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 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

47 Citations (Scopus)

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

Fingerprint

Folic Acid Antagonists
Boron
Lactobacillus casei
Tumors
Mycobacterium avium
Tetrahydrofolate Dehydrogenase
Boron Neutron Capture Therapy
Tissue
Pneumocystis carinii
Poisons
Toxoplasma
Tumor Cell Line
Liver
NAD
Rats
Neoplasms
Neutrons
Tuberculosis
Crystal structure
Phosphates

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Reynolds, R. C., Campbell, S. R., Fairchild, R. G., Kisliuk, R. L., Micca, P. L., Queener, S., ... 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

Novel boron-containing, nonclassical antifolates : Synthesis and preliminary biological and structural evaluation. / Reynolds, Robert C.; Campbell, Shiela R.; Fairchild, Ralph G.; Kisliuk, Roy L.; Micca, Peggy L.; Queener, Sherry; Riordan, James M.; Sedwick, W. David; Waud, William R.; Leung, Adelaine K W; Dixon, Richard W.; Suling, William J.; Borhani, David W.

In: Journal of Medicinal Chemistry, Vol. 50, No. 14, 12.07.2007, p. 3283-3289.

Research output: Contribution to journalArticle

Reynolds, RC, Campbell, SR, Fairchild, RG, Kisliuk, RL, Micca, PL, Queener, S, Riordan, JM, Sedwick, WD, Waud, WR, Leung, AKW, Dixon, RW, Suling, WJ & Borhani, DW 2007, 'Novel boron-containing, nonclassical antifolates: Synthesis and preliminary biological and structural evaluation', Journal of Medicinal Chemistry, vol. 50, no. 14, pp. 3283-3289. https://doi.org/10.1021/jm0701977
Reynolds, Robert C. ; Campbell, Shiela R. ; Fairchild, Ralph G. ; Kisliuk, Roy L. ; Micca, Peggy L. ; Queener, Sherry ; Riordan, James M. ; Sedwick, W. David ; Waud, William R. ; Leung, Adelaine K W ; Dixon, Richard W. ; Suling, William J. ; Borhani, David W. / Novel boron-containing, nonclassical antifolates : Synthesis and preliminary biological and structural evaluation. In: Journal of Medicinal Chemistry. 2007 ; Vol. 50, No. 14. pp. 3283-3289.
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