nificantly increase circulating levels of presumably active curcumin in rats.70 Another study conducted by Maiti et al., showed a 3-fold increase in aqueous solubility and a better hepatoprotective effect for a curcumin phospholipid complex compared to free curcumin. Curcumin–phospholipid complex significantly protected the liver from carbon tetrachloride induced acute liver damage in rats by restoring enzyme levels of liver glutathione system and that of superoxide dismutase, catalase and thiobarbituric acid reactive substances.38 Marczylo et al. explored whether formulation with phosphatidylcholine increases the oral bioavailability or affects the metabolite profile of curcumin in ViVo. Male Wistar rats received 340 mg/kg of either unformulated curcumin or curcumin formu- lated with phosphatidylcholine (Meriva) by oral gavage. Curcumin, the accompanying curcuminoids desmethoxycur- cumin and bisdesmethoxycurcumin, and the metabolites tetrahydrocurcumin, hexahydrocurcumin, curcumin glucu- ronide, and curcumin sulfate were identified in plasma, intestinal mucosa, and liver of rats which had received Meriva. Peak plasma levels for parent curcumin after administration of Meriva were 5-fold higher than the equivalent values seen after unformulated curcumin dosing. Similarly, liver levels of curcumin were higher after admin- istration of Meriva as compared to unformulated curcumin. In contrast, curcumin concentrations in the gastrointestinal mucosa after ingestion of Meriva were somewhat lower than those observed after administration of unformulated cur- cumin.39 These results suggest that curcumin formulated with phosphatidylcholine furnishes higher systemic levels of parent agent than unformulated curcumin. In an attempt to increase the aqueous solubility of hydrophobic drugs, Letch- ford et al., showed a 13 × 10 5 fold increase in curcumin solubility in a polymeric micellar formulation containing methoxy poly (ethylene glycol)-block-polycaprolactone diblock copolymers (MePEG-b-PCL).71 The enormous increase in solubility of curcumin in the above said micelle makes it a promising formulation to be explored further.
Ma, Z.; Shayeganpour, A.; Brocks, D. R.; Lavasanifar, A.; Samuel,
High-performance liquid chromatography analysis of curcumin in rat plasma: application to pharmacokinetics of polymeric micellar formulation of curcumin. Biomed. Chromatogr. 2007, 21 (5), 546–52.
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C4. Derivatives and Analogues. The chemical structure of curcumin plays a pivotal role in its biological activity. For example, isomerization has been proved to have an influence on antioxidant activity of curcumin.72 Thus, researchers hope to achieve improved biological activity of curcumin by structural modifications. Numerous studies dealing with the enhanced biological activity of curcumin derivatives and/or analogues can be found in the literature. A review by Mosley et al.,73 for example, systematically describes several studies dealing with the biological activity relationships of curcumin and its derivatives. A curcumin analogue designated EF-24 was reported to be a lead compound displaying increased antitumor action in Vitro and in ViVo in comparison to curcumin. Only one study reported the pharmacokinetics and bioavailability evaluation of a curcumin analog. In this study, the maximum tolerable dose following intravenous administration to male and female CD2F1 mice was 32 mg/kg of EF-24. EF-24 absorption was rapid after both oral and i.p. administration. The terminal elimination half-life and plasma clearance values for i.v. administration were reported to be 73.6 min and 0.482 L/min/ kg, respectively. Peak plasma concentrations of nearly 1000 nM were detected 3 min after the dose was given intraperi- tonially and the absorption and elimination half-life values were 177 and 219 min, respectively. The bioavailability of oral and i.p. EF-24 was 60% and 35%, respectively.74 A series of curcumin analogues including symmetrical 1,5- diarylpentadienone compounds whose aromatic rings possess two alkoxy substitutes were synthesized and screened for anticancer activity. New analogues that exhibit growth- suppressive activity 30 times that of curcumin and other commonly used anticancer drugs were identified in this study. Moreover, these analogues showed no in ViVo toxicities.75
Another strategy to improve the biological activity of curcumin was to chelate it with metals. The presence of two phenolic groups and one active methelene group in a curcumin molecule makes it an excellent ligand for any chelation. Several metal chelates of curcumin are reported to possess biological activity over that of free curcumin. John et al. studied the antitumor activities of curcumin, pipero- nylcurcumin, 2-hydroxynaphthylcurcumin, cinnamylcur- cumin, and their copper complexes. Copper complexes of curcumin and its derivatives were found to be better antitumor agents than were the parent compounds.76 Studies by Sui et al. showed that the modest activity of curcumin as an in Vitro inhibitor of HIV-1and HIV-2 proteases is enhanced more than 10-fold when curcumin is complexed with boron. The curcumin boron complexes were observed
Shen, L.; Ji, H. F. Theoretical study on physicochemical properties of curcumin. Spectrochim. Acta A Mol. Biomol. Spectrosc. 2007, 67 (3–4), 619–23.
Mosley, C. A.; Liotta, D. C.; Snyder, J. P. Highly active anticancer curcumin analogues. AdV. Exp. Med. Biol. 2007, 595:, 77–103.
Preetha, A.; Banerjee, R.; Huilgol, N. Tensiometric profiles and their modulation by cholesterol: implications in cervical cancer. Cancer InVest. 2007, 25 (3), 172–81.