HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Goldberg, D. E. Articles by Piwnica-Worms, D. Search for Related Content PubMed PubMed Citation Articles by Goldberg, D. E. Articles by Piwnica-Worms, D. Social Bookmarking                      What's this?

Volume 272, Number 10, Issue of March 7, 1997 pp. 6567-6572
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

---

Probing the Chloroquine Resistance Locus of Plasmodium falciparum with a Novel Class of Multidentate Metal(III) Coordination Complexes

(Received for publication, October 2, 1996, and in revised form, December 9, 1996)

Daniel E. Goldberg , Vijay Sharma ^§ , Anna Oksman , Ilya Y. Gluzman , Thomas E. Wellems ^¶ and David Piwnica-Worms ^§

From the ^§ Departments of Radiology and Molecular Biology & Pharmacology,  Howard Hughes Medical Institute, Departments of Medicine and Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110 and the ^¶ NIAID, National Institutes of Health, Bethesda, Maryland 20892

The malaria organism Plasmodium falciparum detoxifies heme released during degradation of host erythrocyte hemoglobin by sequestering it within the parasite digestive vacuole as a polymer called hemozoin. Antimalarial agents such as chloroquine appear to work by interrupting the heme polymerization process, but their efficacy has been impaired by the emergence of drug-resistant organisms. We report here the identification of a new class of antimalarial compounds, hexadentate ethylenediamine-N,N-bis[propyl(2-hydroxy-(R)-benzylimino)]metal(III) complexes [(R)-ENBPI-M(III)] and a corresponding ((R)-benzylamino)] analog [(R)-ENBPA-M(III)], a group of lipophilic monocationic leads amenable to metallopharmaceutical development. Racemic mixtures of Al(III), Fe(III), or Ga(III) but not In(III) (R)-ENBPI metallo-complexes killed intraerythrocytic malaria parasites in a stage-specific manner, the R = 4,6-dimethoxy-substituted ENBPI Fe(III) complex being most potent (IC₅₀ ~1 µM). Inhibiting both chloroquine-sensitive and -resistant parasites, potency of these imino complexes correlated in a free metal-independent manner with their ability to inhibit heme polymerization in vitro. In contrast, the reduced (amino) 3-MeO-ENBPA Ga(III) complex (MR045) was found to be selectively toxic to chloroquine-resistant parasites in a verapamil-insensitive manner. In 21 independent recombinant progeny of a genetic cross, susceptibility to this agent mapped in perfect linkage with the chloroquine resistance phenotype suggesting that a locus for 3-MeO-ENBPA Ga(III) susceptibility was located on the same 36-kilobase segment of chromosome 7 as the chloroquine resistance determinant. These compounds may be useful as novel probes of chloroquine resistance mechanisms and for antimalarial drug development.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?