Since herbal medicines play an important role in the treatment of a wide range of diseases, there is a growing need for their quality control and standardization. Mentha suaveolens Ehrh. (MS) is an ...aromatic herb with fruit and a spearmint flavor, used in the Mediterranean areas as a traditional medicine. It has an extensive range of biological activities, including cytotoxic, antimicrobial, antioxidant, anti-inflammatory, hypotensive and insecticidal properties, among others. This study aims to review the scientific findings and research reported to date on MS that prove many of the remarkable various biological actions, effects and some uses of this species as a source of bioactive natural compounds. On the other hand, piperitenone oxide (PO), the major chemical constituent of the carvone pathway MS essential oil, has been reported to exhibit numerous bioactivities in cells and animals. Thus, this integrated overview also surveys and interprets the present knowledge of chemistry and analysis of this oxygenated monoterpene, as well as its beneficial bioactivities. Areas for future research are suggested.
Alteration in cell death is a hallmark of cancer. A functional role regulating survival, apoptosis, and necroptosis has been attributed to RIP1/3 complexes.
We have investigated the role of RIP1 and ...the effects of MC2494 in cell death induction, using different methods as flow cytometry, transcriptome analysis, immunoprecipitation, enzymatic assays, transfections, mutagenesis, and
studies with different mice models.
Here, we show that RIP1 is highly expressed in cancer, and we define a novel RIP1/3-SIRT1/2-HAT1/4 complex. Mass spectrometry identified five acetylations in the kinase and death domain of RIP1. The novel characterized pan-SIRT inhibitor, MC2494, increases RIP1 acetylation at two additional sites in the death domain. Mutagenesis of the acetylated lysine decreases RIP1-dependent cell death, suggesting a role for acetylation of the RIP1 complex in cell death modulation. Accordingly, MC2494 displays tumor-selective potential
, in leukemic blasts
and
in both xenograft and allograft cancer models. Mechanistically, MC2494 induces bona fide tumor-restricted acetylated RIP1/caspase-8-mediated apoptosis. Excitingly, MC2494 displays tumor-preventive activity by blocking 7,12-dimethylbenz(α)anthracene-induced mammary gland hyperproliferation
These preventive features might prove useful in patients who may benefit from a recurrence-preventive approach with low toxicity during follow-up phases and in cases of established cancer predisposition. Thus, targeting the newly identified RIP1 complex may represent an attractive novel paradigm in cancer treatment and prevention.
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A comprehensive study on essential oils (EOs) extracted from some Mentha suaveolens L. samples, collected in the countryside of Tarquinia, is reported. In this study, the procedure for essential oil ...preparation, in terms of harvesting and extraction time, was analyzed in detail for the first time. The GC/MS analysis, carried out on 18 samples, revealed that piperitenone oxide (PO), the main essential oils' chemical constituent, is primarily responsible for the related antifungal activity. Nevertheless, EOs with lower PO content indicate that other chemicals, such as para-cymenene, may participate in exerting the EOs' antifungal effect. Furthermore, the bacterial reverse mutation assay highlighted lack of mutagenic effect in all tested samples. Analysis of the results indicated that for higher activity, the essential oils should be produced with 3 h maximum hydrodistillation, regardless of the harvesting time. Differently, the maximum essential oil yield can be obtained in August and the highest piperitenone oxide percentage is obtainable in July.
Monoamine oxidase B (MAO B) catalyzes the oxidative deamination of aryalkylamines neurotransmitters with concomitant reduction of oxygen to hydrogen peroxide. Consequently, the enzyme’s malfunction ...can induce oxidative damage to mitochondrial DNA and mediates development of Parkinson’s disease. Thus, MAO B emerges as a promising target for developing pharmaceuticals potentially useful to treat this vicious neurodegenerative condition. Aiming to contribute to the development of drugs with the reversible mechanism of MAO B inhibition only, herein, an extended in silico–in vitro procedure for the selection of novel MAO B inhibitors is demonstrated, including the following: (1) definition of optimized and validated structure-based three-dimensional (3-D) quantitative structure–activity relationships (QSAR) models derived from available cocrystallized inhibitor–MAO B complexes; (2) elaboration of SAR features for either irreversible or reversible MAO B inhibitors to characterize and improve coumarin-based inhibitor activity (Protein Data Bank ID: 2V61 ) as the most potent reversible lead compound; (3) definition of structure-based (SB) and ligand-based (LB) alignment rule assessments by which virtually any untested potential MAO B inhibitor might be evaluated; (4) predictive ability validation of the best 3-D QSAR model through SB/LB modeling of four coumarin-based external test sets (267 compounds); (5) design and SB/LB alignment of novel coumarin-based scaffolds experimentally validated through synthesis and biological evaluation in vitro. Due to the wide range of molecular diversity within the 3-D QSAR training set and derived features, the selected N probe-derived 3-D QSAR model proves to be a valuable tool for virtual screening (VS) of novel MAO B inhibitors and a platform for design, synthesis and evaluation of novel active structures. Accordingly, six highly active and selective MAO B inhibitors (picomolar to low nanomolar range of activity) were disclosed as a result of rational SB/LB 3D QSAR design; therefore, D123 (IC50 = 0.83 nM, K i = 0.25 nM) and D124 (IC50 = 0.97 nM, K i = 0.29 nM) are potential lead candidates as anti-Parkinson’s drugs.
