title: Dissecting the pharmacophore of curcumin. Which structural element is critical for which action?
abstract: The dietary phenolic curcumin (1a) is the archetypal network pharmacological agent, but is characterized by an ill-defined pharmacophore. Nevertheless, structure-activity studies of 1a have mainly focused on a single biological end-point and on a single structural element, the aliphatic bis-enoyl moiety. The comparative investigation of more than one end-point of curcumin and the modification of its aromatic region have been largely overlooked. To address these issues, we have investigated the effect of aromatic C-prenylation in the three archetypal structural types of curcuminoids, namely, curcumin itself (1a), its truncated analogue 2a (C5-curcumin), and (as the reduced isoamyl version) the tetrahydro derivative 3a, comparatively evaluating reactivity with thiols and activity in biochemical (inhibition of NF-κB, HIV-1-Tat transactivation, Nrf2 activation) and phenotypic (anti-HIV action) assays sensitive, to a various extent, to thia-Michael addition. Prenylation, a validated maneuver for bioactivity modulation in plant phenolics, had no effect on Michael reactivity, but was detrimental for all biological end-points investigated, dissecting thiol trapping from activity, while hydrogenation attenuated, but did not completely abrogate, the activity of 1a. The C5-curcuminoid 2a outperformed the natural product in all end-points investigated and was identified as a novel high-potency anti-HIV lead in a cellular model of HIV infection. Taken together, these observations show that Michael reactivity is a critical element of the curcumin pharmacophore, but also reveal a surprising sensitivity of bioactivity to C-prenylation of the vanillyl moiety.
authors.affiliation: Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Via Bovio 6, 28100, Novara, Italy. minassi@pharm.unipmn.it
authors.forename: Alberto
authors.initials: A
authors.lastname: Minassi
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Sánchez-Duffhues
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Collado
authors.forename: Eduardo
authors.initials: E
authors.lastname: Muñoz
authors.forename: Giovanni
authors.initials: G
authors.lastname: Appendino
mesh_terms: D003474:Curcumin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D015394:Molecular Structure; D016328:NF-kappa B; D013329:Structure-Activity Relationship
chemical_list: D016328:NF-kappa B; D003474:Curcumin