The University of Texas System

Pharmacyclics, Inc.

Other

Vladimir A Kral

Jonathan L Sessler

Brent L Iverson

Kevin Shreder

Hiroyuki Furuta

Tarak D Mody

Gregory W Hemmi

Richard E Thomas

Darren Magda

Richard A Miller

Anthony M Harriman

William E Allen

Texaphyrins substituted with imidazda are provided.

Texaphyrins substituted with imidazole are provided

The present invention is directed to highly boronated derivatives of expanded porphyrins including sapphyrins and texaphyrins, and more particularly to expanded porphyrins substituted with carborane clusters. Such compositions are useful in boron neutron capture therapy, radiation therapy, photodynamic therapy, and other applications.

Highly boronated derivatives of texaphyrins

Matrix-supported sapphyrins

Texaphyrins are provided for use as radiation sensitizers. Advantageous properties of texaphyrins for use as a radiation sensitizer include: i) a low redox potential which allows radiation-induced hydrated electrons to flow to texaphyrin rather than neutralizing hydroxyl radicals, allowing hydroxyl radicals to cause cellular damage, ii) a relatively stable texaphyrin radical that reacts readily to covalently modify neighboring molecules causing further cellular damage, iii) intrinsic biolocalization, and iv) indifference to the presence or absence of O.sub.2. These properties allow texaphyrins to be particularly effective for treating the hypoxic areas of solid neoplasms. Methods of treatment for an individual having a neoplasm or atheroma include the use of a texaphyrin as a radiation sensitizer and as an agent for photodynamic tumor therapy, or the use of a texaphyrin for internal and for external ionizing radiation. Novel texaphyrins are provided.

Metal complexes of texaphyrins

The present invention provides various novel covalently modified sapphyrin derivatives and conjugates; polymers including sapphyrin or derivatives thereof; and chromatographic supports including sapphyrins and other expanded porphyrins and derivatives thereof. Disclosed are water soluble sapphyrins, including polyhydroxysapphyrins and sapphyrin-sugar derivatives; sapphyrin-metal chelating conjugates; sapphyrin nucleobase conjugates; oligosapphyrins and polysapphyrins, including sapphyrin dimers, trimers, oligomers and higher polymers; and polymer supported expanded porphyrin compositions, including advantageous rubyrin- and sapphyrin-based chromatography columns and electrophoretic supports. Sapphyrin oligomers and polymers and polymer supported expanded porphyrins, such as, e.g., glass and silica expanded porphyrin constructs, are disclosed which include both repeating units of sapphyrin derivatives alone and which include other units, for example, nucleobases, sapphyrin-nucleobase conjugates and long chain alkyl groups.

Method for separating molecules

Method of cleaving DNA

Pyrole nitrogen-substituted texaphyrins

Sapphyrins are provided having appended functional groups that render the sapphyrin water-soluble. Such water-soluble sapphyrins are useful for photodynamic therapy, for example.

Water-soluble sapphyrins

The present invention provides various covalently modified sapphyrin derivatives and conjugates, and also, polymers including sapphyrin or derivatives thereof. Disclosed are water soluble sapphyrins, including polyhydroxysapphyrins and sapphyrin-sugar derivatives; sapphyrin-metal chelating conjugates; sapphyrin nucleobase conjugates; and polymer supported sapphyrins. Novel sapphyrin dimers, trimers, oligomers and polymers are also described, which polymers may include repeating units of sapphyrin or sapphyrin derivatives alone, or may further incorporate other units such as nucleobases.

Sapphyrin chelator derivatives

A method of using texaphyrins as radiosensitizers. Advantageous properties of texaphyrins for use as a radiosensitizer include i) a low redox potential which allows radiation induced solvated electrons to flow to texaphyrin rather than neutralizing hydroxyl radicals, allowing the hydroxyl radicals to cause cellular damage, ii) a relatively stable texaphyrin radical which, nevertheless, reacts readily to covalently modify neighboring molecules causing further cellular damage, and iii) intrinsic biolocalization and indifference to the presence of O.sub.2 which allow texaphyrin to be particularly effective for treating the hypoxic areas of solid tumors. Sensitizer enhancement ratios of 1.62 and 2.2 were achieved at 20 .mu.M and 80 .mu.M gadolinium-texaphyrin, respectively, with a mouse leukemia cell line. Methods of treatment for an individual having a tumor include the use of a texaphyrin as a radiosensitizer and as an agent for photodynamic tumor therapy, or the use of a texaphyrin for internal and for external ionizing radiation. New water soluble hydroxy-substituted texaphyrins are described.

Growing community of inventors

Austin, TX, United States of America

Vladimir A Kral