Bryostatin analogues, synthetic methods and uses

a technology of biloblastin and analogues, applied in the field of biloblastin, can solve the problems of patient mortality, abnormal tissue or cell population formation, and impaired normal physiological processes

Inactive Publication Date: 2010-11-04
THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0080]In still another aspect, the invention relates to a method of treating hyperproliferative cellular disorders, particularly cancer in a mammal by administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I, II, III, IV, V or VI or a pharmaceutically acceptable salt thereof, either alone or in combination with a second agent, preferably a second anti-cancer agen

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 c

Method used

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  • Bryostatin analogues, synthetic methods and uses
  • Bryostatin analogues, synthetic methods and uses
  • Bryostatin analogues, synthetic methods and uses

Examples

Experimental program
Comparison scheme
Effect test

example 1

Exemplary Precursors

[0452]1A. Protected Diol Aldehyde 102

[0453]Benzyl bromide (7.0 mL, 57.7 mmol) and freshly prepared Ag2O (11.0 g, 48.1 mmol) were added successively to an Et2O (150 mL) solution of R-(+)-methyl lactate (5.0 g, 48.1 mmol) at rt (room temperature). The resulting suspension was brought to reflux and stirred for 2 h. The reaction was cooled to rt, filtered through a pad of Celite™ and concentrated in vacuo. Chromatography on silica gel (10% EtOAc / hexanes) afforded 7.5 g (80%) of benzyl ether A1 as a colorless oil:

[0454]A1: Rf (15% EtOAc / hexanes)=0.66; IR 2988, 2952, 2874, 1750, 1497, 1454, 1372, 1275, 1207, 1143, 1066, 1025, 739, 698 cm−1; 1H NMR (300 MHz, CDCl3) δ 1.44 (3H, d, J=6.8 Hz, C27), 3.75 (3H, S, CH3O), 4.07 (1H, q, J=6.8 Hz, C26), 4.45 (1H, d, J=11.7 Hz, CH2Ph), 4.69 (1H, d, J=11.7 Hz, CH2Ph), 7.28-7.37 (5H, m, Ph); 13C NMR (75 MHz, CDCl3) δ 18.6, 51.8, 71.9, 73.9, 127.7, 127.8, 128.3, 137.4, 173.6; HRMS Calcd for C11H14O3 (M+): 194.0943. Found: 194.0942.

[0...

example 2

Exemplary Linkers

[0494]2A. Ketal Acid 406

[0495]Formula 402

[0496]To a stirred solution of the 1,3 menthone acetal of 1,3,5-pentanetriol 401 (3.33 g, 13 mmol) prepared by the method of Harada et al. (1993) in 23 mL of anhydrous CH2Cl2 was added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin periodinane, 6.60 g, 15.6 mmol) in a single portion. The mixture was stirred at rt for 30 min, poured onto a column of silica gel and the product eluted with 15% EtOAc / hexanes to afford 3.013 g (90%) of pure aldehyde 402 as a colorless oil.

[0497]402: Rf (20% EtOAc / hexanes)=0.50; IR (film) 2952, 2869, 1728, 1456, 1383, 1308, 1265 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.80 (1H, dd, J=1.8, 2.5 Hz), 4.36 (1H, dddd, J=2.9, 4.3, 7.4, 8.2 Hz), 4.13 (1H, ddd, J=2.7, 11.7, 11.9 Hz), 3.83 (1H, ddd, J=1.3, 5.2, 11.7 Hz), 2.72 (1H, ddd, J=1.9, 3.1, 13.5 Hz), 2.56 (1H, ddd, J=2.5, 8.2, 16.1 Hz), 2.44 (1H, ddd, J=1.8, 4.3, 16.1 Hz), 2.39 (1H, dsept, J=1.6, 7.1 Hz), 1.54-1.76 (3H, m), 1.29-1.53 (4H...

example 3

Exemplary Bryostatin Analogues

[0561]3A. Formula II—C26 Des-Methyl Bryostatin Analogue (702)

201.1 (Formula 201 where R20 is —O—CO—C7H15 and R21 is ═CH—CO2Me)

[0562]To di-benzyl ether 111.1 (Example 1C, 503 mg, 0.169 mmol) in EtOAc (12.3 mL) at room temperature is added Pd(OH)2 / C (82 mg). The black slurry was stirred vigorously and the flask was evacuated and refilled 4 times with hydrogen (1 atm). After 1 h, the reaction was poured directly onto a silica column and eluted (50% EtOAc / pentane to 100% EtOAc) to provide 201.1 (240.2 mg, 65%) as a colorless oil.

[0563]201.1: Rf (50% EtOAc / pentane)=0.36; IR (film)=3424, 2955, 2930, 2857, 1748, 1722, 1156, 1081, 837, 776 cm−1; 1H NMR (300 MHz, CDCl3) δ 0.00 (6H, s), 0.84-0.93 (12H, m), 0.96 (3H, s), 0.98 (3H, s), 1.20 (3H, d, J=6.0 Hz), 1.15-1.38 (10H, m), 1.62 (1H, t, J=7.1 Hz), 1.71 (1H, t, J=5.7 Hz), 2.25-2.45 (2H, m), 2.54 (1H, s), 2.89 (1H, d, J=4.2 Hz), 3.34-3.48 (1H, m), 3.36 (3H, s), 3.52 (2H, dd, J=15.9, 9.6 Hz), 3.58-3.76 (3H, m), 3...

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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...

Claims

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Application Information

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IPC IPC(8): C07D493/16
CPCC07D493/22
Inventor WENDER, PAUL A.
Owner THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV
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