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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.

Publication ,  Journal Article
Kuyper, LF; Baccanari, DP; Jones, ML; Hunter, RN; Tansik, RL; Joyner, SS; Boytos, CM; Rudolph, SK; Knick, V; Wilson, HR; Caddell, JM ...
Published in: J Med Chem
February 16, 1996

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 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.

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Published In

J Med Chem

DOI

ISSN

0022-2623

Publication Date

February 16, 1996

Volume

39

Issue

4

Start / End Page

892 / 903

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Toxoplasma
  • Structure-Activity Relationship
  • Quinazolines
  • Protein Structure, Secondary
  • Pneumonia, Pneumocystis
  • Molecular Weight
  • Molecular Structure
  • Molecular Conformation
  • Models, Molecular
 

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Kuyper, L. F., Baccanari, D. P., Jones, M. L., Hunter, R. N., Tansik, R. L., Joyner, S. S., … Stables, J. N. (1996). 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. J Med Chem, 39(4), 892–903. https://doi.org/10.1021/jm9505122
Kuyper, L. F., D. P. Baccanari, M. L. Jones, R. N. Hunter, R. L. Tansik, S. S. Joyner, C. M. Boytos, et al. “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.J Med Chem 39, no. 4 (February 16, 1996): 892–903. https://doi.org/10.1021/jm9505122.
Kuyper LF, Baccanari DP, Jones ML, Hunter RN, Tansik RL, Joyner SS, et al. 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. J Med Chem. 1996 Feb 16;39(4):892–903.
Kuyper LF, Baccanari DP, Jones ML, Hunter RN, Tansik RL, Joyner SS, Boytos CM, Rudolph SK, Knick V, Wilson HR, Caddell JM, Friedman HS, Comley JC, Stables JN. 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. J Med Chem. 1996 Feb 16;39(4):892–903.
Journal cover image

Published In

J Med Chem

DOI

ISSN

0022-2623

Publication Date

February 16, 1996

Volume

39

Issue

4

Start / End Page

892 / 903

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Toxoplasma
  • Structure-Activity Relationship
  • Quinazolines
  • Protein Structure, Secondary
  • Pneumonia, Pneumocystis
  • Molecular Weight
  • Molecular Structure
  • Molecular Conformation
  • Models, Molecular