Novel boron-containing, nonclassical antifolates: synthesis and preliminary biological and structural evaluation.
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.
Reynolds
Robert C
RC
Drug Discovery Division, Southern Research Institute, Birmingham, Alabama 35205, USA. reynolds@sri.org
Campbell
Shiela R
SR
Fairchild
Ralph G
RG
Kisliuk
Roy L
RL
Micca
Peggy L
PL
Queener
Sherry F
SF
Riordan
James M
JM
Sedwick
W David
WD
Waud
William R
WR
Leung
Adelaine K W
AK
Dixon
Richard W
RW
Suling
William J
WJ
Borhani
David W
DW
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
D005493:Folic Acid Antagonists; D013762:Tetrahydrofolate Dehydrogenase; D001895:Boron