Arizona State University

Arizona Board of Regents, a Body Corporate

Noeleen Melody

George R Pettit

George Robert Pettit

The present disclosure relates to Betulastatin compounds, pharmaceutical compositions and kits comprising such compounds, and methods for using such compounds or pharmaceutical compositions.

Betulastatin compounds

The present disclosure relates to Emetine Auristatin compounds, pharmaceutical compositions and kits comprising such compounds, and methods for using such compounds or pharmaceutical compositions.

Emetine auristatin compounds

The present disclosure relates to Quinstatin compounds, pharmaceutical compositions comprising such compounds, kits, and methods for using such compounds or pharmaceutical compositions.

Quinstatin compounds

The present invention provides prodrugs derived from the sparingly soluble anticancer isocarbostyril narciclasine, a component of variousspecies, said prodrugs having potential for use against animal and human cancers. Also disclosed is an efficient procedure for the synthetic conversion of narciclasine to several more soluble cyclic phosphate compounds, including 'narcistatin'. 

Narcistatin prodrugs

The present invention involves use of the compounds narciclasine (2a) and 7-deoxy-narciclasine (2c), which are obtained via isolation from the medicinal plant species(Amaryllidaceae), as precursors in a novel synthesis method in which each of these compounds are selectively hydrogenated to produce trans-dihydronarciclasine (1a) and 7-deoxy-trans-dihydronarciclasine (1c). Also described herein is a novel synthesis method for producing sodium narcistatin (11) from narciclasine (2a). Further described herein are certain novel 3,4-cyclic phosphate prodrugs, including sodium-7-deoxynarcistatin (8), sodium-7-deoxy-transdihydronarcistatin (9), and sodium transdihydronarcistatin (10).

Synthesis of sodium narcistatin and related compounds

Selective phosphorylation of phenpanstatin (3a) with tetrabutylammonium dihydrogen phosphate and dicyclohexylcarbodiimide in pyridine followed by cation exchange chromatographic procedures was found to provide an efficient route to a new series (3b-3d) of promising 3,4-O-cyclic phosphate prodrugs designated phenpanstatin phosphates. Application of analogous reaction conditions to pancratistatin (1a) led to a mixture of monophosphate derivatives where sodium pancratistatin 4-O-phosphate (4a) was isolated and the structure confirmed by x-ray crystallography. Modification of the reaction conditions allowed direct phosphorylation of pancratistatin followed by cation exchange chromatography to afford sodium pancratistatin 3,4-O-cyclic phosphate (5b) which was selected for preclinical development.

Pancratistatin cyclic phosphate prodrugs and phenpanstatin cyclic phosphate prodrugs

The present invention provides prodrugs derived from the sparingly soluble anticancer isocarbostyril narciclasine, a component of various Narcissus species, said prodrugs having potential for use against animal and human cancers. Also disclosed is an efficient procedure for the synthetic conversion of narciclasine to several more soluble cyclic phosphate compounds, including 'narcistatin'. 

Selective phosphorylation of phenpanstatin () with tetrabutylammonium dihydrogen phosphate and dicyclohexyl-carbodiimide in pyridine followed by cation exchange chromatographic procedures was found to provide an efficient mute to a new series (-) of promising 3,4-O-cyclic phosphate prodrugs designated phenpanstatin phosphates. Application of analogous reaction conditions to pancratistatin () led to a mixture of monophosphate derivatives where sodium paancratistatin 4-O-phosphate () was isolated and the structure confirmed by x-ray craxtallography. Modification of the reaction conditions allowed direct phosphorylation of pancratistatin followed by cation exchange chromatography to afford sodium pancratistatin 3,4-O-cyclic phosphate () which was selected for preclinical development.

(+)-Narciclasine (2), available in quantity from certainspecies or by total synthesis, is employed in for a ten step synthetic conversion (3.6% overall yield) to natural (+)-pancratistatin (1a). The key procedures involve the epoxidation of natural (+)-narciclasine (2) to an epoxide (6), reduction of the epoxide (6) to diol (8), formation of cyclic sulfate (12) and its ring opening with cesium benzoate followed by saponification of the benzoate to afford (+)-pancratistatin (1a).

Growing community of inventors

Mesa, AZ, United States of America

Noeleen Melody