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 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.
Koo
Myoung-Seo
MS
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94143, USA.
Ozawa
Tomoko
T
Santos
Raquel A
RA
Lamborn
Kathleen R
KR
Bollen
Andrew W
AW
Deen
Dennis F
DF
Kahl
Stephen B
SB
D000818:Animals; D000838:Anions; D001880:Boranes / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D006331:Heart Diseases / Q000139:chemically induced; D006470:Hemorrhage / Q000139:chemically induced; D007674:Kidney Diseases / Q000139:chemically induced; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced; D008297:Male; D020714:Maximum Tolerated Dose; D009336:Necrosis; D011166:Porphyrins / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344; D013921:Thrombocytopenia / Q000139:chemically induced; D015430:Weight Gain / Q000187:drug effects
C509964:5,10,15,20-tetraphenylporphyrin; D000838:Anions; D001880:Boranes; D011166:Porphyrins