A Multicomponent Carba‐Betti Strategy to Alkylidene Heterodimers – Total Synthesis and Structure–Activity Relationships of Arzanol

Abstract

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).

NMR screening approach for discovery of new 6-methylpyridinone derivatives from the marine-derived fungus Leptosphaerulina sp.

“…Its NMR data were identical to the reference value (Minassi et al, 2012). The single crystals of 6 were obtained from the EtOAc solution.…”

Bioactive Phloroglucinyl Heterodimers: The Tautomeric and Rotameric Equlibria of Arzanol

“…Calculated vs. experimental [6] data are summarized in Figure 4. Calculated vs. experimental [6] data are summarized in Figure 4.…”

“…[4] The structure elucidation of these compounds is complicated by a combination of tautomeric and rotational equilibria that make the interpretation of the NMR spectra difficult without derivatization by intramolecular cyclization or silylation. [4,5] Arzanol interrupts proinflammatory signals and increases antioxidant protection by acting at distinct time-domain targets, with pro-inflammatory enzymes (5LO, mPGES-1) and pro-inflammatory transcription factors (NF-kB) being its major short-and long-time do-tive 4, and its corresponding homodimers [helipyrone (5) and demethylmallotojaponin C (6)]. Our interest in these compounds was piqued by the biological profile of arzanol (1), a phloroglucinyl pyrone that represents the major anti-inflammatory constituent of everlasting (Helichrysum italicum L.).…”

“…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. [6] The definition of an arzanol chemotype is complicated by the same factors that plague the analysis of the NMR spectra, namely the presence of tautomeric and rotational equilibria. Interestingly, this conformational bias was associated with a marked decrease of bioactivity.…”

Arzanol, a Potent mPGES‐1 Inhibitor: Novel Anti‐Inflammatory Agent

“…Minassi et al [21] focussed on the alkylidene linker and pyrone moiety to find out structure activity relationship of arzanol (Figure 4). The pharmacological activity of derivatives of arzanol was assayed using inhibitory potency towards mPGES-1 and 5-LOX.

In a compound (vii a ) replacement of CH 3 to H at R 2 and R 3 position from pyrone ring does not affect the biological activity.

Addition of methyl group at R 1 on alkylidene linker (vii b and vii c ) slightly decreased the activity against mPGES-1 and 5-LOX.

n-Hexyl residue attached to R 1 (vii d and vii e ) to analyse the effect of elongated alkyl group leads to beneficial effect.

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