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Novel boron-containing, nonclassical antifolates: synthesis and preliminary biological and structural evaluation
Robert C Reynolds1, Shiela R Campbell, Ralph G Fairchild
1Drug Discovery Division, Southern Research Institute, Birmingham, Alabama 35205, USA. reynolds@sri.org
Journal of Medicinal Chemistry
|June 16, 2007
Summary
Two novel boron-containing antifolates targeting dihydrofolate reductase (DHFR) were synthesized and tested. While showing modest antibacterial and cytotoxic effects, one compound exhibited enhanced activity, but neither proved suitable for boron neutron capture therapy.
Area of Science:
- Medicinal Chemistry
- Biochemistry
- Structural Biology
Background:
- Antifolates are crucial in treating infections and cancer.
- Dihydrofolate reductase (DHFR) is a key enzyme in folate metabolism and a target for antifolate drugs.
- Boron-containing compounds offer unique properties for therapeutic applications.
Purpose of the Study:
- To synthesize and characterize novel boron-containing, ortho-icosahedral carborane lipophilic antifolates.
- To evaluate the inhibitory activity of these compounds against human and microbial DHFR enzymes.
- To assess their potential as antibacterial agents, cytotoxic agents against human tumors, and candidates for boron neutron capture therapy.
Main Methods:
- Synthesis of two boron-containing carborane antifolates.
- Determination of crystal structures of ternary complexes with human DHFR and dihydronicotinamide adenine dinucleotide phosphate.
- Enzyme inhibition assays against DHFR from six different species.
- Antibacterial assays against relevant bacterial strains.
- Cytotoxic assays against human tumor cell lines.
- Evaluation for boron neutron capture therapy potential.
Main Results:
- The crystal structures of ternary complexes were determined.
- Compounds exhibited good to modest activity against DHFR from various sources.
- Modest antibacterial and cytotoxic activities were observed.
- Closo-carborane 4 showed approximately 10-fold greater activity compared to other tested compounds.
- Nido-carborane 2 demonstrated poor tumor retention and low selectivity ratios for boron neutron capture therapy.
Conclusions:
- The synthesized carborane antifolates demonstrate inhibitory activity against DHFR and possess modest antimicrobial and anticancer potential.
- The closo-carborane derivative shows promise for further development due to its enhanced activity.
- The nido-carborane derivative is not suitable for boron neutron capture therapy due to insufficient tumor targeting and selectivity.
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