Archive for February 6, 2011

Metalloporphyrin Reactivity

Metalloporphyrins are powerful catalysts capable of a wide variety of chemical transformations. Simple modifications to the catalyst system allow for tuning a catalyst for relatively mild oxidations or more difficult to oxidize substrates. Recently, Zhdankin and coworkers have demonstrated a co-catalyst system with an iron porphyrin with a mixture of iodobenzene and oxone allowing for the quantitative conversion of anthracene to anthroquine (1). This system has also shown promise for the oxidation of alkanes and alkenes such as tetrahydronaphthalene, dihydroanthrane and styrene in moderate yields.

With tuning of the catalyst and reaction conditions, metalloporphyrins are also capable of mild oxidations such as sulfoxidations even in the presence of reactive C-H or alcohol functional groups. Huang and coworkers have used a manganese porphyrin-hypochlorite system for the selective oxidation of glycosyl sulfides to the sulfoxides with high diasteromeric excesses (2). Very little sulfone formation and no oxidation on the sugar occurred. These two recent examples show both the selectivity and powerful oxidation capabilities of metalloporphyrins.

1. Yoshimura, A.; Neu, H. M.; Nemykin, V. N.; Zhdankin, V. V., Metalloporphyrin/Iodine(III)-Cocatalyzed Oxygenation of Aromatic Hydrocarbons. Advanced Synthesis & Catalysis 2010, 352, (9), 1455-1460.
2. Huang, J. Y.; Li, S. J.; Wang, Y. G., Selective Oxidation of Glycosyl Sulfides to Sulfoxides with Sodium Hypochlorite and Catalyzed by Metalloporphyrins. Journal of Carbohydrate Chemistry 2010, 29, (3), 142-153.

Structure-Activity Relationship of Hepatotoxicity

Drug induced liver injury is a major cause for withdrawing a drug from development or more dramatically from the market. In a recent article, Dr. Dennis J. Pelletier et Al. performed a SAR study of hepatotoxicity. They used the data from literature and built a structure searchable database. The resulting database was analyzed to identify the chemical structures associated with liver toxicity. Data from over 1266 compounds were collected and a SAR of 38 chemical structures was developed. An interesting chemical structure highlighted as a potential liver toxin is the thiophene ring. Metabolic activation of thiophene leads to a reactive intermediate that can undergo Michael type addition with cellular nucleophiles. See figure below.

 

Interestingly, hepatotoxicity is often due to an activation of the drug resulting from Phase I metabolization. Moreover, this kind of reactive metabolite is present at low levels in the blood stream which makes them difficult to be detected.
Biomimetic technology can allow for the production of such metabolites for biological and toxicology studies which could reduce the drug development attrition due to liver toxicity.
Dennis J. Pelletier et Al.; Chem. Res. Toxicol., 2010, 23, 1215-1222