title: Novel boron-containing, nonclassical antifolates: synthesis and preliminary biological and structural evaluation.
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.
authors.affiliation: Drug Discovery Division, Southern Research Institute, Birmingham, Alabama 35205, USA. reynolds@sri.org
authors.forename: Robert C
authors.initials: RC
authors.lastname: Reynolds
authors.forename: Shiela R
authors.initials: SR
authors.lastname: Campbell
authors.forename: Ralph G
authors.initials: RG
authors.lastname: Fairchild
authors.forename: Roy L
authors.initials: RL
authors.lastname: Kisliuk
authors.forename: Peggy L
authors.initials: PL
authors.lastname: Micca
authors.forename: Sherry F
authors.initials: SF
authors.lastname: Queener
authors.forename: James M
authors.initials: JM
authors.lastname: Riordan
authors.forename: W David
authors.initials: WD
authors.lastname: Sedwick
authors.forename: William R
authors.initials: WR
authors.lastname: Waud
authors.forename: Adelaine K W
authors.initials: AK
authors.lastname: Leung
authors.forename: Richard W
authors.initials: RW
authors.lastname: Dixon
authors.forename: William J
authors.initials: WJ
authors.lastname: Suling
authors.forename: David W
authors.initials: DW
authors.lastname: Borhani
mesh_terms: D000818:Animals; D001895:Boron / Q000737:chemistry*; D016754:Boron Neutron Capture Therapy; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D013762:Tetrahydrofolate Dehydrogenase / Q000187:drug effects
chemical_list: D005493:Folic Acid Antagonists; D013762:Tetrahydrofolate Dehydrogenase; D001895:Boron