Novel boron-containing, nonclassical antifolates: Synthesis and preliminary biological and structural evaluation

Robert C. Reynolds, Shiela R. Campbell, Ralph G. Fairchild, Roy L. Kisliuk, Peggy L. Micca, Sherry F. Queener, James M. Riordan, W. David Sedwick, William R. Waud, Adelaine K.W. Leung, Richard W. Dixon, William J. Suling, David W. Borhani

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

Two boron-containing, ortho-icosahedral carborane lipophilic antifolates were synthesized, and the crystal structures of their ternary complexes with human dihydrofolate reductase (DHFR) and dihydronicotinamide adenine dinucleotide phosphate were determined. The compounds were screened for activity against DHFR from six sources (human, rat liver, Pneumocystis carinii, Toxoplasma gondii, Mycobacterium avium, and Lactobacillus casei) and showed good to modest activity against these enzymes. The compounds were also tested for antibacterial activity against L. casei, M. tuberculosis H37Ra, and three M. avium strains and for cytotoxic activity against seven different human tumor cell lines. Antibacterial and cytotoxic activity was modest, with one sample, the closo-carborane 4, showing about 10-fold greater activity. The less toxic nido-carborane 2 was also tested as a candidate for boron neutron capture therapy, but showed poor tumor retention and low selectivity ratios for boron distribution in tumor tissue versus normal tissue.

Original languageEnglish (US)
Pages (from-to)3283-3289
Number of pages7
JournalJournal of Medicinal Chemistry
Volume50
Issue number14
DOIs
StatePublished - Jul 12 2007

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Reynolds, R. C., Campbell, S. R., Fairchild, R. G., Kisliuk, R. L., Micca, P. L., Queener, S. F., Riordan, J. M., Sedwick, W. D., Waud, W. R., Leung, A. K. W., Dixon, R. W., Suling, W. J., & Borhani, D. W. (2007). Novel boron-containing, nonclassical antifolates: Synthesis and preliminary biological and structural evaluation. Journal of Medicinal Chemistry, 50(14), 3283-3289. https://doi.org/10.1021/jm0701977