Selective inhibition of KDAC isoforms while maintaining potency remains a challenge. Using the largazole macrocyclic depsipeptide structure as a starting point for developing new KDACIs with ...increased selectivity, a combination of four different simplified largazole analogue (SLA) scaffolds with diverse zinc-binding groups (for a total of 60 compounds) were designed, synthesized, and evaluated against class I KDACs 1, 3, and 8, and class II KDAC6. Experimental evidence as well as molecular docking poses converged to establish the cyclic tetrapeptides (CTPs) as the primary determinant of both potency and selectivity by influencing the correct alignment of the zinc-binding group in the KDAC active site, providing a further basis for developing new KDACIs of higher isoform selectivity and potency.
Arylsulfatase A (ARSA) plays a crucial role in the reproduction of mammals due to its involvement in the specific gamete interaction preceding sperm and egg fusion leading to fertilization. Recently, ...it has been shown that zona pellucida (ZP) sperm binding and
fertilization in mice are markedly hampered by using a specific anti-ARSA antibody. Herein, the design and discovery of the first ARSA small molecule inhibitor based on a coumarin-containing polycycle are presented. Through a structure-based approach applied on our in-house library, compound
was identified as an ARSA reversible inhibitor (ARSAi); then its activity was validated through both surface plasmon resonance and biochemical inhibition experiments, the first providing a
value of 21 μM and the latter an IC
value of 13.2 μM. Further investigations highlighted that compound
induced 20% sperm death at 25 μM and also impaired sperm motility; nevertheless both the effects were mediated by ROS production, since they were rescued by the cotreatment of
and
-acetyl cysteine (NAC). Interestingly, while
was not able to hamper the ZP/sperm binding, it markedly decreased the
oocyte fertilization by mouse sperm up to 60%. Notably, this effect was not hampered by
/NAC coadministration, hence allowing the ruling out of an ROS-dependent mechanism. In conclusion, herein is reported the first ever hit of ARSAi as a chemical tool that will enable better exploration of ARSA's biological role in fertilization as well as provide a starting point for developing
structure optimization aimed at increasing enzyme inhibition potency but also providing a deeper understanding of the involvement of ARSA in the fertilization pathway mechanism.
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We report herein the synthesis, biological evaluation and docking analysis of a new series of methylsulfonyl, sulfamoyl acetamides and ethyl acetates that selectively inhibit ...cyclooxygenase-2 (COX-2) isoform. Among the newly synthesized compounds, some of them were endowed with a good activity against COX-2 and a good selectivity COX-2/COX-1 in vitro as well as a desirable analgesic activity in vivo, proving that replacement of the ester moiety with an amide group gave access to more stable derivatives, characterized by a good COX-inhibition.
Vascular endothelial growth factor receptor-2, (VEGFR-2), is a key element in angiogenesis, the process by which new blood vessels are formed, and is thus an important pharmaceutical target. Here, ...3-D quantitative structure–activity relationship (3-D QSAR) were used to build a quantitative screening and pharmacophore model of the VEGFR-2 receptors for design of inhibitors with improved activities. Most of available experimental data information has been used as training set to derive optimized and fully cross-validated eight mono-probe and a multi-probe quantitative models. Notable is the use of 262 molecules, aligned following both structure-based and ligand-based protocols, as external test set confirming the 3-D QSAR models’ predictive capability and their usefulness in design new VEGFR-2 inhibitors. From a survey on literature, this is the first generation of a wide-ranging computational medicinal chemistry application on VEGFR2 inhibitors.
In the present study, we have further extended the structure–activity relationships for the tetrazolyl ureas class of compounds as potential FAAH and/or MAGL inhibitors, by replacing the ...dimethylamino group of the parent compounds 1 and 2 with bulkier groups or by introducing on the distal phenyl ring of 1 and 2 a selected set of substituents. Some of the new compounds (16, 20, 21, 25, and 28) inhibited FAAH potently (IC50 = 3.0–9.7 nM) and selectively (39- to more than 141-fold) over MAGL, while tetrazole 27 turned out to be a promising dual FAAH–MAGL inhibitor of potential therapeutic use. Covalent docking studies on FAAH indicated that the binding modes of tetrazoles 1–32 did not display a unique pattern. The ability of tetrazoles 1–32 to act as TRPV1 and TRPA1 modulators was also investigated.
Display omitted A new series of carbamoyl tetrazoles has been synthesized and evaluated as inhibitors of FAAH and MAGL and as TRPV1 and TRPA1 modulators.
► A series of 30 new biaryl tetrazolyl ureas has been synthesized. ► Some of the prepared compounds inhibited FAAH potently and selectively over MAGL. ► The action on TRPV1 and TRPA1 channels was also investigated. ► Results were discussed using covalent docking.
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