A Novel Achiral Seco-cyclopropylpyrido[e]indolone (CPyI) Analog of CC-1065 and the Duocarmycins: Synthesis, DNA Interactions, in Vivo Anticancer and Anti-parasitic Evaluation

Authors

Sameer Chavda, Hope College
Balaji Babu, Hope College
Stephanie K. Yanow, University of Alberta; Institute of Parasitology
Armando Jardim, Institute of Parasitology
Terry W. Spithill, Institute of Parasitology; Charles Sturt University
Konstantinos Kiakos, University College London
Jerome Kluza, University College London
Moses Lee, Hope CollegeFollow

Document Type

Article

Publication Date

7-15-2010

Publication Source

Bioorganic and Medicinal Chemistry

Volume Number

18

Issue Number

14

First Page

5016

Last Page

5024

Publisher

Pergamon-Elsevier Science LTD

ISSN

0968-0896

Abstract

The synthesis of an achiral seco-hydroxy-aza-CBI-TMI analog (8) of the duocarmycins is reported. Its specificity for the DNA minor groove of AT-rich sequences and covalent bonding to adenine-N3 was ascertained by a thermal cleavage assay. Compound 8 was found to be cytotoxic in the nanomolar range against murine and human cancer cells. It was further demonstrated that compound 8 was active against murine melanoma (B16-F0) grown in C57BL/6 mice. Compound 8 was also shown to inhibit the growth of the protozoan parasites Leishmania donovani, Leishmania mexicana, Trypanosoma brucei, and Plasmodium falciparum in culture.

Recommended Citation

Published in: Bioorganic and Medicinal Chemistry, Volume 18, Issue 14, July 15, 2010, pages 5016-5024. Copyright © 2010 Pergamon-Elsevier Science LTD, Oxford. The final published version is available at: http://dx.doi.org/10.1016/j.bmc.2010.05.078