Synthesis and hypoxic-cytotoxic activity of some 3-amino-1,2,4-benzotriazine-1,4-dioxide derivatives

被引：19
作者：
Jiang, Faqin
Yang, Bo
Fan, Lingling
He, Qiaojun
Hu, Yongzhou
机构：
[1] Zhejiang Univ, ZJU ENS Joint Lab Med Chem, Sch Pharmaceut Sci, Hangzhou 310031, Peoples R China
[2] Zhejiang Univ, Dept Pharmacol & Toxicol, Sch Pharmaceut Sci, Hangzhou 310031, Peoples R China
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 16期
关键词：
3-amino-1,2,4-benzotriazine-1,4-dioxide derivatives; synthesis; cytotoxicity; hypoxia;
D O I：
10.1016/j.bmcl.2006.05.095
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
A series of 3-amino-1,2,4-benzotriazine-1,4-dioxide derivatives I have been synthesized and evaluated for their cytotoxic activity in vitro against human leukemia cell lines: Molt-4, K562, HL60, human liver cancer cell Hep-G2, human prostate cancer cell PC-3 in hypoxia. Most of the compounds showed more potent activity than TPZ. Compounds 1i and 1m displayed encouraging superior activity against Molt-4 and HL-60 cell lines. Three potential derivatives received the test of the activity in hypoxia and in normoxia against Molt-4 and HL-60 cell lines and showed obvious hypoxia selectivity. Further mechanism study revealed that the cytotoxic activities of compounds 1i and 1k in Molt-4 cells might be mediated by modulation of p53 protein expression and mitochondrial membrane potential (Delta Psi(m)). (c) 2006 Elsevier Ltd. All rights reserved.
引用
收藏
页码：4209 / 4213
页数：5
相关论文
共 25 条
[1]   Enhanced conversion of DNA radical damage to double strand breaks by 1,2,4-benzotriazine 1,4-dioxides linked to a DNA binder compared to tirapazamine [J].
Anderson, RF ;
Harris, TA ;
Hay, MP ;
Denny, WA .
CHEMICAL RESEARCH IN TOXICOLOGY, 2003, 16 (11) :1477-1483
[2]   SR-4233 (TIRAPAZAMINE) - A NEW ANTICANCER DRUG EXPLOITING HYPOXIA IN SOLID TUMORS [J].
BROWN, JM .
BRITISH JOURNAL OF CANCER, 1993, 67 (06) :1163-1170
[3]   1,2,4-triazine N-oxide derivatives:: Studies as potential hypoxic cytotoxins.: Part II. [J].
Cerecetto, H ;
González, M ;
Onetto, S ;
Saenz, P ;
Ezpeleta, O ;
de Ceráin, AL ;
Monge, A .
ARCHIV DER PHARMAZIE, 2004, 337 (05) :247-258
[4]   1,2,4-Triazine N-oxide derivatives:: Studies as potential hypoxic cytotoxins.: Part III [J].
Cerecetto, H ;
González, M ;
Risso, M ;
Saenza, P ;
Olea-Azar, C ;
Bruno, AM ;
Azqueta, A ;
de Ceráin, AL ;
Monge, A .
ARCHIV DER PHARMAZIE, 2004, 337 (05) :271-280
[5]   N-Oxides as Hypoxia Selective Cytotoxins [J].
Cerecetto, Hugo ;
Gonzalez, Mercedes .
MINI-REVIEWS IN MEDICINAL CHEMISTRY, 2001, 1 (03) :219-231
[6]  
Cerecetto K, 2001, MED CHEM RES, V10, P328
[7]   Prodrug strategies in cancer therapy [J].
Denny, WA .
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2001, 36 (7-8) :577-595
[8]   Concurrent chemo-radiotherapy with mitomycin C compared with porfiromycin in squamous cell cancer of the head and neck: Final results of a randomized clinical trial [J].
Haffty, BG ;
Wilson, LD ;
Son, YH ;
Cho, EI ;
Papac, RJ ;
Fischer, DB ;
Rockwell, S ;
Sartorelli, AC ;
Ross, DA ;
Sasaki, CT ;
Fischer, JJ .
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS, 2005, 61 (01) :119-128
[9]   DNA-targeted 1,2,4-benzotriazine 1,4-dioxides: Potent analogues of the hypoxia-selective cytotoxin tirapazamine [J].
Hay, MP ;
Pruijn, FB ;
Gamage, SA ;
Liyanage, HDS ;
Kovacs, MS ;
Patterson, AV ;
Wilson, WR ;
Brown, JM ;
Denny, WA .
JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (02) :475-488
[10]  
Kelson AB, 1998, ANTI-CANCER DRUG DES, V13, P575
123