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Indolocarbazole glycosides in inactive conformations
Michaël Facompré1, Carolina Carrasco, Hervé Vezin
1INSERM U524 et Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, IRCL, Place de Verdun 59045 Lille, France.
Chembiochem : a European Journal of Chemical Biology
|May 13, 2003
Summary
Indolocarbazole glycosides are potent antitumor agents. Modifying the indole NH group to N-methyl disrupts DNA interaction and abolishes topoisomerase I inhibition, reducing cytotoxicity.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Biochemistry
Background:
- Indolocarbazole glycosides are promising antitumor agents.
- These compounds target DNA and topoisomerase I.
- They typically adopt a closed conformation crucial for activity.
Purpose of the Study:
- To investigate the impact of indole NH modification on indolocarbazole glycoside activity.
- To explore the molecular and cellular effects of replacing indole NH with N-methyl.
Main Methods:
- Synthesis of NH and N-methyl indolocarbazole monoglycosides.
- Surface plasmon resonance (SPR) for DNA binding affinity.
- 1H NMR and molecular modeling for conformational analysis.
- Cytotoxicity assays against leukemia cells.
Main Results:
- N-methylation reduced DNA interaction and abolished topoisomerase I inhibition.
- Both NH and N-methyl derivatives bound DNA, but N-methyl had restricted access.
- N-methylation caused a conformational change, hindering DNA binding site access.
- NH compounds showed potent cytotoxicity (IC50 ~1 µM), while N-methyl analogues were 10-100x less potent.
Conclusions:
- The closed conformation is critical for indolocarbazole glycoside interaction with DNA and topoisomerase I.
- Indole NH modification significantly impacts antitumor efficacy.
- These findings support the development of conformationally locked indolocarbazoles for cancer therapy.