Delocalized Electronic Structure of the Thiol Sulfur Substantially Prevents Nucleic Acid Damage Induced by Neocarzinostatin
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- 作者：Hsiu-Maan Kuo ; Pei-Dawn Lee Chao ; and Der-Hang Chin
- 刊名：Biochemistry
- 出版年：2002
- 出版时间：January 22, 2002
- 年：2002
- 卷：41
- 期：3
- 页码：897 - 905
- 全文大小：120K
- 年卷期：v.41,no.3(January 22, 2002)
- ISSN：1520-4995
文摘
Neocarzinostatin is a potent antitumor antibiotic and is a prodrug, which induces genomedamage after activation by a thiol. The prodrug is stored as a protein-bound chromophore that containsan enediyne nucleus. A thiolate attack on the chromophore cyclizes the nucleus and produces radicalsthat abstract hydrogen from DNA. Because thiol is the only cofactor in the vital activation process, thestructure of the thiol plays an important role in the activity of the drug. Here we systematically examinethe effect of the electronic structure of some thiols on the efficiency of the drug, and compare particularlyaromatic with aliphatic thiols. The values of drug-induced base release from DNA are remarkably differentbetween thiophenol (3.6%) and benzyl mercaptan (12.5%), the activity of which is comparable with thoseof aliphatic thiols. Cleavage results determined by DNA electrophoresis are consistent with the results ofbase release; they show that the total number of DNA lesions is more than 3-fold lower for thiophenolthan for aliphatic thiols or benzyl mercaptan. We conclude that among aromatic thiols, only those thathave delocalized thiol sulfur electrons can substantially reduce the DNA cleavage activity. This resultsuggests that the effect of an aromatic ring arises from an inductive effect imposed on the thiol sulfurelectron through 
-resonance rather than through effects such as aromatic stacking, steric hindrance, orhydrophobic interaction. Replacing thiophenol with substituted derivatives with electron-releasing or-withdrawing groups changes the drug activity and supports the important role of the electronic structureof the thiol sulfur in determining the drug activity.
-resonance rather than through effects such as aromatic stacking, steric hindrance, orhydrophobic interaction. Replacing thiophenol with substituted derivatives with electron-releasing or-withdrawing groups changes the drug activity and supports the important role of the electronic structureof the thiol sulfur in determining the drug activity.