Elsevier

Biochemical Pharmacology

Volume 76, Issue 11, 1 December 2008, Pages 1590-1611
Biochemical Pharmacology

Biological activities of curcumin and its analogues (Congeners) made by man and Mother Nature

https://doi.org/10.1016/j.bcp.2008.08.008Get rights and content

Abstract

Curcumin, a yellow pigment present in the Indian spice turmeric (associated with curry powder), has been linked with suppression of inflammation; angiogenesis; tumorigenesis; diabetes; diseases of the cardiovascular, pulmonary, and neurological systems, of skin, and of liver; loss of bone and muscle; depression; chronic fatigue; and neuropathic pain. The utility of curcumin is limited by its color, lack of water solubility, and relatively low in vivo bioavailability. Because of the multiple therapeutic activities attributed to curcumin, however, there is an intense search for a “super curcumin” without these problems. Multiple approaches are being sought to overcome these limitations. These include discovery of natural curcumin analogues from turmeric; discovery of natural curcumin analogues made by Mother Nature; synthesis of “man-made” curcumin analogues; reformulation of curcumin with various oils and with inhibitors of metabolism (e.g., piperine); development of liposomal and nanoparticle formulations of curcumin; conjugation of curcumin prodrugs; and linking curcumin with polyethylene glycol. Curcumin is a homodimer of feruloylmethane containing a methoxy group and a hydroxyl group, a heptadiene with two Michael acceptors, and an α,β-diketone. Structural homologues involving modification of all these groups are being considered. This review focuses on the status of all these approaches in generating a “super curcumin.”.

Introduction

Curcumin, commonly called diferuloyl methane, is a hydrophobic polyphenol derived from the rhizome (turmeric) of the herb Curcuma longa. Turmeric has been used traditionally for many ailments because of its wide spectrum of pharmacological activities. Curcumin has been identified as the active principle of turmeric; chemically, it is a bis-α, β-unsaturated β-diketone that exhibits keto-enol tautomerism. Curcumin has been shown to exhibit antioxidant, anti-inflammatory, antimicrobial, and anticarcinogenic activities. It also has hepatoprotective and nephroprotective activities, suppresses thrombosis, protects against myocardial infarction, and has hypoglycemic and antirheumatic properties. Moreover, curcumin has been shown in various animal models and human studies to be extremely safe even at very high doses [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]. In spite of its efficacy and safety, curcumin has not yet been approved as a therapeutic agent. The poor aqueous solubility, relatively low bioavailability, and intense staining color of curcumin have been highlighted as major problems; and consequently search for a “super curcumin” without these problems and with efficacy equal to or better than that of curcumin is ongoing. This review presents the current status of the efforts toward finding this “super curcumin.”

The strategies used in the search for “super curcumin” can be categorized under two broad headings, namely (1) synthetic analogues or derivatives and (2) formulations. The most explored of these two is the analogues and derivatives. The literature describes numerous synthetic curcumin analogues with a wide range of applications. This review analyzes the curcumin analogues with special reference to their biological activity. The formulation part of this review describes the adjuvant, nanoparticle, liposomal and micellar delivery systems, phospholipid complexes, prodrugs and PEGylation of curcumin.

Section snippets

Analogues and derivatives

Curcumin is a member of the linear diarylheptanoid class of natural products in which two oxy-substituted aryl moieties are linked together through a seven-carbon chain (Fig. 1). The C7 chain of linear diarylheptanoids is known to have unsaturation, oxo functions, enone moiety, and a 1,3-diketone group. Except for the oxo and hydroxy functions, the C7 chain is generally unsubstituted. This unsaturation in the linker unit has an E-configuration (trans Cdouble bondC bonds). The aryl rings may be

Formulations

Apart from the synthetic analogues, several other strategies have been evaluated to enhance the biological activity of curcumin. These strategies include adjuvants, nanoparticles, liposomes, micelles, and phospholipid complexes. The adjuvants were selected on the basis of their ability to prevent the rapid metabolism of curcumin by interfering with the enzymes that catalyze the metabolism of curcumin. All other formulations mentioned are designed primarily to increase absorption of curcumin

Conclusion

The fast growing research on curcumin, curcuminoids, and natural and synthetic curcumin analogues clearly confirms the versatility and flexibility of curcumin for structural modifications. However the actual role of different functionalities in curcumin in influencing its special physico-chemical properties and pleiotropic effects of natural and synthetic curcuminoids is far from understood. Such structure-activity studies are still rewarding and would definitely provide a proper basis for

Acknowledgments

Dr. Aggarwal is the Ransom Horne, Jr., Professor of Cancer Research. This work was supported by grants from the Clayton Foundation for Research. The authors thank Ms. Kathryn Hale for carefully reviewing this manuscript.

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