Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 54, Issue 14, Pages 4937-4953Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm101338z
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Funding
- National Institutes of Health (NIH) [UO1 CA89566]
- Purdue University
- Purdue Research Foundation [203202]
- DCTD, National Cancer Institute [NO1-CO-56000]
- NIH, National Cancer Institute, Center for Cancer Research
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The DNA-relaxing enzyme topoisomerase I (Top 1) can be inhibited by heterocyclic compounds such as indolocarbazoles and indenoisoquinolines. Carbohydrate and hydroxyl-containing side chains are essential for the biological activity of indolocarbazoles. The current study investigated how similar functionalities could be translated to the indenoisoquinoline system and how stereochemistry and hydrogen bonding affect biological activity. Herein is described the preparation and assay of indenoisoquinolines substituted with short-chain alcohols, diols, and carbohydrates. Several compounds (including those derived from sugars) display potent Top1 poisoning and antiproliferative activities. The Top1 poisoning activity of diol-substituted indenoisoquinolines is dependent upon stereochemistry. Although the effect is striking, molecular modeling and docking studies do not indicate any reason for the difference in activity due to similar calculated interactions between the ligand and Top1-DNA complex and ambiguity about the binding mode. A stereo chemical dependence was also observed for carbohydrate-derived indenoisoquinolines. Although similar trends were observed in other classes of Top1 inhibitors, the exact nature of this effect has yet to be elucidated.
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