Abstract��OBJECTIVE To design and synthesize a series of oleanolic acid analogs posessing anti-tumor activity based on survivin target. METHODS Using the techniques of computer-aided drug design, the docking of Survivin and known active small molecules was simulated and then the key amino acid residue fragment of the target protein was analyzed. It led to the discovery of active groups capable of binding to the critical sites. Through using the natural product, oleanolic acid, as a lead compound, the active groups were introduced onto its A-ring, and the carboxyl group at the C-28 position was modified using amidation. SGC-7901 and A549 cells were used to screen the antitumor activity in vitro through the standard MTT method. RESULTS Ten new oleanolic acid derivatives were designed and synthesized,and their structures were confirmed by MS and NMR. The compounds ��5 and ��5 exhibited more potent cytotoxicity than the positive control drugs. CONCLUSION The novel oleanolic acid analogues have better antitumor activity than the parent compound, which are worthy of further study.
����, ��ТТ, ��ٻ��, ������. ����Survivin�е����չ���������ϳɼ���������о�[J]. �й�ҩѧ��־, 2018, 53(17): 1438-1446.
KUAI Zhen-yu, LI Xiao-xiao, LI Qian-wen, MENG Yan-qiu. Synthesis and Biological Evaluation of Oleanolic Acid Analogs Based on Survivin Target. Chinese Pharmaceutical Journal, 2018, 53(17): 1438-1446.
LI Y L, FENG W, CHEN H Y, et al. Study on pharmacological action of oleanolic acid. Biotechworld(���＼������), 2015, (4):125-127.
[2]
WAN X L, XIE X L, LIU J, et al. Hepatoprotective effect of oleanolic acid on D-galactosamine-induced acute liver injury in the mice. West China J Pharm Sci(����ҩѧ��־), 2016, 31(1):26-29.
[3]
WU L L, ZHOU E X, ZHAO R D, et al. A survey of oleanolic acid in malignant tumors. Translat Med J(ת��ҽѧ��־), 2015, 4(2):115-117.
[4]
ZHANG M F, SHEN Y Q. Research advances in pharmacological effects of oleanolic acid in hypoglycemia and antidiabetic complications. Anti Infect Pharm, 2015, 12(6):801-806.
[5]
HUANG K S, ZHU L L, LIU D, et al. Effects of oleanolic acid on proliferation and apoptosis of human hepatom a cell line Hep3B. J Third Mil Med Univ(������ҽ��ѧѧ��), 2011, 33(5):531-534.
[6]
MENG Y Q, FENG C Q, ZHANG L F, et al. Synthesis and anti-tumor activity of oleanolic acid derivatives. Acta Pharm Sin(ҩѧѧ��),2015, 50(4):469-474.
[7]
MENG Y Q, ZHANG L F, LIU D Y, et al. Synthesis and antitumor activity evaluation of novel ursolic acid derivatives. J Asian Nat Prod Res(������Ȼ�����о�), 2016, 18(3):280-288.
[8]
MENG Y Q, LIU D, BAI Z W, et al. Synthesis and anti-tumor activity of ursolic acid derivatives. Acta Pharm Sin(ҩѧѧ��), 2011, 46(5):556-560.
[9]
MENG Y Q, ZHANG W C, NING Z T, et al. Synthesis and anti-tumor activity of novel asiatic acid Aring-cleavage derivatives in vitro. Chin J New Drugs(�й���ҩ��־), 2017,26(10):1157-1162.
[10]
MENG Y Q, ZHAO Y W, KUAI Z Y, et al. Synthesis and antitumor activity evaluation of novel oleanolic acid derivatives. J Asian Nat Prod Res(������Ȼ�����о�),2017, 31(6):1000-1010.
[11]
MENG Y Q, XING W, KUAI Z Y, et al. Synthesis and anti-tumor activities of ring a derived analogues of oleanolic acid. Chin J Org Chem(�л���ѧ), 2017, 37(6):1417-1425.
[12]
COUMAR M S, TSAI F Y, KANWAR J R, et al. Treat cancers by targeting survivin:just a dream or future reality?. Cancer Treat Rev, 2013, 39(7):802-811.
[13]
MAHAL K, BIERSACK B, SCHOBERT R. New oxazole-bridged combretastatin A-4 analogues as potential vascular-disrupting agents. Int J Clin Pharmacol Ther, 2013, 51(1):41-43.
[14]
WEI J, LIU H, LIU M, et al. Oleanolic acid potentiates the antitumor activity of 5-fluorouracil in pancreatic cancer cells. Oncol Rep, 2012, 28(4):1339-1345.
[15]
LUCIO K A, ROCHA GDA G, MONÇÃO-RIBEIRO L C, et al. Oleanolic acid initiates apoptosis in non-small cell lung cancer cell lines and reduces metastasis of a B16F10 melanoma model in vivo. PLoS One, 2011, 6(12):65-65.
[16]
PENNATI M, SBARRA S, DE CESARE M, et al. YM155 sensitizes triple-negative breast cancer to membrane-bound TRAIL through p38 MAPK-and CHOP-mediated DR5 upregulation. Int J Cancer, 2015, 36(2):299-309.
[17]
KUDCHADKAR R, ERNST S, CHMIELOWSKI B, et al. A phase 2, multicenter, open-label study of sepantronium bromide (YM155) plus docetaxel in patients with stage III (unresectable) or stage IV melanoma. Cancer Med, 2015, 4(5):643-650.
[18]
XU S, ADISETIYO H, TAMURA S, et al. Dual inhibition of survivin and MAOA synergistically impairs growth of PTEN-negative prostate cancer. Br J Cancer, 2015, 113(2):1-10.
2018, Vol. 53 
