2. Academic Validation
  3. Synthesis and biological evaluation of new fluorinated and chlorinated indenoisoquinoline topoisomerase I poisons

Synthesis and biological evaluation of new fluorinated and chlorinated indenoisoquinoline topoisomerase I poisons

  • Bioorg Med Chem. 2016 Apr 1;24(7):1469-79. doi: 10.1016/j.bmc.2016.02.015.
Daniel E Beck 1,  Wei Lv 1,  Monica Abdelmalak 2,  Caroline B Plescia 2,  Keli Agama 2,  Christophe Marchand 2,  Yves Pommier 2,  Mark Cushman 3
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States.
  • 2 Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 21892, United States.
  • 3 Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States. Electronic address: cushman@purdue.edu.
PMID: 26906474 DOI: 10.1016/j.bmc.2016.02.015
Abstract

Fluorine and chlorine are metabolically stable, but generally less active replacements for a nitro group at the 3-position of indenoisoquinoline Topoisomerase IB (Top1) poisons. A number of strategies were employed in the present investigation to enhance the Top1 inhibitory potencies and Cancer cell growth inhibitory activities of halogenated indenoisoquinolines. In several cases, the new compounds' activities were found to rival or surpass those of similarly substituted 3-nitroindenoisoquinolines, and several unusually potent analogs were discovered through testing in human Cancer cell cultures. A hydroxyethylaminopropyl side chain on the lactam nitrogen of two halogenated indenoisoquinoline Top1 inhibitors was found to also impart inhibitory activity against tyrosyl DNA phosphodiesterases 1 and 2 (TDP1 and TDP2), which are Enzymes that participate in the repair of DNA damage induced by Top1 poisons.

Keywords

Anticancer; Cytotoxicity; Indenoisoquinoline; Topoisomerase I; Tyrosyl DNA phosphodiesterase 1; Tyrosyl DNA phosphodiesterase 2.

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