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An approach to biogenetically overlooked areas of the isoprenoid chemical space is presented. This strategy is based on the generation of a cationic center in functionalized polyolefins by Lewis acid activation of a carbonyl group, rather than by electrophilic attack at a double bond. Starting from the monocyclic humulane trienone zerumbone, polycyclic sesquiterpenoid skeletons which are either not reported as natural products or biogenetically enigmatic in terms of the isoprenoid rule, were obtained by modulating the Lewis acid catalyst. In the course of these studies, the surprising formation of a strained E-cyclooctene motif was observed in a cyclization reaction.

Arzanol (1) exemplifies a large number of heterodimeric bioactive natural products based on an alkylidene-bridged β-dicarbonyl-acylphloroglucinyl structural motif. The NMR spectra of these compounds are complicated by tautomeric and rotational equilibria that, despite growing synthetic and biomedical interest in the area, have not been systematically investigated. By combining information from NMR spectroscopy and DFT calculations, we have comparatively characterized the solution structures and conformations of the anti-inflammatory agent arzanol (1), its inactive monomethyl derivative 4, and its corresponding homodimers [helipyrone (5) and demethylmallotojaponin C (6)]. The results highlight the relevance of a network of intramolecular hydrogen bonds for the tautomeric and rotameric equilibria of these compounds, with arzanol (1) existing in two almost equally populated rotameric forms of a 2-pyrone tautomer, and its phloroglucinyl homodimer 6 in four major forms. Conversely, the monomethyl derivative 4 of arzanol and its dipyrone homodimer 5 exist in essentially a single solution form. Interestingly, this conformational bias was associated with a marked decrease of bioactivity.

Although Michael acceptors are traditionally shunned in modern drug discovery, trapping of thiols by covalent coupling represents an important mechanism of bioactivity, and many biologically relevant and druggable pathways are targeted by thiol-reactive compounds. Research on Michael acceptors, long confined to the realm of toxicology, was rekindled by the development of the antioxidant inflammation modulator (AIM) homo-triterpenoid bardoxolone methyl (RTA402, 1). This orally bioavailable biological

Using the synthesis of the heterodimeric phloroglucinyl pyrone arzanol as a benchmark reaction, a carba-version of the Betti multicomponent reaction has been developed. Capitalizing on the fluorous activation of the phenolic component and the use of iminium ions as bivalent and "transmissive" aldehyde equivalents, the reaction has been used to colonize a biologically privileged but previously inaccessible area of chemical space and investigate the structure―activity relationships of arzanol towards a series of proinflammatory targets (mPGES-1, 5-LO).

The Biginelli dihydropyrimidine synthesis is one of the most important and oldest multicomponent reactions and has been extensively investigated in terms of application and mechanism. Surprisingly, little information is available on its discoverer, the Piedmontese chemist Pietro Biginelli, who also carried out the first studies on the purification and characterization of the (in)famous Gosio's gas. The reasons for the lack of a current biography on Biginelli can be traced back to his early demise from the research community. This, combined with the prematurity of bio-organometallic chemistry and the scarce popularity of pyrimidines before the discovery of their biological relevance, resulted in a paradoxical situation that led Biginelli to be remembered mostly for his administrative merits and career. By capitalizing on original documentation retrieved in archives or provided by his family, we present an account of the life of this forgotten chemist in the context of his contemporary chemical research.

Background and purpose: Phenolic compounds exert cytoprotective effects; our purpose was to investigate whether the isosteric polyphenolic compounds clovamide and rosmarinic acid are neuroprotective. Experimental approach: Three in vitro models of neuronal death were selected: (i) differentiated SH-SY5Y human neuroblastoma cells exposed to tert-butylhydroperoxide (t-BOOH), for oxidative stress; (ii) differentiated SK-N-BE(2) human neuroblastoma cells treated with L-glutamate, for excitotoxicity; and (iii) differentiated SH-SY5Y human neuroblastoma cells exposed to oxygen-glucose deprivation/reoxygenation, for ischaemia–reperfusion. Cell death was evaluated by lactate dehydrogenase measurements in the cell media, while the mechanisms underlying the effects by measuring: (i) t-BOOH-induced glutathione depletion and increase in lipoperoxidation; and (ii) L-glutamate-induced intracellular Ca2+ overload (fura-2 method) and inducible gene expression (c-fos, c-jun), by reverse transcriptase-PCR. The ability of compounds to modulate nuclear factor-κB and peroxisome proliferator-activated receptor-γ activation was evaluated by Western blot in SH-SY5Y cells not exposed to harmful stimuli. Key results: Both clovamide and rosmarinic acid (10–100 µmol·L−1) significantly protected neurons against insults with similar potencies and efficacies. The EC50 values were in the low micromolar range (0.9–3.7 µmol·L−1), while the maximal effects ranged from 40% to −60% protection from cell death over untreated control at 100 µmol·L−1. These effects are mediated by the prevention of oxidative stress, intracellular Ca2+ overload and c-fos expression. In addition, rosmarinic acids inhibited nuclear factor-κB translocation and increased peroxisome proliferator-activated receptor-γ expression in SH-SY5Y cells not exposed to harmful stimuli. Conclusion and implications: Clovamide and rosmarinic acid are neuroprotective compounds of potential use at the nutritional/pharmaceutical interface.

