莽草酸衍生物的合成及其对紫杉醇耐药人乳腺癌细胞的逆转作用研究

OBJECTIVE：To structurally modify shikimic acid，and to investigate the reversal effects of its derivatives on paclitaxel-resistant human breast cancer cells MCF-7/PTX. METHODS：Using shikimic acid as the lead structure，1-position carboxyl group was structurally modified to synthesize a series of shikimic acid derivatives through esterification，amidation，hydrogenation and reduction，etc. Using non-drug resistant cells MCF-7 as reference，MTT assay was used to screen derivatives with inhibitory activity as well as half-inhibitory concentration（IC50）and reversal index（RI）of derivatives to MCF-7/PTX. With the drug resistance-related transgelin 2 as the target，the molecular docking of the active derivatives with the drug resistance-related protein was carried out by using Glide 1.0 computer-aided design software. RESULTS：Totally 15 derivatives were obtained（T1-T15），of which T4-T15 were obtained for the first time. MTT assay showed that （3R， 4S， 5R） -N-benzyl-3， 4，5-trihydroxy-1-cyclohexene-1-formamide （T7），（3R，4S，5R）-N-（3，4，5-trihydroxy-1-cyclohexenylmethyl）-benzylamine （T14），（3R，4S，5R）-3，4-O-isopropyl-5-O-acetyl-1-cyclohexene-1-methyl formate （T15） inhibited MCF-7 and MCF-7/PTX cells to a certain extent；IC50 values of T7，T14 and T15 combined with pacliaxel to MCF-7/PTX cells were significantly lower than that in negative control（Paclitaxel alone）group（P＜0.05）. RIs of T14 and T15 were higher，and RIs of the highest dose were 8.8 and 9.3，which were equivalent to positive control verapamil（10.8）. The results of molecular docking showed that the hydroxyl groups at positions 3，4 of T7 could form multiple hydrogen bonds with Arg625 and Asp627 in the catalytic region of transgelin 2. In addition to the hydrogen bond mentioned above at T7，the secondary amine side chain at position 1 of T14 could also form hydrogen bond with Glu657 of transgelin 2. When the hydroxyl group on the T15 mother nucleus was derived from the donor group，the binding of the hydroxyl group to transgelin 2 was closer and the inhibition was enhanced. CONCLUSIONS：The derivatives T7，T14 and T15 have certain reverse activity to paclitaxel-resistant human breast cancer cells. The polyhydroxy structure of the mother nucleus is the main structural region of the hydrogen bond between shikimic acid and its derivatives and transgelin 2. The derivation of its power supply group or the introduction of secondary amines and hydrophobic groups into the 1-carboxyl group of shikimic acid is benifit for enhancing the drug resistance reversal effect of derivative.