Antitumor activity of mono- and dimetallic transition metal carborane complexes of Ta, Fe, Co, Mo, or W.
Complexes containing Ta, Fe, Co, Mo, or W metal centers that are bound to C2B4 or C2B3 small carborane ligands proved to be potent cytotoxic agents in murine and human tissue cultured cells, being more effective in suspended leukemia and lymphomas but surprisingly also effective against the growth of selected solid tumors. These complexes inhibited nucleic acid metabolism, specifically DNA and purine de novo syntheses. Key enzyme activities in nucleic acid metabolism which were inhibited by the complexes were P388 DNA polymerase a, ribonucleotide reductase, dihyrofolate reductase, PRRP-amidotransferase and IMP dehydrogenase. The complexes afforded a moderate amount of DNA-fragmentation in P388 lymhocytic leukemia cells and were moderate inhibitors of human DNA topoisomerase II activity; however, the DNA molecule itself was not a target of the complexes in that there was no evidence that the complexes caused intercalation between base pairs, caused cross-linking of the strands of DNA or alkylated the bases of DNA.
Hall
I H
IH
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27599-7360, USA.
Lackey
C B
CB
Kistler
T D
TD
Durham
R W
RW
Russell
J M
JM
Grimes
R N
RN
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001880:Boranes / Q000494:pharmacology*; D003035:Cobalt / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis; D006801:Humans; D007501:Iron / Q000494:pharmacology*; D007941:Leukemia P388 / Q000188:drug therapy / Q000473:pathology; D008982:Molybdenum / Q000494:pharmacology*; D009942:Organometallic Compounds / Q000494:pharmacology*; D013635:Tantalum / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured; D014414:Tungsten / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001880:Boranes; D009942:Organometallic Compounds; D059005:Topoisomerase II Inhibitors; D003035:Cobalt; D013635:Tantalum; D008982:Molybdenum; D004247:DNA; D007501:Iron; D014414:Tungsten