Abstract
Curcumin is a natural product with several thousand years of heritage. Its traditional Asian application to human ailments has been subjected in recent decades to worldwide pharmacological, biochemical and clinical investigations. Curcumin’s Achilles heel lies in its poor aqueous solubility and rapid degradation at pH ~ 7.4. Researchers have sought to unlock curcumin’s assets by chemical manipulation. One class of molecules under scrutiny are the monocarbonyl analogs of curcumin (MACs). A thousand plus such agents have been created and tested primarily against cancer and inflammation. The outcome is clear. In vitro, MACs furnish a 10–20 fold potency gain vs. curcumin for numerous cancer cell lines and cellular proteins. Similarly, MACs have successfully demonstrated better pharmacokinetic (PK) profiles in mice and greater tumor regression in cancer xenografts in vivo than curcumin. The compounds reveal limited toxicity as measured by murine weight gain and histopathological assessment. To our knowledge, MAC members have not yet been monitored in larger animals or humans. However, Phase 1 clinical trials are certainly on the horizon. The present review focuses on the large and evolving body of work in cancer and inflammation, but also covers MAC structural diversity and early discovery for treatment of bacteria, tuberculosis, Alzheimer’s disease and malaria.
Highlights
Curcumin (1, diferuloylmethane, Figure 1) is an ancient and tantalizing molecule characterized by nicknames such as Indian Saffron, The Spice of Life and Indian Solid Gold
A host of monocarbonyl analogs of curcumin (MACs) has shown potent anti-tumorigenic activity when tested by in vitro and in vivo models spanning a wide range of cancers and inflammatory conditions
Four other features have surfaced as advantageous elements for overall improved activity: (1) A doubly conjugated carbonyl is generally more potent than a single enone; (2) Double or triple methoxy substitution on the terminal aromatic rings, often accompanied by an aromatic OH group, frequently provides increased activity; (3) Terminal pyridine rings furnish both superior potency and solubility; (4) A piperidone ring at the center of a MAC imparts solubility, and creates the opportunity to append extensions through an amide-like linker with additional beneficial properties
Summary
Curcumin (1, diferuloylmethane, Figure 1) is an ancient and tantalizing molecule characterized by nicknames such as Indian Saffron, The Spice of Life and Indian Solid Gold. The extended list includes protection for heart ailments, arthritis, wound healing, depression and Alzheimer’s disease among many others It is not surprising, that considerable health care research has been devoted to testing the efficacy of curcumin as a pure agent, in various formulations and in combination with other proven drugs. Influential structural modifications of curcumin that improve stability and solubility involve elimination of the hydrolysis-prone keto-enol functionality in 1–3 [5,6,7,8] and incorporate a range of alternative substituents on the terminal phenyl rings Two such replacements involve dialkyl substitution of the hydrogens on the carbon between the two carbonyl groups in the diketo tautomer (the FLLL family, 4, Figure 2) [9] or installation of a single carbonyl group either as an acyclic agent or embedded in a small ring (the MAC family) (5, Figure 2). Several excellent reviews detailing the diversity, applications and biological foundations of MACs for utility in human disease have appeared in the recent past [10,22,27,28,29,30,31,32]
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