Targeting DNA Mismatches with Rhodium Metalloinsertors.
Targeting DNA Mismatches with Rhodium Metalloinsertors.
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DOI：
10.1016/j.ica.2016.01.021
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发表时间：
2016-10-01
影响因子：
2.8
通讯作者：
Barton JK
中科院分区：
文献类型：
--
作者：
Boyle KM;Barton JK
自20世纪40年代以来，DNA一直被用作化疗药物的生物靶点。传统的化疗药物，如顺铂和DNA烷化剂，主要依靠快速增殖的癌细胞增加摄取来达到治疗效果，但这种策略可能会导致健康组织的非靶点毒性。最近，研究兴趣转向靶向化疗，即一种药物针对癌症的特定生物学特征，导致对癌细胞的选择性毒性。在这里，我们回顾了一系列被称为Rh金属插入物的复合体，它们选择性地靶向DNA碱基对错配，这是错配修复(MMR)缺陷型癌症的标志。这些Rh金属插入物以高度的特异性结合DNA错配，并且对MMR缺乏的细胞和MMR熟练的细胞表现出高选择性的杀伤。这种细胞选择性对于结合DNA的小分子来说是独一无二的。当前几代Rh金属插入物已显示出纳摩尔效力以及对MMR缺陷细胞的高选择性，并显示出有望成为治疗MMR缺陷癌症的新家族化疗药物的基础。Rh金属插入物选择性地靶向dna碱基对错配，导致错配碱基从dnaπ堆叠中排出。金属插入物与DNA错配的选择性结合为靶向错配修复缺陷细胞作为新的化疗设计策略提供了基础。
DNA has been exploited as a biological target of chemotherapeutics since the 1940s. Traditional chemotherapeutics, such as cisplatin and DNA-alkylating agents, rely primarily on increased uptake by rapidly proliferating cancer cells for therapeutic effects, but this strategy can result in off-target toxicity in healthy tissue. Recently, research interests have shifted towards targeted chemotherapeutics, in which a drug targets a specific biological signature of cancer, resulting in selective toxicity towards cancerous cells. Here, we review a family of complexes, termed rhodium metalloinsertors, that selectively target DNA base pair mismatches, a hallmark of mismatch-repair (MMR) deficient cancers. These rhodium metalloinsertors, bind DNA mismatches with high specificity and display high selectively in killing MMR-deficient versus MMR-proficient cells. This cell selectivity is unique for small molecules that bind DNA. Current generations of rhodium metalloinsertors have shown nanomolar potency along with high selectivity towards MMR-deficient cells, and show promise as a foundation for a new family of chemotherapeutics for MMR-deficient cancers. Rhodium metalloinsertors selectively target DNA base pair mismatches, leading to the ejection of the mismatched bases from the DNA π-stack. The selective binding of metalloinsertors to DNA mismatches provides the basis for targeting mismatch-repair deficient cells as a strategy for new chemotherapeutic design.
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影响因子：
2.9
作者：
EASTMAN, A
通讯作者：
EASTMAN, A
影响因子：
2.9
作者：
Jackson, BA;Barton, JK
通讯作者：
Barton, JK
影响因子：
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作者：
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通讯作者：
Barton, JK
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
KOLODNER, RD