Bryostatin analogues, synthetic methods and uses

Abstract

Biologically active compounds related to the bryostatin family of compounds, having simplified spacer domains and / or improved recognition domains are disclosed, including methods of preparing and utilizing the same.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application No. 60 / 981,256, filed Oct. 19, 2007, which is incorporated herein by reference in its entirety.GOVERNMENT INTEREST[0002]This invention was made with the support of NIH grant number CA31845. Accordingly, the U.S. Government may have certain rights in this invention.FIELD OF THE INVENTION[0003]The present invention concerns biologically active compounds related to the bryostatin family of compounds, and to methods of preparing and utilizing the same.BACKGROUND[0004]Protein kinase C (PKC) related disorders are important causes of illness, disability and death worldwide, and represent important therapeutic targets. The broad range of disorders which are mediated by PKC include, for example, hyperproliferative diseases, immune related disorders, and cognitive disorders among others. There is need for new therapeutic agents which can target PKC to treat patients with these cond...

AI Technical Summary

Benefits of technology

[0012]where R1 and R2 are independently H, —OH, —OR′, —NH2, —NR′, ═CH2, ═CHR′, ═O, —R′, halogen, —C(R)2—COOR′, —C(R)2—COO—C(R)2—R′, —C(R)2—COO—C(R)2—C═CR′, —(CH2)qO(O)CR′ or —(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, providing that valency is not violated;

[0023]where R1 and R2 are independently H, —OH, —OR′, —NH2, —NR′, ═CH2, ═CHR′, ═O, —R′, halogen, —C(R)2—COOR′, —C(R)2—COO—C(R)2—R′, —C(R)2—COO—C(R)2—C═CR′, —(CH2)qO(O)CR′ or —(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, providing that valency is not violated;

[0035]where R1 and R2 are independently H, —OH, —OR′, —NH2, —NR′, ═CH2, ═CHR′, ═O, —R′, halogen, —C(R)2—COOR′, —C(R)2—COO—C(R)2—R′, —C(R)2—COO—C(R)2—C═CR′, —(CH2)qO(O)CR′ or —(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl, providing that valency is not violated;

[0046]where R1 and R2 are independently H, —OH, —OR′, —NH2, —NR′, ═CH2, ═CHR′, ═O, —R′, halogen, —C(R)2—COOR′, —C(R)2—COO—C(R)2—R′, —C(R)2—COO—C(R)2—C═CR′, —(CH2)qO(O)CR′ or —(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, providing that valency is not violated;

Problems solved by technology

Cancers are generally the result of the transformation of normal cells into modified cells that proliferate excessively, leading to the formation of abnormal tissues or cell populations.

Cancers can significantly impair normal physiological processes, ultimately leading to patient mortality.

However, these approaches are most effective with cancerous lesions that have not yet metastasized to other regions of the body.

Although the bryostatins have been known for some time, their low natural abundance, difficulties in isolation and severely limited availability through total synthesis have impeded efforts to elucidate their mode of action and to advance their clinical development.

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