Synthesis and Comparative Toxicology of a Series of Polyhedral Borane Anion-Substituted Tetraphenyl Porphyrins

Three structurally similar tetraphenylporphyrins bearing polyhedral borane anions have been synthesized and their toxicological profiles obtained in rats. These conjugates were found to have quite different acute toxicities as manifested at the maximum tolerated dose (MTD). When given at the MTD and...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2007-02, Vol.50 (4), p.820-827
Main Authors: Koo, Myoung-Seo, Ozawa, Tomoko, Santos, Raquel A, Lamborn, Kathleen R, Bollen, Andrew W, Deen, Dennis F, Kahl, Stephen B
Format: Article
Language:English
Subjects:
Animals
Anions
Biological and medical sciences
Boranes - chemical synthesis
Boranes - chemistry
Boranes - toxicity
Chemical and Drug Induced Liver Injury - etiology
Drug toxicity and drugs side effects treatment
Heart Diseases - chemically induced
Hemorrhage - chemically induced
Kidney Diseases - chemically induced
Liver - drug effects
Liver - enzymology
Liver - pathology
Lung Diseases - chemically induced
Male
Maximum Tolerated Dose
Medical sciences
Necrosis
Pharmacology. Drug treatments
Porphyrins - chemical synthesis
Porphyrins - chemistry
Porphyrins - toxicity
Rats
Rats, Inbred F344
Thrombocytopenia - chemically induced
Toxicity: blood
Weight Gain - drug effects
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Summary:Three structurally similar tetraphenylporphyrins bearing polyhedral borane anions have been synthesized and their toxicological profiles obtained in rats. These conjugates were found to have quite different acute toxicities as manifested at the maximum tolerated dose (MTD). When given at the MTD and observed over 28 days, the most acutely toxic porphyrin was found to be devoid of toxicity, as measured by blood chemistry panels. The remaining two less acutely toxic compounds both elicited significant changes, characterized by moderate to severe thrombocytopenia, failure to gain weight normally and changes in liver enzymes indicative of mild hepatotoxicity. All toxic effects were transient, with platelets rebounding to above normal levels at day 28. We conclude that thrombocytopenia is the dose limiting toxicity for boronated porphyrins in mammals and suggest that these effects may be due to the porphyrin, not the borane or carborane.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm060895b