Synthesis and preliminary evaluation of water-soluble curcumins as anticancer agents Free

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Phytochemicals play a major role in the design and development of different types of pharmaceuticals. Curcumin (CCMN) is the major yellow pigment isolated from the dried rhizome of the perennial herb Curcuma Longa. CCMN has apoptosis-inducing effects and inhibitory activities against protein kinase C and epidermal growth factor receptor tyrosine kinase. Furthermore, cytotoxic activity against some cancer cell lines of human origin has been reported for this compound. Accordingly, CCMN may be considered a potential candidate molecule for the development of anticancer drugs.

A serious shortcoming of CCMN, however, is the low aqueous solubility, which lowers the bioavailability and hinders the development of a clinically applicable formulation of this otherwise promising agent. In an attempt to overcome these deficiencies, we have synthesized novel water-soluble CCMN conjugates* using the highly soluble and biocompatible polymer poly(ethylene glycol) (PEG). Thus, commercially available CCMN was covalently conjugated to PEGs with high (H) and low (L) molecular weights (MWs) and through chemically different linker molecules.

All conjugates were highly water-soluble yielding a clear bright yellow solution. Analysis of the timing of drug release under physiological conditions was performed using HPLC chromatography. The HMW CCMNPEG released the CCMN nucleus with a half-life (t_1/2) of 54 min whereas the LMW conjugate showed a longer t_1/2 of 3.5 h. In high-purity (18 MΩ) water, the HPLC pattern of the LMW conjugate was unchanged for over 24 days at room temperature. To evaluate the cytotoxic activity, the conjugates were screened against two different human cancer cell lines. Different concentrations of CCMN, HMW CCMNPEG, and LMW CCMNPEG, were incubated with either LS-174T human colorectal, or PC-3 human prostate carcinoma cell lines. In all cases, the conjugates showed higher cytotoxicity than the free drug with the LMW CCMNPEG showing the greatest activity. The cytotoxic activities in the form of IC₅₀ (uM) were CCMN: 8.9 (LS-174T) and 12.3 (PC-3); LMW CCMNPEG: 4.7 (LS-174T) and 5.4 (PC-3). Furthermore, it was demonstrated that the conjugate activity was linker-specific since a differently linked HMW conjugate lacked any significant activity. These results demonstrate that specially designed CCMNPEG conjugates were highly water-soluble with extended solution stability, had enhanced cytotoxicity as compared to the unconjugated drug, and therefore, are potential candidates for in vivo studies.

*US/International patents pending.