(Curcuma

longa Curcumin,

the

yellow

diarylheptanoid

of

turmeric

L.),

is 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione. Its structure can be read in three parts: two guaiacol rings, two trans alkene bridges, and a central β-diketone that exists in solution almost entirely as the hydrogen-bonded keto-enol tautomer (Payton et al., 2007). Each part contributes to the long list of activities reported for the compound in cell culture, and each is also a point of weakness (Priyadarsini, 2014).

The gap between that list of activities and clinical usefulness has been recognised for a long time. Early clinical pharmacology found very low concentrations of the parent compound in plasma after oral doses measured in grams (Sharma et al., 2005), and an influential review attributed the problem to poor absorption, rapid metabolism and rapid elimination acting together (Anand et al., 2007). Two responses followed. One was formulation: phospholipid complexes, nanoparticles, micelles and co-administration with inhibitors of conjugation. The other, the subject of this review, was to change the molecule.

The literature on synthetic curcumin analogues is now very large, and several surveys have catalogued it by biological activity (Anand et al., 2008). This article takes a narrower view. It asks which structural changes have made the scaffold more stable, by what mechanism, and what happened to activity when they were made.

This is a narrative review of the medicinal chemistry literature published from roughly the mid-2000s onward, with earlier papers on degradation and metabolism included where they explain the design logic. It is organised by the site of modification, not by disease area. Stability is taken in two senses that the literature often runs together: chemical stability in aqueous media at physiological pH, and metabolic stability towards reduction and conjugation. Formulation approaches are outside the scope. No claim of exhaustive coverage is made, and potency values from individual papers are not tabulated, because they were obtained in different cell lines and assay formats and cannot be compared across laboratories.

Design for stability presupposes an account of instability. Three processes are well documented, and they act on different parts of the molecule.

The modifications that have been tried fall naturally into three groups according to the part of the scaffold they change, as Figure 1 shows. The groups are not exclusive, and the most studied compounds combine changes at two sites.

Four trends appear repeatedly across independent series. First, the β-diketone is dispensable for cytotoxic and anti-inflammatory activity in cell assays: both the monocarbonyl dienones and the heterocyclic analogues retain or exceed the potency of curcumin. Second, at least one α,β-unsaturated carbonyl is required for most of the cell-based activities; analogues in which the alkenes are saturated are consistently weaker in those assays. Third, a free phenol is not necessary for cytotoxic potency, though it is necessary for direct radical-scavenging activity. Fourth, electron-withdrawing substituents on the aryl rings of monocarbonyl analogues tend to raise potency, in line with a mechanism involving conjugate addition of cellular thiols to the enone (Adams et al., 2004; Mosley et al., 2007).

Taken at face value these trends describe a pharmacophore that is essentially a bis-aryl enone. That conclusion is chemically coherent and has been reached by several groups, but it also raises the central difficulty of the field.

The feature that most analogue series preserve, a doubly activated Michael acceptor, is the feature that makes the compounds react with glutathione and with cysteine residues across many proteins. Potency that rises with electrophilicity is as likely to reflect indiscriminate covalent reactivity as selective target engagement. Curcumin itself matches several of the substructure patterns that Baell and Holloway (2010) identified as characteristic of pan-assay interference compounds, and a detailed critical review described it as unstable, reactive and not a viable lead, noting in addition that it aggregates, fluoresces and chelates metals in ways that distort assay readouts (Nelson et al., 2017).

Stabilised analogues answer the first of those charges and not necessarily the others. A monocarbonyl dienone that persists for hours in phosphate buffer may still be consumed in minutes by thiols in a cell or in plasma, and persistence in buffer has too often been reported as though it settled the question of metabolic fate. Few papers measure reactivity towards glutathione, stability in liver microsomes or hepatocytes, and plasma protein binding alongside potency. Fewer still identify the metabolites of the analogue, as was done for dimethoxycurcumin (Tamvakopoulos et al., 2007). A further complication is that the degradation products of curcumin are themselves biologically active, and some of the effects attributed to the parent in long cell incubations may belong to its oxidation products (Gordon et al., 2015). An analogue that cannot autoxidise may therefore lack an activity for reasons that have nothing to do with target affinity.

Three gaps stand out. The first is measurement. Stability should be reported under stated and comparable conditions, covering buffer, plasma and a metabolically competent system, with curcumin run alongside as a reference and with thiol reactivity determined explicitly. The second is selectivity. Claims of target engagement for enone-containing analogues need support from orthogonal assays, from counter-screens for aggregation and interference, and where possible from analogues in which the electrophile is removed while the shape is kept. The third is translation: very few analogues have progressed to rigorous pharmacokinetic and toxicological evaluation in animals, and none has become an approved medicine, so the clinical value of the whole approach is unproven.

There is also a case for asking a different question. If the reproducible activities of the scaffold reduce to those of a tunable electrophile, then the more promising route may be to design that reactivity deliberately, with a defined target and a reversible or weakly reactive warhead, and to treat the natural product as a starting point of historical interest.

Two decades of analogue work have shown convincingly how to make the curcumin scaffold last longer. Removing the active methylene and the enol, by deleting a carbonyl or by building the diketone into a heterocycle, suppresses the autoxidation and cleavage that destroy the parent at physiological pH, and masking the phenol slows conjugation. The associated structure activity trends are consistent between laboratories. What the work has not yet shown is that a stabilised analogue is a selective and well-behaved drug candidate. The field's next advances are more likely to come from stricter characterisation of the compounds already in hand than from further additions to an already long list.

To be declared by the author(s) before publication.

To be declared by the author(s) before publication.