Pharmaceutical Technology (International) Program, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand.
Molecules. 2011 Feb 22;16(2):1888-900. doi: 10.3390/molecules16021888.
A novel series of succinyl derivatives of three curcuminoids were synthesized as potential prodrugs. Symmetrical (curcumin and bisdesmethoxycurcumin) and unsymmetrical (desmethoxycurcumin) curcuminoids were prepared through aldol condensation of 2,4-pentanedione with different benzaldehydes. Esterification of these compounds with a methyl or ethyl ester of succinyl chloride gave the corresponding succinate prodrugs in excellent yields. Anticolon cancer activity of the compounds was evaluated using Caco-2 cells. The succinate prodrugs had IC₅₀ values in the 1.8-9.6 μM range, compared to IC₅₀ values of 3.3-4.9 μM for the parent compounds. Curcumin diethyl disuccinate exhibited the highest potency and was chosen for stability studies. Hydrolysis of this compound in phosphate buffer at pH 7.4 and in human plasma followed pseudo first-order kinetics. In phosphate buffer, the k(obs) and t(½) for hydrolysis indicated that the compound was much more stable than curcumin. In human plasma, this compound was able to release curcumin, therefore our results suggest that succinate prodrugs of curcuminoids are stable in phosphate buffer, release the parent curcumin derivatives readily in human plasma, and show anti-colon cancer activity.
合成了一系列新型的姜黄素的琥珀酰衍生物作为潜在的前药。通过 2,4-戊二酮与不同苯甲醛的醛缩合反应制备对称（姜黄素和双脱甲氧基姜黄素）和非对称（脱甲氧基姜黄素）姜黄素。这些化合物与琥珀酰氯的甲酯或乙酯进行酯化反应，以优异的收率得到相应的琥珀酸前药。使用 Caco-2 细胞评估了化合物的抗结肠癌活性。琥珀酸前药的 IC₅₀ 值在 1.8-9.6 μM 范围内，而母体化合物的 IC₅₀ 值在 3.3-4.9 μM 范围内。姜黄素二乙酯二琥珀酸显示出最高的效力，因此选择其进行稳定性研究。该化合物在 pH 7.4 的磷酸盐缓冲液和人血浆中的水解遵循拟一级动力学。在磷酸盐缓冲液中，水解的 k(obs)和 t(½)表明该化合物比姜黄素稳定得多。在人血浆中，该化合物能够释放出姜黄素，因此我们的结果表明，姜黄素衍生物的琥珀酸前药在磷酸盐缓冲液中稳定，在人血浆中容易释放出母体姜黄素衍生物，并具有抗结肠癌活性。
