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首页> 外文期刊>Journal of Inorganic Biochemistry: An Interdisciplinary Journal >Preclinical characterization of anticancer gallium(III) complexes: Solubility, stability, lipophilicity and binding to serum proteins
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Preclinical characterization of anticancer gallium(III) complexes: Solubility, stability, lipophilicity and binding to serum proteins

机译：抗癌镓（III）复合物的临床前表征：溶解性，稳定性，亲脂性和与血清蛋白的结合

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The discovery and development of gallium(III) complexes capable of inhibiting tumor growth is an emerging area of anticancer drug research. A range of novel gallium coordination compounds with established cytotoxic efficacy have been characterized in terms of desirable chemical and biochemical properties and compared with tris(8-quinolinolato)gallium(III) (KP46), a lead anticancer gallium-based candidate that successfully finished phase I clinical trials (under the name FFC11), showing activity against renal cell cancer. In view of probable oral administration, drug-like parameters, such as solubility in water, saline and 0.5% dimethyl sulfoxide, stability against hydrolysis, measured as the rate constant of hydrolytic degradation in water or physiological buffer using a capillary zone electrophoresis (CZE) assay, and the octanol-water partition coefficient (logP) providing a rational estimate of a drug's lipophilicity, have been evaluated and compared. The differences in bioavailability characteristics between different complexes were discussed within the formalism of structure-activity relationships. The reactivity toward major serum transport proteins, albumin and transferrin, was also assayed in order to elucidate the drug's distribution pathway after intestinal absorption. According to the values of apparent binding rate constants determined by CZE, both KP46 and bis(2-acetylpyridine-4,4-dimethyl-3-thiosemicarbazonato-N,N,S)gallium(III) tetrachlorogallate(III) (KP1089) bind to transferrin faster than to albumin. This implies that transferrin would rather mediate the accumulation of gallium antineoplastic agents in solid tumors. A tendency of being faster converted into the protein-bound form found for KP1089 (due possibly to non-covalent binding) seems complementary to its greater in vitro antiproliferative activity. (c) 2006 Elsevier Inc. All rights reserved.
机译：能够抑制肿瘤生长的镓（III）配合物的发现和开发是抗癌药物研究的新兴领域。一系列具有确定的细胞毒性功效的新型镓配位化合物已通过理想的化学和生物化学特性进行了表征，并与三（8-喹啉基）镓（III）（KP46）（一种成功地完成该阶段的领先的基于抗癌的镓基候选物）进行了比较我进行了一项临床试验（名称为FFC11），显示出抗肾细胞癌的活性。考虑到可能的口服给药，使用毛细管区带电泳（CZE）作为药物在水中，在生理盐水和0.5％二甲基亚砜中的溶解度，对水解的稳定性等类似药物的参数，以在水中或生理缓冲液中水解降解的速率常数来衡量分析和辛醇-水分配系数（logP）可以合理估计药物的亲脂性，已经进行了评估和比较。在构效关系的形式论中讨论了不同复合物之间生物利用度特征的差异。还测定了对主要血清转运蛋白，白蛋白和转铁蛋白的反应性，以阐明肠道吸收后药物的分布途径。根据CZE确定的表观结合速率常数的值，KP46和双（2-乙酰吡啶-4,4-二甲基-3-硫代半碳氮杂-N，N，S）镓（III）四氯没食子酸酯（III）（KP1089）结合转铁蛋白比白蛋白更快。这意味着转铁蛋白宁愿介导实体肿瘤中镓抗肿瘤药的蓄积。更快地转化为KP1089的蛋白质结合形式的趋势（可能是由于非共价结合）似乎与其更大的体外抗增殖活性互补。 （c）2006 Elsevier Inc.保留所有权利。

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