High-Affinity Inhibitors of Dihydrofolate Reductase: Antimicrobial and Anticancer Activities of 7,8-Dialkyl-1,3-diaminopyrrolo[3,2-f]quinazolines with Small Molecular Size

A series of 7,8-dialkylpyrrolo[3,2-f]quinazolines were prepared as inhibitors of dihydrofolate reductase (DHFR). On the basis of an apparent inverse relationship between compound size and antifungal activity, the compounds were designed to be relatively small and compact. Inhibitor design was aided...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 39; no. 4; pp. 892 - 903
Main Authors:	Kuyper, Lee F, Baccanari, David P, Jones, Michael L, Hunter, Robert N, Tansik, Robert L, Joyner, Suzanne S, Boytos, Christine M, Rudolph, Sharon K, Knick, Vince, Wilson, H. Robert, Caddell, J. Marc, Friedman, Henry S, Comley, John C. W, Stables, Jeremy N
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 16-02-1996
Subjects:	Animals Anti-Infective Agents - chemical synthesis Anti-Infective Agents - pharmacology Anti-Infective Agents - toxicity Antineoplastic Agents - chemical synthesis Antineoplastic Agents - pharmacology Antineoplastic Agents - toxicity ATP-Binding Cassette, Sub-Family B, Member 1 - drug effects Brain Neoplasms - drug therapy Candidiasis - drug therapy Cell Division - drug effects Cell Line Crystallography, X-Ray Drug Design Drug Resistance, Multiple Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - pharmacology Folic Acid Antagonists - chemistry Humans Lung Neoplasms - drug therapy Magnetic Resonance Spectroscopy Mass Spectrometry Mice Mice, Nude Mice, SCID Models, Molecular Molecular Conformation Molecular Structure Molecular Weight Pneumonia, Pneumocystis - drug therapy Protein Structure, Secondary Quinazolines - chemical synthesis Quinazolines - pharmacology Quinazolines - toxicity Structure-Activity Relationship Toxoplasma - drug effects Tumor Cells, Cultured
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Summary:	A series of 7,8-dialkylpyrrolo[3,2-f]quinazolines were prepared as inhibitors of dihydrofolate reductase (DHFR). On the basis of an apparent inverse relationship between compound size and antifungal activity, the compounds were designed to be relatively small and compact. Inhibitor design was aided by a GRID analysis of the three-dimensional structure of Candida albicans DHFR, which suggested that relatively small, branched alkyl groups at the 7- and 8-positions of the pyrroloquinazoline ring system would provide optimal interactions with a hydrophobic region of the protein. The compounds were potent inhibitors of fungal and human DHFR, with K i values as low as 7.1 and 0.1 pM, respectively, and were highly active against C. albicans and an array of tumor cell lines. In contrast to known lipophilic inhibitors of DHFR such as trimetrexate and piritrexim, members of this series of pyrroloquinazolines were not susceptible to P-glycoprotein-mediated multidrug resistance and also showed significant distribution into lung and brain tissue. The compounds were active in lung and brain tumor models and displayed in vivo activity against Pneumocystis carinii and C. albicans.
Bibliography:	ark:/67375/TPS-4BLVTWXB-B Abstract published in Advance ACS Abstracts, January 15, 1996. istex:FDE5B4A3C3D5CE87BC500FC11B16152DB51B064D
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm9505122