The replacement of amide and alkene groups in a biological setting with the 1,2,3-triazole group led to the discovery of compounds with a unique vanilloid/cannabinoid mixed profile. For example, the natural amides (see picture, above) and their triazole mimics (below) exhibit similar agonistic (X = H) or antagonistic (X = I) activity towards the TRPV1 receptor; however, only the triazole derivatives also show cannabinomimetic activity.

Phorboid 20-homovanillates modified on ring C to mimic the constitution and conformation of the ultrapotent vanilloid resiniferatoxin (RTX) and on the AB ring system to suppress the tumour-promoting potential of the terpenoid core were prepared. Several unexpected reactions were discovered, and the structure-activity relationships for this class of vanilloid ligands were expanded. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

The Biginelli dihydropyrimidine synthesis is one of the most important and oldest multicomponent reactions and has been extensively investigated in terms of application and mechanism. Surprisingly, little information is available on its discoverer, the Piedmontese chemist Pietro Biginelli, who also carried out the first studies on the purification and characterization of the (in)famous Gosio's gas. The reasons for the lack of a current biography on Biginelli can be traced back to his early demise from the research community. This, combined with the prematurity of bio-organometallic chemistry and the scarce popularity of pyrimidines before the discovery of their biological relevance, resulted in a paradoxical situation that led Biginelli to be remembered mostly for his administrative merits and career. By capitalizing on original documentation retrieved in archives or provided by his family, we present an account of the life of this forgotten chemist in the context of his contemporary chemical research.

The reaction of aldehydes with β-dicarbonyls and electron-rich aromatics was investigated to generate in a multicomponent fashion crossed adducts of biological relevance. 4-Hydroxycoumarin, triacetic acid lactone, indole, and a selection of aliphatic and aromatic aldehydes representative of various electronic and steric conditions were employed. The reaction showed a surprising dependence on the solvent, with 1:1 chloroform–water giving the best yield of heterodimeric adducts. The mechanistic rationale for the formation of hetero- rather than homodimeric adducts is discussed.

A mild and operationally simple method for the chemoselective esterification of phenolic alcohols is described. The reaction overcomes the tyranny of protection, and capitalizes on the activation of acyl halides with cerium(III) chloride to selectively esterify alcohol hydroxyls in the presence of phenolic ones. The generality of the reaction was demonstrated with a series of phenolic alcohols of dietary relevance (vanillol, hydroxytyrosol, epicatechin), providing an expeditious entry into a series of compounds of relevance for biomedical research, some of which previously available only by enzymatic methods.

The cover picture showsEuphorbia resinifera Berg and its constituent resiniferatoxin (RTX), a phorboid that acts as an ultrapotent biological analogue of capsaicin, the hot principle of chili pepper and the archetypal vanilloid. Ever since its isolation, interest within the organic community for phorbol has been high on account of its challenging structure, puzzling reactivity, and remarkable bioactivity. Diacyl derivatives of phorbol can act as ultrapotent analogues of the endolipid sn-1,2-diacylglycerol (DAG) and show powerful tumour-promoting properties. The more recent discovery that certain non-tumour-promoting phorbol derivatives and phorbol-related compounds can activate vanilloid receptors of the TRPV1 and TRPV4 type has made phorbol very interesting also for neurosciences. The article by G. Appendino et al. on p. 3413 ff. describes the synthesis of hybrid phorbol-resiniferatoxin of interest for the study of vanilloid receptors, which discloses some new and unpredictable aspects of the chemistry of phorbol. (Photo courtesy by Prof. Mauro Ballero, University of Cagliari)

Capsiate and its dihydroderivatives are the major capsaicinoids of sweet pepper. These new capsaicinoids do not activate the vanilloid receptor type 1 (VR1) but they share with capsaicin (CPS)some biological activities mediated in a VR1-independent fashion. In this study we show that CPS and nordihydrocapsiate (CPT) inhibit early and late events in T cell activation, including CD69, CD25 and ICAM-1 cell surface expression, progression to the S phase of the cell cycle and proliferation in response to TCR and CD28 co-engagement. Moreover, both CPS and CPT inhibit NF-kappaB activation in response to different agents including TNF-alpha. CPS itself does not affect the DNA-binding ability of NF-kappaB but it prevents IkappaB kinase activation and IkappaBalpha degradation in a dose-dependent manner, without inhibiting the activation of the mitogen-activated protein kinases, p38, extracellular regulated kinase and c-Jun N-terminal protein kinase. Moreover, intraperitoneal pretreatment with CPT prevented mice from lethal septic shock induced by lipopolysaccharide. In a second model of inflammation CPT pretreatment greatly reduced the extensive damage in the glandular epithelium observed in the bowel of DSS-treated mice. Taken together, these results suggest that CPT and related synthetic analogues target specific pathways involved in inflammation, and hold considerable potential for dietary health benefits as well as for pharmaceutical development.