SEQUENCE PREFERENCES OF DNA INTERSTRAND CROSS-LINKING AGENTS - IMPORTANCE OF MINIMAL DNA STRUCTURAL REORGANIZATION IN THE CROSS-LINKING REACTIONS OF MECHLORETHAMINE, CISPLATIN, AND MITOMYCIN-C
SEQUENCE PREFERENCES OF DNA INTERSTRAND CROSS-LINKING AGENTS - IMPORTANCE OF MINIMAL DNA STRUCTURAL REORGANIZATION IN THE CROSS-LINKING REACTIONS OF MECHLORETHAMINE, CISPLATIN, AND MITOMYCIN-C
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DOI：
10.1016/s0040-4020(01)81782-8
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发表时间：
1991-04-08
期刊：
影响因子：
2.1
通讯作者：
RAUCHER, S
中科院分区：
文献类型：
--
作者：
HOPKINS, PB;MILLARD, JT;RAUCHER, S
DNA的链间交联被认为是许多双功能烷化剂的细胞毒性的原因，其中一些可用于治疗人类癌症。 这些交联形成的核苷酸序列已经在几种药物的DNA片段中以单核苷酸分辨率定义，包括氮芥、顺铂、丝裂霉素C和一些结构相关的药物。 总之，双链体DNA的结构、交联的序列和DNA上连接的原子位点表明，交联优先发生在将导致B-DNA最小变形的位置。 该建议，这种偏好主要是表示通过最小化的能量的过渡态转化的单加合物的交联的实验与氮芥的支持。 有人建议，这些交联剂的适度的序列识别能力的延伸，通过缀合到高度序列选择性的“运载工具”，可能会产生第二代，有针对性的抗肿瘤药物。
Interstrand cross-linking of DNA is believed to account for the cytotoxicity of many bifunctional alkylating agents, some of which are useful in the treatment of human cancer. The nucleotide sequences at which these cross-links are formed have been defined at single nucleotide resolution in DNA fragments for several agents, including mechlorethamine, cisplatin, mitomycin C, and some structurally related agents. Taken together, the structure of duplex DNA, the sequences which are cross-linked, and the atomic sites on DNA which are linked, indicate that cross-linking occurs preferentially at locations which will result in minimal distortion of B-DNA. The proposal that this preference is primarily expressed by minimizing the energy of the transition state for conversion of monoadducts to cross-links is supported by experiments with mechlorethamine. It is suggested that extension of the modest sequence-recognizing capacity of these cross-linking agents by conjugation to highly sequence-selective "delivery vehicles" may yield second generation, targeted antitumor drugs.