Synthesis of Quinoline and Dihydroquinoline Embelin Derivatives as Cardioprotective Agents.

A set of new dihydroquinoline embelin derivatives was obtained from the reaction of the natural benzoquinone embelin (1) with anilines and aromatic aldehydes in the presence of AgOTf. The synthesis of these compounds involves the formation of a Knoevenagel adduct, followed by nucleophilic addition of aniline and subsequent electrocyclic ring closure. The scope of the reaction regarding the aldehydes and anilines was determined. Quinoline derivatives were also obtained from the corresponding dihydroquinolines under oxidation with DDQ. The cardioprotective activity of the synthesized compounds was screened using a doxorubicin-induced cardiotoxicity model in H9c2 cardiomyocytes. Some structure-activity relationships were outlined, and the best activities were achieved with quinoline-embelin derivatives having a 4-nitrophenyl group attached at the pyridine ring. The obtained results indicated that embelin derivatives 4i, 6a, 6d, 6k, and 6m could have potential as cardioprotective agents, as they attenuated a DOX-induced cardiotoxicity effect acting on oxidative stress and apoptosis.

Phenolic and quinone methide nor-triterpenes as selective NLRP3 inflammasome inhibitors.

Dysregulated inflammasome activity, particularly of the NLRP3 inflammasome, is associated with the development of several inflammatory diseases. The study of molecules directly targeting NLRP3 is an emerging field in the discovery of new therapeutic compounds for the treatment of inflammatory disorders. Friedelane triterpenes are biologically active phytochemicals having a wide range of activities including anti-inflammatory effects. In this work, we evaluated the potential anti-inflammatory activity of phenolic and quinonemethide nor-triterpenes (1-11) isolated from Maytenus retusa and some semisynthetic derivatives (12-16) through inhibition of the NLRP3 inflammasome in macrophages. Among them, we found that triterpenes 6 and 14 were the most potent, showing markedly reduced caspase-1 activity, IL-1ß secretion (IC50 = 1.15 µM and 0.19 µM, respectively), and pyroptosis (IC50 = 2.21 µM and 0.13 µM, respectively). Further characterization confirmed their selective inhibition of NLRP3 inflammasome in both canonical and non-canonical activation pathways with no effects on AIM2 or NLRC4 inflammasome activation.

Labdane conjugates protect cardiomyocytes from doxorubicin-induced cardiotoxicity.

The cardiovascular side effects associated with doxorubicin (DOX), a wide spectrum anticancer drug, have limited its clinical application. Therefore, to explore novel strategies with cardioprotective effects, a series of new labdane conjugates were prepared (6a-6c and 8a-8d) from the natural diterpene labdanodiol (1). These hybrid compounds contain anti-inflammatory privileged structures such as naphthalimide, naphthoquinone, and furanonaphthoquinone. Biological activity of these conjugates against DOX-induced cardiotoxicity was tested in vitro and the potential molecular mechanisms of protective effects were explored in H9c2 cardiomyocytes. Three compounds 6c, 8a, and 8b significantly improved cardiomyocyte survival, via inhibition of reactive oxygen species-mediated mitogen-activated protein kinase signaling pathways (extracellular signal-regulated kinase and c-Jun N-terminal kinase) and autophagy mediated by Akt activation. Some structure-activity relationships were outlined, and the best activity was achieved with the labdane-furonaphthoquinone conjugate 8a having an N-cyclohexyl substituent. The findings of this study pave the way for further investigations to obtain more compounds with potential cardioprotective activity.

Dehydroisohispanolone as a Promising NLRP3 Inhibitor Agent: Bioevaluation and Molecular Docking.

