perfumery, cigarettes, cosmetics, and the food industry. Despite considerable attention to this research area over the years, an environmentally friendly and practical method for synthesizing (-)-ambrox has remained elusive. This study presents a succinct and efficient approach to (-)-ambrox synthesis, involving two consecutive alkylations at C-6, followed by an acid-catalyzed cyclization to give bicyclic ketones starting from (R)-carvone. Subsequent reduction, Barton Vinyl Iodide synthesis, alkylation, and an acid-catalyzed cyclization collectively achieved the synthesis of (-)-ambrox with a satisfactory yield of 26.2 %.

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This work describes the successful synthesis of a series of three novel thiazolidinone-carvone-O-alkyl hybrids through a two-step approach involving heterocyclization and O-alkylation reactions. Comprehensive structural characterization of the obtained products was achieved using NMR and HRMS spectroscopic techniques. This study assessed in vitro antiproliferative activity of synthesized thiazolidinone-carvone-O-alkyl hybrids (5a-c) against various human cancer cell lines, viz. HT-1080 (fibrosarcoma), A-549 (lung cancer), MCF-7 (breast cancer) and MDA-MB-231 (breast cancer). MTT assay revealed promising results for compounds 5b and 5c, demonstrating good antiproliferative activity against A-549 and MCF-7 cell lines comparable to the positive control, Doxorubicin. Compound 5a, harbouring an O-acetoxy group, displayed limited anticancer activity against MCF-7 and MDA-MB-231 cells, with IC50 values of 69.33 ± 0.42 µM and >100 µM, respectively. Docking results confirmed that the compounds 5a-c binds at the active site of p21 with docking scores -2.0, -4.8, and -7.0 kcal/mol, respectively. Compound 5a-c also showed good binding potential against Bcl2 protein with docking score of -4.9, -6.0, -5.5 kcal/mol, respectively. Furthermore, binding energy analysis and dynamics simulation studies of compounds towards p21 and Bcl2 yielded promising results. In PAK4 assay, compound 5c showed comparable potency (IC50 6.76 µM) with the standard control UC2288 (IC50 6.40 µM), while in BCL-2 TR-FRET assay, 5c exhibited good inhibition (IC50 1.78 µM) as compared to Venetoclax (IC50 0.016 µM). In conclusion, compounds 5a-c could be used as a structural framework for the discovery of novel therapeutics to combat different types of cancer.Communicated by Ramaswamy H. Sarma.

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To explore the molecular mechanisms underlying the anti-inflammatory activity of (R)-(-)-carvone, we evaluated its ability to inhibit the signaling pathways involving the mitogen-activated protein kinases (MAPKs) and the transcription factor, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). (R)-(-)-carvone significantly decreased c-Jun N-terminal kinase (JNK) 1phosphorylation, but not that of the other MAPKs, induced by bacterial lipopolysaccharides (LPS) in the RAW 264.7 macrophage cell line. Although (R)-(-)-carvone significantly inhibited resynthesis of the inhibitor of NF-κB (IκB)-α induced by LPS, it did not interfere with the canonical NF-κB activation pathway, suggesting that it may interfere with its transcriptional activity. (R)-(-)-carvone also showed a tendency to decrease the levels of acetylated NF-κB/p65 in the nucleus, without affecting the activity and protein levels of Sirtuin-1, the major NF-κB/p65 deacetylating enzyme. Interestingly, the nuclear protein levels of the transcription factor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and the expression of its target,, heme oxygenase-1 (HO-1), an antioxidant enzyme, also showed a tendency to increase in the presence of (R)-(-)-carvone. Taken together, these results suggest that the ability of (R)-(-)-carvone to inhibit JNK1 and to activate Nrf2 can underlie its capacity to inhibit the transcriptional activity of NF-κB and the expression of its target genes. This study highlights the diversity of molecular mechanisms that can be involved in the anti-inflammatory activity of monoterpenes.

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Aseries of novel 1,4-disubstituted 1,2,3-triazoles were synthesized from an (R)-carvone terminal alkyne derivative via a Cu (I)-catalyzed azide-alkyne cycloaddition reaction using CuSO4,5H2O as the copper (II) source and sodium ascorbate as a reducing agent which reduces Cu (II) into Cu (I). All the newly synthesized 1,2,3-triazoles 9a-h were fully identified on the basis of their HRMS and NMR spectral data and then evaluated for their cell growth inhibition potential by MTS assay against HT-1080 fibrosarcoma, A-549 lung carcinoma, and two breast adenocarcinoma (MCF-7 and MDA-MB-231) cell lines. Compound 9d showed notable cytotoxic effects against the HT-1080 and MCF-7 cells with IC50 values of 25.77 and 27.89 µM, respectively, while compound 9c displayed significant activity against MCF-7 cells with an IC50 value of 25.03 µM. Density functional calculations at the B3LYP/6-31G* level of theory were used to confirm the high reactivity of the terminal alkyne as a dipolarophile. Quantum calculations were also used to investigate the mechanism of both the uncatalyzed and copper (I)-catalyzed azide-alkyne cycloaddition reaction (CuAAC). The catalyzed reaction gives complete regioselectivity via a stepwise mechanism streamlining experimental observations. The calculated free-energy barriers 4.33 kcal/mol and 29.35 kcal/mol for the 1,4- and 1,5-regioisomers, respectively, explain the marked regioselectivity of the CuAAC reaction.

