Curcumin has been shown to have other activities that suggest potential clinical applications, as follows:

• Curcumin was found to be a potent and selective inhibitor of HIV-1 long terminal repeat-directed gene expression, which governs the transcription of HIV-1 provirus.

• Curcumin has been shown to prevent cataractogenesis in an in vitro rat model.

• Treatment with curcumin prevented experimental alcoholic liver disease.

• Curcumin has a protective effect on cyclophosphamide-induced early lung injury.

• Chemotherapy-induced nephrotoxicity can be prevented with curcumin [13].

7.6 Structure Activity Relationship of Curcumin

To elucidate which portion of the molecule is critical for the activity, a large number of structural analogs of curcumin have been synthesized. Some analogues are more active than native curcumin, while others are less active [82]. It was found that the phenolic analogues were more active than the nonphenolic analogues [83]. The highest antioxidant activity was obtained when the phenolic group was steri-cally hindered by the introduction of two methyl groups at the ortho position. The phenolic group is essential for the free-radical scavenging activity, and the presence of the methoxy group further increases the activity [84]. Curcumin shows both antioxidant and pro-oxidant effects. Ahsan et al. have shown that both these effects are determined by the same structural moieties of the curcuminoids [85]. Dinkova-Kostova showed that the presence of hydroxyl groups at the ortho position on the aromatic rings and that beta-diketone functionality was required for high potency in inducing Phase 2 detoxification enzymes [86]. Curcumin is a noncompetitive inhibitor of rat liver microsomal delta 5 desaturase and delta 6 desaturase. Kawashima et al. [87] have shown that only half the structure is essential for the desaturase inhibition. A 3-hydroxy group of the aromatic ring is essential for the inhibition and a free carboxyl group at the end opposite to the aromatic ring interferes with the inhibitory effect. Simon et al. found that the presence of the diketone moiety in the curcumin molecule seems to be essential for its ability to inhibit the proliferation of MCF-7 human breast tumor cells [49]. The aromatic enone and dienone analogs of curcumin have been demonstrated to have potent antiangiogenic property in an in vitro SVR assay [88].

7.7 Conclusions

The medicinal properties of curcumin have been known for centuries, although the scientific basis of its actions has been investigated only over the last couple of decades. Curcumin has been shown to target numerous molecules inside the cell that are known to modulate several signaling pathways. Curcumin is a potent antiox-idant, anti-inflammatory, and anticancer agent and has therapeutic efficacy in numerous diseases. Despite its proven safety over the ages, its efficacy has been limited by its poor solubility, and poor bioavailability. Several analogs of curcumin have been designed to overcome these limitations. Some of these analogs have yielded promising results in in vitro and animal studies, but whether these more bioavailable forms are equally safe is still unknown. Therefore, it is important to evaluate the curcumin analogs for bioavailability and clinical efficacy.

Acknowledgements This work was supported by the Clayton Foundation for Research and a PO1 grant (CA91844) from the National Institutes of Health on lung cancer chemoprevention to BBA.


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