Study On Design, Synthesis Of Curcumin Analogues, And Their Inhibition Of ALDH1and Anticancer Activity

The aldehyde dehydrogenasel (ALDH1) family plays an important role in the detoxification of peroxidic aldehydes, which catalyzes the oxidation of aliphatic and aromatic aldehydes to the corresponding carboxylic acids in the presence of NAD+or NADP+as cofactor and mainly present in the cytoplasm of various tissues and the minority distributed in mitochondria. The majority of literatures have reported that ALDH1plays an important role in identifying, diagnosing, isolating and treating cancer stem cells and the prognosticating the resistance of cancer tumor cells. Curcumin is an effective natural ingredients in Curcuma longa L, there are a lot of literatures suggest that curcumin possess antioxidant, anti-inflammatory, anti-viral, anti-bacterial, anti-fungal and anti-cancer effects. Our research group previously reported that curcumin and its analogues synthesized in our laboratory possessed potent inhibitory activities on PC-3, H1299, and HT-29cells, which have high expression of ALDH1.This thesis studied the inhibition of ALDH1and the anti-tumor activity of curcumin and its analogues. It includes as follows:(1) By screening the inhibition of curcumin and its analogues against ALDH1, the result suggested that compound6had the strongest inhibitory activity with IC503.41μmol/L. Compared to the positive control Disulfide (IC502.91μmol/L) in the same order of magnitude, and the inhibitory activity of compound6is about10-fold higher than that of curcumin (IC5036.9μmol/L).(2) Based on the inhibition data of curcumin and curcumin analogues to ALDH1, the model parameters of CoMFA and CoMSIA as follows: q2is0.597and0.56, respectively. N (optimal number of principal components) is8and6, respectively. r2(non cross-validated correlation coefficient) is0.998and0.987, respectively. The3D-QSAR model showed a good stability and predictability, which hinted that it is helpful to enhance the inhibitory activity while increase the hydrogen bond acceptor and electron withdrawing substituent of phenyl ring, and increase hydrogen bond donor and structure of glutaric enone precursor structure. Using this3D-QSAR model,20novel curcumin analogues were designed, synthesized, and characterized by means of1HNMR spectrum and mass spectrum. (3) All the synthesized curcumin analogues were evaluated for their effects on the proliferation of prostate cancer PC-3cells, colon cancer HT-29cells and lung cancer H1299cells. Inhibitory effects of these compounds on the proliferation of PC-3, HT-29and H1299cells were determined by the MTT assay. The IC50for these compounds was less than2μM in the proliferation of the three cancer cell lines. Compound a2, a4, b2, b4, b7and c4were10-90fold more active than curcumin for inhibiting the proliferation of PC-3, HT-29and H1299cells, respectively.