Cytotoxicity and DNA Interaction of the Enantiomers of 6-Amino-3-(chloromethyl)-1-[(5,6,7-trimethoxyindol-2-yl)carbonyl]indoline (Amino-seco-CI-TMI)

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• 作者：Moana Tercel ; Michael A. Gieseg ; Jared B. Milbank ; Maruta Boyd ; Jun-Yao Fan ; L. Karin Tan ; William R. Wilson ; and William A. Denny
• 刊名：Chemical Research in Toxicology
• 出版年：1999
• 出版时间：August 1999
• 年：1999
• 卷：12
• 期：8
• 页码：700 - 706
• 全文大小：184K
• 年卷期：v.12,no.8(August 1999)
• ISSN：1520-5010

文摘

The enantiomers of the previously reported racemic 6-amino-3-(chloromethyl)-1-[(5,6,7-trimethoxyindol-2-yl)carbonyl]indoline (amino-seco-CI-TMI) were prepared via resolution of aprecursor by chiral HPLC. The only detectable product isolated from reaction of the racemiccompound with calf thymus DNA, followed by thermal cleavage, was shown by massspectrometry and two-dimensional NMR spectroscopy to be the adenine N3 adduct. Polyacrylamide gel electrophoresis assays with the racemate and with each enantiomer also showedadenine to be the only site of alkylation. While the racemic amino compound exhibited sequenceselectivity identical to that of the previously characterized phenol analogue, the enantiomersexhibited distinctly different sequence selectivities, allowing the (+) enantiomer to be assignedthe "natural" S configuration. The (+)-(S) enantiomer is 3-fold more cytotoxic than the (-)-(R)enantiomer (IC₅₀ values of 240 and 700 nM, respectively, in AA8 cells, after exposure for 4 h).