Johns Hopkins University

Surojit Sur

Bert Vogelstein

Kenneth W Kinzler

Jean-Francois Geschwind

Shanmugasundaram Ganapathy-Kanniappan

Gary H Posner

Theresa A Shapiro

Ik-Hyeon Paik

Andrew J McRiner

Tanzina Labonte

Kristina Borstnik

Jean-François Geschwind

Methods for treating or preventing liver fibrosis in a subject by administering to the subject a therapeutically effective amount of 3-bromopyruvate (3-BrPA) are provided. In addition, methods for promoting the reversal of an activated hepatic stellate cell (HSC) to an inactivated HSC by contacting the activated HSC with at least one 3-bromopyruvate (3-BrPA) molecule are also provided.

Methods of treating liver fibrosis by administering 3-bromopyruvate

The invention provides compositions comprising cyclodextrins encapsulating a selective ATP inhibitor, as well as uses thereof.

Cyclodextrin compositions encapsulating a selective ATP inhibitor and uses thereof

In only two steps and in 65% overall yield, natural trioxane artemisinin (I) was converted on gram scale into C-10-carba trioxane dimer (3). This new, very stable dimer was then transformed easily in one additional step into four different dimers (4-7). Alcohol and diol dimers (4 and 5) and ketone dimer (7) are 10 times more antimalarially potent in vitro than artemisinin (I), and alcohol and diol dimers (4 and 5) are strongly inhibitory but not cytotoxic toward several human cancer cell lines. Water-soluble carboxylic acid derivatives (8-10and 12) were easily prepared from dimers (4-6); they are thermally stable even at 60&#xb0; C. for 24 hours, are more orally efficacious as antimalarials than either artelinic acid or sodium artesunate, and have potent and selective anticancer activities. Further derivitization of the alcohol dimers (4 and 17), diol dimer (5) and ketone (7) has produced a number of analogs also antimalarially active in vitro at sub-nanomolar concentrations (most notably: pyridine N-oxides (13, 15, 18, 23, 24 and 25), phosphoric acid triesters (26 and 27), sulfonamide (40) and cyclic carbonate (41)). In addition, dimers (13 and 19) are more efficacious (when administered both orally and i.v.) and less toxic (when administered intraperitoneally to mice as a single dose) than clinically-used sodium artesunate, thereby giving them a better antimalarial therapeutic index than sodium artesunate.

Orally active, antimalarial, anticancer, artemisinin-derived trioxane dimers

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Gaithersburg, MD, United States of America

Surojit Sur