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In the current study, natural (R)-carvone was used as starting material for the efficient synthesis of several 1,2,3-triazole derivatives. The produced products were obtained in good yields and characterized by 1H and 13C NMR and HRMS analysis. The newly synthesized monoterpenic 1,2,3-triazole 4 and derivatives were analyzed by viability tests (MTT) for their cytotoxic activity against three human cancer cells. Product 5 showed a medium antitumor activity, for which the IC50 values against selected cells HT-1080, A-549 and MCF-7 were 29.25 µM, 31.62 µM and 26.02 µM, respectively. The regioselectivity of the condensation reaction and the molecular structure of the title compounds were determined by Density Functional Theory (DFT) using B3LYP calculations at 6-311 + G(d,p) level. The orbitals HOMO and LUMO were studied to determine the electronic properties of the synthesized compounds. In addition, the global reactivity indices were used to explain the regioselectivity for the formation of compound 6, and the theoretical results agree well with the experimental results. Molecular docking and molecular dynamics confirmed the empirical test results and confirmed the stability of the complex during inhibition of the anti-apoptotic protein for killing cancer cells. Communicated by Ramaswamy H. Sarma.

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Background: Doxorubicin is one of the most potent broad-spectrum antitumor and chemotherapeutic agents. However, it produces cardiotoxicity. Aims: To investigate whether R-(-)-carvone exerts a cardioprotective effect against doxorubicin toxicity in vivo and in vitro. Study Design: Cell culture and animal experiment. Methods: The synergistic effect of R-(-)-carvone with doxorubicin was evaluated in the MCF 7 cancer cell line while its protective effect against doxorubicin toxicity was evaluated in the normal heart cell line (H9C2) and in vivo. Furthermore, the mechanism of its cardioprotective effect was studied. Results: R-(-)-carvone exerted cytotoxic action on the MCF 7 cancer cell line with an IC50 value of 14.22 µM and potentiated the cytotoxic action of doxorubicin, while it decreased the toxicity of doxorubicin on a normal heart cell line. In BALB/c mice, R-(-)-carvone protected the heart from the toxic action of doxorubicin, as was evident by biochemical and histological studies. The protective effect of R-(-)-carvone on the H9C2 heart cell line and on heart in vivo was due to an increase in catalase activity. Conclusion: R-(-)-carvone has synergistic anticancer action with doxorubicin on the MCF 7 cell line while decreasing its cardiotoxicity.

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(2R,5R)-dihydrocarvone is an industrially applied building block that can be synthesized by site-selective and stereo-selective C=C bond bio-reduction of (R)-carvone. Escherichia coli (E. coli) cells overexpressing an ene reductase from Nostoc sp. PCC7120 (NostocER1) in combination with a cosubstrate regeneration system proved to be very effective biocatalysts for this reaction. However, the industrial applicability of biocatalysts is strongly linked to the catalysts' activity. Since the cell-internal NADH concentrations are around 20-fold higher than the NADPH concentrations, we produced E. coli cells where the NADPH-preferring NostocER1 was exchanged with three different NADH-accepting NostocER1 mutants. These E. coli whole-cell biocatalysts were used in batch operated stirred-tank reactors on a 0.7 l-scale for the reduction of 300 mM (R)-carvone. 287 mM (2R,5R)-dihydrocarvone were formed within 5 h with a diasteromeric excess of 95.4% and a yield of 95.6%. Thus, the whole-cell biocatalysts were strongly improved by using NADH-accepting enzymes, resulting in an up to 2.1-fold increased initial product formation rate leading to a 1.8-fold increased space-time yield when compared to literature.

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OBJECTIVES: To characterize a novel ene-reductase from Meyerozyma guilliermondii and achieve the ene-reductase-mediated reduction of activated C=C bonds. RESULTS: The gene encoding an ene-reductase was cloned from M. guilliermondii. Sequence homology analysis showed that MgER shared the maximal amino acid sequence identity of 57 % with OYE2.6 from Scheffersomyces stipitis. MgER showed the highest specific activity at 30 °C and pH 7 (100 mM sodium phosphate buffer), and excellent stereoselectivities were achieved for the reduction of (R)-carvone and ketoisophorone. Under the reaction conditions (30 °C and pH 7.0), 150 mM (R)-carvone could be completely converted to (2R,5R)-dihydrocarvone within 22 h employing purified MgER as catalyst, resulting in a yield of 98.9 % and an optical purity of >99 % d.e. CONCLUSION: MgER was characterized as a novel ene-reductase from yeast and showed great potential for the asymmetric reduction of activated C=C bonds of α,ß-unsaturated compounds.

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