Dehydroisohispanolone (DIH), is a labdane diterpene that has exhibited anti-inflammatory activity via inhibition of NF-κB activation, although its potential effects on inflammasome activation remain unexplored. This study aims to elucidate whether DIH modulates NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome in macrophages. Our findings show that DIH inhibited NLRP3 activation triggered by Nigericin (Nig), adenosine triphosphate (ATP) and monosodium urate (MSU) crystals, indicating broad inhibitory effects. DIH significantly attenuated caspase-1 activation and secretion of the interleukin-1ß (IL-1ß) in J774A.1 cells. Interestingly, the protein expressions of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), pro-caspase-1 and pro-IL-1ß were not affected by DIH treatment. Furthermore, we found that DIH pretreatment also inhibited the lipopolysaccharide (LPS)-induced NLRP3 inflammasome priming stage. In addition, DIH alleviated pyroptosis mediated by NLRP3 inflammasome activation. Similar results on IL-1ß release were observed in Nig-activated bone marrow-derived macrophages (BMDMs). Covalent molecular docking analysis revealed that DIH fits well into the ATP-binding site of NLRP3 protein, forming a covalent bond with Cys415. In conclusion, our experiments show that DIH is an effective NLRP3 inflammasome inhibitor and provide new evidence for its application in the therapy of inflammation-related diseases.

Dehydrohispanolone Derivatives Attenuate the Inflammatory Response through the Modulation of Inflammasome Activation.

The NLRP3 inflammasome plays a critical role in inflammation-mediated human diseases and represents a promising drug target for novel anti-inflammatory therapies. Hispanolone is a labdane diterpenoid isolated from the aerial parts of Ballota species. This diterpenoid and some derivatives have demonstrated anti-inflammatory effects in classical inflammatory pathways. In the present study, a series of dehydrohispanolone derivatives (1-19) was synthesized, and their anti-inflammatory activities toward NLRP3 inflammasome activation were evaluated. The structures of the dehydrohispanolone analogues produced were elucidated by NMR spectroscopy and mass spectrometry. Four derivatives significantly inhibited IL-1ß secretion, with 15 and 18 being the most active (IC50 = 18.7 and 13.8 µM, respectively). Analysis of IL-1ß and caspase-1 expression revealed that the new diterpenoids 15 and 18 are selective inhibitors of the NLRP3 inflammasome, reinforcing the previously demonstrated anti-inflammatory properties of hispanolone derivatives.

Current status of terpenoids as inflammasome inhibitors.

Increasing evidence supports NLRP3 inflammasome as a new target to control inflammation. Dysregulation of NLRP3 inflammasome has been reported to be involved in the pathogenesis of several human inflammatory diseases. However, no NLRP3 inflammasome inhibitors are available in clinic. Terpenoids are natural products with multi-target activities against inflammation. Recent studies have revealed that these compounds are capable of inhibiting the activation of NLRP3 inflammasome in several mouse models of NLRP3 inflammasome-related pathogenesis. Thus, terpenoids represent an interesting pharmacological approach for the treatment of inflammatory diseases as they are endowed with a dual mechanism of inhibition of NF-KB transcription factor and inflammasome activation, both critically involved in their anti-inflammatory effects. This work provides an overview of the current knowledge on the therapeutic potential of terpenoids as NLRP3 inflammasome inhibitors.

Molecular Targets Involved in the Neuroprotection Mediated by Terpenoids.

Natural products and their derivatives represent the most consistently successful source of drug leads. Terpenoids, a structurally diverse group, are secondary metabolites widely distributed in nature, endowed with a wide range of biological activities such as antibacterial, anti-inflammatory, antitumoral, or neuroprotective effects, which consolidate their therapeutic value. During the last decades, and taking into consideration the prevalence of aging-related diseases, research activity into the neuroprotective effects of these types of compounds has increased enormously. Several signaling pathways involved in neuroprotection are targets of their mechanism of action and mediate their pleiotropic protective activity in neuronal cell damage. In the present review, molecular basis of the neuroprotection exerted by terpenoids is presented, focusing on preclinical evidence of the therapeutic potential of diterpenoids and triterpenoids on neurodegenerative disorders. By acting on diverse mechanisms simultaneously, terpenoids have been emphasized as promising multitarget agents.