ZFIN ID: ZDB-PUB-170823-12
Design and Synthesis of Chlorinated and Fluorinated 7-Azaindenoisoquinolines as Potent Cytotoxic Anticancer Agents That Inhibit Topoisomerase I
Elsayed, M.S.A., Su, Y., Wang, P., Sethi, T., Agama, K., Ravji, A., Redon, C.E., Kiselev, E., Horzmann, K.A., Freeman, J.L., Pommier, Y., Cushman, M.
Date: 2017
Source: Journal of medicinal chemistry   60: 5364-5376 (Journal)
Registered Authors: Freeman, Jennifer, Wang, Ping
Keywords: none
MeSH Terms:
  • Animals
  • Antineoplastic Agents/chemical synthesis
  • Antineoplastic Agents/chemistry
  • Antineoplastic Agents/pharmacology*
  • Cell Proliferation/drug effects
  • DNA Cleavage
  • DNA Topoisomerases, Type I/metabolism*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Humans
  • Isoquinolines/chemical synthesis
  • Isoquinolines/chemistry
  • Isoquinolines/pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship
  • Topoisomerase I Inhibitors/chemical synthesis
  • Topoisomerase I Inhibitors/chemistry
  • Topoisomerase I Inhibitors/pharmacology*
  • Tumor Cells, Cultured
  • Zebrafish
PubMed: 28657311 Full text @ J. Med. Chem.
ABSTRACT
The 7-azaindenoisoquinolines are cytotoxic topoisomerase I (Top1) inhibitors. Previously reported representatives bear a 3-nitro group. The present report documents the replacement of the potentially genotoxic 3-nitro group by 3-chloro and 3-fluoro substituents, resulting in compounds with high Top1 inhibitory activities and potent cytotoxicities in human cancer cell cultures and reduced lethality in an animal model. Some of the new Top1 inhibitors also possess moderate inhibitory activities against tyrosyl-DNA phosphodiesterase 1 (TDP1) and tyrosyl-DNA phosphodiesterase 2 (TDP2), two enzymes that are involved in DNA damage repair resulting from Top1 inhibitors, and they produce significantly more DNA damage in cancer cells than in normal cells. Eighteen of the new compounds had cytotoxicity mean-graph midpoint (MGM) GI50 values in the submicromolar (0.033-0.630 μM) range. Compounds 16b and 17b are the most potent in human cancer cell cultures with MGM GI50 values of 0.063 and 0.033 μM, respectively. Possible binding modes to Top1 and TDP1were investigated by molecular modeling.
ADDITIONAL INFORMATION No data available