A novel platinum complex of the histone deacetylase inhibitor belinostat: Rational design, development and in vitro cytotoxicity

被引：31
作者：
Parker, James P. [1 ]
Nimir, Hassan [2 ]
Griffith, Darren M. [1 ]
Duff, Brian [3 ]
Chubb, Anthony J. [4 ]
Brennan, Marian P. [5 ]
Morgan, Maria P. [5 ]
Egan, Denise A. [3 ]
Marmion, Celine J. [1 ]
机构：
[1] Royal Coll Surgeons Ireland, Dept Pharmaceut & Med Chem, Ctr Synth & Chem Biol, Dublin 2, Ireland
[2] Univ Qatar, Coll Arts & Sci, Dept Chem & Earth Sci, Doha, Qatar
[3] Dublin Inst Technol, Dept Sci, Ctr Pharmaceut Res & Dev, Dublin 24, Ireland
[4] Natl Univ Ireland Univ Coll Dublin, Complex & Adapt Syst Lab, Dublin 4, Ireland
[5] Royal Coll Surgeons Ireland, Dublin 2, Ireland
来源：
JOURNAL OF INORGANIC BIOCHEMISTRY | 2013年 / 124卷
基金：
爱尔兰科学基金会;
关键词：
Platinum; Histone deacetylases; Histone deacetylase inhibitors; Belinostat; Anti-cancer; Cytotoxicity; CRYSTAL-STRUCTURE; ANTICANCER AGENT; OVARIAN-CANCER; SOLID TUMORS; ACID; CARBOPLATIN; HYDROLYSIS; RESISTANCE; CISPLATIN; LYMPHOMA;
D O I：
10.1016/j.jinorgbio.2013.03.011
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：
The successful design and synthesis of a novel Pt complex of the histone deacteylase inhibitor belinostat are reported. Molecular modelling assisted in the identification of a suitable malonate derivative of belinostat (mal-p-Bel) for complexation to platinum. Reaction of [Pt(NH3)(2)(H2O)(2)](NO3)(2) with the disodium salt of mal-p-Bel gave cis-[Pt(NH3)(2)(mal-p-Bel(-2H))] (where -(2H) indicates that mal-p-Bel is doubly deprotonated) in excellent yield. An in vitro cytotoxicity study revealed that cis-[Pt(NH3)(2)(mal-p-Bel(-2H)] possesses (i) considerable cytotoxicity against reported ovarian cancer cell lines, (ii) enhanced cytotoxicity relative to the previously reported Pt histone deacetylase inhibitor conjugate, cis-[Pt-II(NH3)(2)(malSAHA(-2H))] and (iii) favourable cyto-selective properties as compared to cisplatin and belinostat. (C) 2013 Elsevier Inc. All rights reserved.
引用
收藏
页码：70 / 77
页数：8
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