Synthesis of novel ursolic acid heterocyclic derivatives with improved abilities of antiproliferation and induction of p53, p21waf1 and NOXA in pancreatic cancer cells

被引：58

作者：

Leal, Ana S. ^{[1
,2
,3
]}

Wang, Rui ^{[3
]}

Salvador, Jorge A. R. ^{[1
,2
]}

Jing, Yongkui ^{[3
]}

机构：

[1] Univ Coimbra, Quim Farmaceut Lab, Fac Farm, P-3000548 Coimbra, Portugal

[2] Univ Coimbra, CNC Ctr Neurociencias & Biol Celular, P-3000517 Coimbra, Portugal

[3] Mt Sinai Sch Med, Tisch Canc Inst, Div Hematol Oncol, New York, NY 10029 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2012年 / 20卷 / 19期

关键词：

Ursolic acid; Heterocyclic derivatives; Antiproliferative; p53; NOXA; OLEANOLIC ACID; INHIBITION; APOPTOSIS; PROLIFERATION; ACTIVATION; PATHWAY; GROWTH;

D O I：

10.1016/j.bmc.2012.08.010

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A series of new heterocyclic derivatives of ursolic acid 1 were synthesized and evaluated for their anti-proliferative activity against AsPC-1 pancreatic cancer cells. Compounds 24-32, with an alpha,beta unsaturated ketone in conjugation with an heterocyclic ring in ring A have improved antiproliferative activities. Compound 32 is the most active compound with an IC50 of 1.9 mu M which is sevenfold more active than ursolic acid 1. Compound 32 arrests cell cycle in G1 phase and induces apoptosis in AsPC-1 cells with upregulation of p53, p21(waf1) and NOXA protein levels. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：5774 / 5786

页数：13

共 50 条

[41] Prognostic significance of p53 and p21waf1/cip1 immunoreactivity in epithelial cancers of the ovary
Werness, BA
Freedman, AN
Piver, MS
Romero-Gutierrez, M
Petrow, E
GYNECOLOGIC ONCOLOGY, 1999, 75 (03) : 413 - 418
[42] TNF-α induced p21WAF1 but not Bax in colon cancer cells WiDr with mutated p53:: Important role of protein stabilization
Kobayashi, N
Takada, Y
Hachiya, M
Ando, K
Nakajima, N
Akashi, M
CYTOKINE, 2000, 12 (12) : 1745 - 1754
[43] Importance of p53, bcl-2, p21WAF1 and PCNA positivities in renal angiomyolipomas
Budak, Metin
Yalcin, Omer
Usta, Ufuk
Tokuc, Burcu
BIOMEDICAL RESEARCH-INDIA, 2017, 28 (10): : 4696 - 4702
[44] HCT116 cells deficient in p21Waf1 are hypersensitive to tyrosine kinase inhibitors and adriamycin through a mechanism unrelated to p21 and dependent on p53
Ferrandiz, Nuria
Martin-Perez, Jorge
Blanco, Rosa
Donertas, Derya
Weber, Axel
Eilers, Martin
Dotto, Paolo
Dolores Delgado, M.
Leon, Javier
DNA REPAIR, 2009, 8 (03) : 390 - 399
[45] Clinical significance of p21WAF1/CIP1 and p53 expression in serous cystadenocarcinoma of the ovary
Terauchi, F
Okamoto, A
Nagashima, T
Kobayashi, Y
Moritake, T
Yamamoto, Y
Takakura, S
Iwaki, S
Ogura, H
ONCOLOGY REPORTS, 2005, 14 (02) : 363 - 368
[46] A novel p21WAF1/CIP1 transcript is highly dependent on p53 for its basal expression in mouse tissues
Andrei L Gartel
Senthil K Radhakrishnan
Michael S Serfas
Young H Kwon
Angela L Tyner
Oncogene, 2004, 23 : 8154 - 8157
[47] A novel p21WAF1/CIP1 transcript is highly dependent on p53 for its basal expression in mouse tissues
Gartel, AL
Radhakrishnan, SK
Serfas, MS
Kwon, YH
Tyner, AL
ONCOGENE, 2004, 23 (49) : 8154 - 8157
[48] p53 expression overcomes p21WAF1/CIP1-mediated G1 arrest and induces apoptosis in human cancer cells
Shunsuke Kagawa
Toshiyoshi Fujiwara
Akio Hizuta
Tatsuji Yasuda
Wei-Wei Zhang
Jack A Roth
Noriaki Tanaka
Oncogene, 1997, 15 : 1903 - 1909
[49] Resveratrol induces cell cycle arrest and apoptosis with docetaxel in prostate cancer cells via a p53/p21WAF1/CIP1 and p27KIP1 pathway
Singh, Santosh Kumar
Banerjee, Saswati
Acosta, Edward P.
Lillard, James W.
Singh, Rajesh
ONCOTARGET, 2017, 8 (10) : 17216 - 17228
[50] p21Waf1/Cip1 protects against p53-mediated apoptosis of human melanoma cells
Myriam Gorospe
Corrado Cirielli
Xiantao Wang
Prem Seth
Maurizio C Capogrossi
Nikki J Holbrook
Oncogene, 1997, 14 : 929 - 935

← 1 2 3 4 5 →