Hara M, Saitoh Y, Nakano H
Tokyo Research Laboratories, Kyowa Hakko Kogyo Ltd., Japan.
Biochemistry. 1990 Jun 19;29(24):5676-81. doi: 10.1021/bi00476a005.
Leinamycin is a recently discovered antitumor antibiotic with an unusual 1,3-dioxo-1,2-dithiolane structure. It preferentially inhibits the incorporation of [3H]thymidine into the acid-insoluble fraction of Bacillus subtilis. In vitro, leinamycin causes single-strand cleavage of supercoiled double-helical pBR322 DNA in the presence of thiol cofactors. Scavengers of oxygen radical did not supress the DNA-cleaving activity. Thiol-activated leinamycin binds calf thymus DNA at 4 degrees C and thermal treatment of the leinamycin-DNA adduct released a chemically modified leinamycin from the complex. The lack of cytotoxicity and DNA-cleaving activity for S-deoxyleinamycin indicates that the 1,3-dioxo-1,2-dithiolane moiety is essential for the activity of leinamycin. Thus, the primary cellular target of leinamycin appears to be DNA. It binds DNA and causes single-strand break at low concentrations, which may account for the potent antitumor activity.
链黑霉素是一种最近发现的具有不寻常的1,3 - 二氧代 - 1,2 - 二硫杂环戊烷结构的抗肿瘤抗生素。它优先抑制[³H]胸腺嘧啶核苷掺入枯草芽孢杆菌的酸不溶性部分。在体外，链黑霉素在硫醇辅因子存在下会导致超螺旋双链pBR322 DNA的单链断裂。氧自由基清除剂不能抑制DNA切割活性。硫醇激活的链黑霉素在4℃下与小牛胸腺DNA结合，对链黑霉素 - DNA加合物进行热处理会从复合物中释放出化学修饰的链黑霉素。S - 脱氧链黑霉素缺乏细胞毒性和DNA切割活性表明1,3 - 二氧代 - 1,2 - 二硫杂环戊烷部分对链黑霉素的活性至关重要。因此，链黑霉素的主要细胞靶点似乎是DNA。它在低浓度下结合DNA并导致单链断裂，这可能解释了其强大的抗肿瘤活性。
