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

Article Details

Citation

Reynolds RC, Campbell SR, Fairchild RG, Kisliuk RL, Micca PL, Queener SF, Riordan JM, Sedwick WD, Waud WR, Leung AK, Dixon RW, Suling WJ, Borhani DW

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

J Med Chem. 2007 Jul 12;50(14):3283-9. Epub 2007 Jun 15.

PubMed ID
17569517 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Dihydrofolate reductaseP00374Details
Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
MethotrexateDihydrofolate reductaseIC 50 (nM)20N/AN/ADetails