Cytotoxicity of ferratricarbadecaboranyl complexes in murine and human tissue cultured cell lines.
The ferratricarbadecaboranyl salts [1-(eta 5-C5H5)Fe-2-CH3-2,3,4-C3B7H9] + X-(X- = AsF6-, 1 and SbF6-, 2), as well as the neutral complex, 1-(eta 5-C5H5)Fe-2-CH3-2,3,4-C3B7H9, 4, are effective cytotoxic agents, causing cell death in a number of tissue culture lines, e.g. L-1210, Tmolt3, HL-60, and HeLa-S3. In general, these agents were not active against the solid cell growth, i.e. KB nasopharynx, A431 skin, HCT-8 ileum, SW480 colon, osteosarcoma, and glioma. However, they were active against the growth of lung bronchogenic MB-9812. The mode of action of the derivatives involves inhibition of de novo purine synthesis of L-1210 cells, which reduces DNA and RNA syntheses. Purine synthesis was reduced by complexes [1-(eta 5-C5H5)Fe-2-CH3-2,3,4-C3B7H9]+ [SbF6]- 2 and ¿[1-(eta 5-C5H5)Fe-2-CH3-2,3,4-C3B7H9]+ [SbF6]- [1-(eta 5-C5H5)Fe-4-CH3-2,3,4-C3B7H9]+ [SbF6]-¿ [20:1] 3, at the regulatory enzyme, i.e. PRPP amido transferase. The agents lowered d[ATP] and d[CTP] pools, further reducing DNA synthesis. The salts 1, 2, and 3 were shown to be moderate inhibitors of isolated L-1210 DNA topoisomerase activity. DNA strand scission was evident after incubation with compounds 1-4 and [1-(eta 5-C5H5)Fe-2-CH3-2,3,4-C3B7H9 and 1-(eta 5-C5H5)Fe-4-CH3-2,3,4-C3B7H9] [20:1] 5, for 24 hours at 100 microM, lowering DNA synthesis, and causing cell death. The ferratricarbadecaboranes show activities and specificities different than those found for the analogous ferrocenium salts [(eta 5-C5H5)2Fe]+ [AsF6]- 6 and [(eta 5-C5H5)2Fe]+ [SbF6]- 7, and the neutral ferrocene compound (eta 5-C5H5)2Fe 8. The bioactivites of both the tricarbaboranyl and metallocenium salts are attributed to the cations, since Na+[AsF6]- 9, K+ [AsF6]- 10, Na+[SbF6]- 11, and K+[SbF6]- 12 were found to be inactive at equivalent ionic concentration.
Hall
I H
IH
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27559-7360, USA.
Warren
A E
AE
Lee
C C
CC
Wasczcak
M D
MD
Sneddon
L G
LG
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D005296:Ferrous Compounds / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D005296:Ferrous Compounds; D059005:Topoisomerase II Inhibitors