The Johns Hopkins University

Other

Hauser, Inc.

Research Triangle Institute

The University of Liverpool

Theresa A Shapiro

Gary H Posner

Christopher K Murray

Michael H Parker

Randall J Daughenbaugh

Qun Y Zheng

Poonsakdi Ploypradith

Soon Hyung Woo

Suji Xie

Hardwin O'Dowd

Mansukh C Wani

Monroe E Wall

Steven Paul Rannard

Andrew Owen

Surojit Sur

John Northrop

Tanzina Labonte

Jeffrey S Elias

Mikhail Krasavin

Kristina Borstnik

Annette L Bodley

Ik-Hyeon Paik

Andrew J McRiner

Abhai Tripathi

Alison Savage

Rahul P Bakshi

Godfree Mlambo

Lee Tatham

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

Artemisinin analogs having antimalarial, antiproliferative, and antitumor activities and chemoselective methods of making the same

Methods for producing novel artemisinin analogs and artemisinin dimers having antimalarial, antiproliferative and antitumor activities are described herein. These novel artemisinin analogs and artemisinin dimers have the following structure

Artemisinin analogs having antimalarial antiproliferative and antitumor activities and chemoselective methods of making the same

The present invention provides a two-step procedure for the replacement of the pyranose anomeric 10-OH group in dihydroartemisinin by a variety of carbon nucleophiles, resulting in the novel C-10 carbon-substituted trioxanes of structure: ##STR1## wherein, when n is 1, R is selected from a group of unsubstituted or substituted aryls, heteroaryls, polyethylene glycol, acetylenics, or benzoylmethylenes, or alkanoylmethylenes; or when n is 2, R is selected from a group of unsubstituted or substituted aryls, heteroaryls, polyethylene glycol, alkenyls, alkyls, diketones or bis-acetylenes; or when n is 3, R is selected from a group of unsubstituted or substituted aryls, heteroaryls, polyethylene glycol, alkenyls, alkyls, diketones or bis-acetylenes.

C-10 carbon-substituted artemisinin-like trioxane compounds having

The present invention provides a two-step procedure for the replacement of the pyranose anomeric 10-OH group in dihydroartemisinin by a variety of carbon nucleophiles, resulting in the novel C-10 carbon-substituted trioxanes of structure: ##STR1## wherein, when n is 1, R is selected from a group of unsubstituted or substituted aryls, heteroaryls, polyethylene glycol, acetylenics, or benzoylmethylenes, or alkanoylmethylenes; or when n is 2, R is selected from a group of unsubstituted or substituted aryls, heteroaryls, polyethylene glycol, alkenyls, alkyls, diketones or bis-acetylenes.

Biologically-active, water soluble, 3-substituted trioxanes of the formula ##STR1## wherein R represents a COOH-- substituted aryl group, a substituted or unsubstituted heteroaryl group or an alkyl group, and C.sub.12 -(p-carboxy)benzyloxy trioxanes of formula ##STR2## wherein R represents a substituted or unsubstituted alkyl, alkenyl, aryl or heteroaryl group and methods for their use as antiparasitic agents, particularly for the treatment of malaria.

Water-soluble trioxanes as potent and safe antimalarial agents

Camptothecin compounds are effective inhibitors of hemoflagellate growth and are useful in treating leishmaniasis and trypanosomiasis in livestock, other domestic animals and humans.

Inhibition of hemoflagellates by camptothecin compounds

Growing community of inventors

Towson, MD, United States of America

Theresa A Shapiro