Metabolic fate of combretastatin A-1: LC-DAD-MS/MS investigation and biological evaluation of its reactive metabolites

被引：9

作者：

Aprile, Silvio ^{[1
]}

Zaninetti, Roberta ^{[1
]}

Del Grosso, Erika ^{[1
]}

Genazzani, Armando A. ^{[1
]}

Grosa, Giorgio ^{[1
]}

机构：

[1] Univ Piemonte Orientale, Dipartimento Sci Farmaco, I-28100 Novara, Italy

来源：

JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS | 2013年 / 78-79卷

关键词：

Combretastatin A-1; LC-MS analysis; Quinones; Reactive metabolites; Tubulin; HUMAN LIVER-MICROSOMES; IN-VITRO; ANTINEOPLASTIC AGENTS; IDENTIFICATION; BENZOQUINONE; PHOSPHATE; OXIDATION; A1;

D O I：

10.1016/j.jpba.2013.02.030

中图分类号：

O65 [分析化学];

学科分类号：

070302 ; 081704 ;

摘要：

Combretastatin A-1, an antineoplastic agent characterized by a remarkable cytotoxicity and a strong antitubulinic activity, is currently under investigation in phase I clinical trials. Yet a comprehensive metabolic study of CA-1 in human and animal models has so far not been reported in the literature. We have therefore investigated, through LC-UV and LC-MS analysis the in vitro/in vivo metabolism of CA-1, have synthesized its reactive quinone metabolite Q1, and have evaluated its cytotoxic and antitubulinic activities. In vitro CA-1 metabolism was studied in rat and human liver microsomes in the presence of the nucleophilic trapping agent GSH were performed while urine samples of the CA-1-treated rats were analyzed to establish the in vivo metabolic pathways. The metabolite Ql, that was synthesized in good yield using a polymer supported oxidant, displayed a significant cytotoxicity but was devoid of significant antitubulinic activity. Finally the chemical interaction of Q1 and the other combretastatin quinone metabolites with sulphydryl groups of tubulin was measured by Ellman's method: the results suggested the haptenization of the tubulin through the formation of a covalent bond. (C) 2013 Elsevier B.V. All rights reserved.

引用

页码：233 / 242

页数：10

共 23 条

[1] Synthesis, biological evaluation and molecular modeling of 1,2,3-triazole analogs of combretastatin A-1 [J].

Akselsen, Oyvind W. ;

Odlo, Kristin ;

Cheng, Jing-Jy ;

Maccari, Giorgio ;

Botta, Maurizio ;

Hansen, Trond Vidar .

BIOORGANIC & MEDICINAL CHEMISTRY, 2012, 20 (01) :234-242

[2] In vitro metabolism study of combretastatin A-4 in rat and human liver Microsomes [J].

Aprile, Silvio ;

Del Grosso, Erika ;

Tron, Gian Cesare ;

Grosa, Giorgio .

DRUG METABOLISM AND DISPOSITION, 2007, 35 (12) :2252-2261

[3] Identification of the Human UDP-Glucuronosyltransferases Involved in the Glucuronidation of Combretastatin A-4 [J].

Aprile, Silvio ;

Del Grosso, Erika ;

Grosa, Giorgio .

DRUG METABOLISM AND DISPOSITION, 2010, 38 (07) :1141-1146

[4] Human UDP-glucuronosyltransferases: Feedback loops between substrates and ligands of their transcription factors [J].

Bock, Karl Walter .

BIOCHEMICAL PHARMACOLOGY, 2012, 84 (08) :1000-1006

[5] Oxidative metabolism of combretastatin A-1 produces quinone intermediates with the potential to bind to nucleophiles and to enhance oxidative stress via free radicals [J].

Folkes, Lisa K. ;

Christlieb, Martin ;

Madej, Edyta ;

Stratford, Michael R. L. ;

Wardman, Peter .

CHEMICAL RESEARCH IN TOXICOLOGY, 2007, 20 (12) :1885-1894

[6] Identification of 2,3-diaminophenazine and of o-benzoquinone dioxime as the major in vitro metabolites of benzofuroxan [J].

Grosa, G ;

Galli, U ;

Rolando, B ;

Fruttero, R ;

Gervasio, G ;

Gasco, A .

XENOBIOTICA, 2004, 34 (04) :345-352

[7]

Hill SA, 2002, ANTICANCER RES, V22, P1453

[8] 2-[(1-methylpropyl)dithio]-1H-imidazole inhibits tubulin polymerization through cysteine oxidation [J].

Huber, Kelly ;

Patel, Poulam ;

Zhang, Lei ;

Evans, Helen ;

Westwell, Andrew D. ;

Fischer, Peter M. ;

Chan, Stephen ;

Martin, Stewart .

MOLECULAR CANCER THERAPEUTICS, 2008, 7 (01) :143-151

[9] Comparative preclinical pharmacokinetic and metabolic studies of the combretastatin prodrugs combretastatin A4 phosphate and A1 phosphate [J].

Kirwan, IG ;

Loadman, PM ;

Swaine, DJ ;

Anthoney, DA ;

Pettit, GR ;

Lippert, JW ;

Shnyder, SD ;

Cooper, PA ;

Bibby, MC .

CLINICAL CANCER RESEARCH, 2004, 10 (04) :1446-1453

[10] Vascular disrupting agents [J].

Lippert, John W., III .

BIOORGANIC & MEDICINAL CHEMISTRY, 2007, 15 (02) :605-615

← 1 2 3 →