Cytotoxicity of tantalum(V) and niobium(V) small carborane complexes and mode of action in P388 lymphocytic leukemia cells

Abstract

The metallacarboranes (Et2C2B4H4)‐­TaCl2(C5H5) (1), (Et2C2B4H4)NbCl2(C5H5) (2), (Et2C2B4H4)TaCl2(C5Me5) (3), [(Me3Si)2­C2B4H4]TaCl2(C5H5) (4) and (Me2C2B4H4)‐­TaCl2(C5H5) (5) are potent cytotoxic agents against suspended tumors, producing cell death in several tissue culture lines; for example, all were effective against murine L1210 lymphoid leukemia, and all except 5 against murine P388 lymphocytic growth. Human leukemic growth is also retarded since 1–4 were effective against Tmolt3 cell leukemia, all except 4 against Tmolt4 leukemia, and 1, 2, and 5 against HI‐60 leukemia. Cytotoxicity was found towards HuT‐8 lymphoma, THP‐1 acute monocytic leukemia and suspended HeLa‐S3 uterine carcinoma. Some but not all of the complexes were active against Sk‐2 melanoma and Mcf‐7 breast effusion growth. Mode‐of‐action studies in P388 lymphocytic leukemia cells showed that de novo purine synthesis was inhibited; this inhibition reduces DNA and RNA syntheses. Purine synthesis was reduced by compounds 3 and 4 at the regulatory enzymes, i.e. phosphoribosyl pyrophosphate (PRPP) amidotransferase and dihydrofolate reductase. The agents lowered d[ATP] and d[CTP] pools, further reducing DNA synthesis. The complexes afforded DNA fragmentation leading to apoptosis, but this was not by a mechanism of nucleoside alkylation, intercalation between base‐pairs or cross‐linking of the DNA strands. Copyright © 2000 John Wiley & Sons, Ltd.

Metallacarborane Sulfamides: Unconventional, Specific, and Highly Selective Inhibitors of Carbonic Anhydrase IX

“…Despite the successful exploitation of icosahedral dicarbaboranes in drug design, relatively little attention has been paid to metallacarboranes and other chemically and thermally stable boron cage compounds. ,,, Some smaller metallacarboranes have a cytostatic effect, ,− and derivatives of icosahedral cobalt bis­(dicarbollide) ion [(1,2-C 2 B 9 H 11 ) 2 -3,3′-Co] − can specifically inhibit HIV protease. − Antiviral, antifungal, and antibacterial activity and the ability to penetrate artificial lipid bilayers and cellular membranes have been reported for some metallacarborane derivatives. ,− …”