Method of treating cancer using C-26 modified bryostatin

Details Method of treating cancer using C-26 modified bryostatin Method of treating cancer using C-26 modified bryostatin

1999-02-16

2000-05-09

Krass, Frederick

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

549267, 514451, 514459, 514460, 514883, 514885, 514908, 514950, A01N 4302

Patent

active

060605057

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD OF THE INVENTION

The present invention relates to modified bryostatins and the use of these compounds as anticancer drugs.


BACKGROUND OF THE INVENTION

Bryostatin is a potential cancer chemotherapeutic agent in clinical trials with positive responses observed for some cancers. Bryostatins are typically isolated from the marine bryozoan Bugula neritina, although those skilled in the art will appreciate that other sources for bryostatins and closely related compounds will exist.
Bryostatins comprise macrocyclic lactones of the structure shown in FIG. 1. Bryostatins derived from nature contain R.sub.1, and R.sub.2 groups selected according to Table 1.


Table 1

Side-chain group designations for isolated bryostatins.


______________________________________ R.sub.1 R.sub.2 ______________________________________ BRYO- STATIN 1 #STR1## #STR2## - BRYO- STATIN 2 OH #STR3## - BRYO- STATIN 4 #STR4## #STR5## - BRYO- STATIN 5 #STR6## #STR7## - BRYO- STATIN 6 #STR8## #STR9## - BRYO- STATIN 7 #STR10## #STR11## - BRYO- STATIN 8 #STR12## #STR13## - BRYO- STATIN 9 #STR14## #STR15## - BRYO- STATIN 10 H TR16## - BRYO- STATIN 11 H TR17## - BRYO- STATIN 12 #STR18## #STR19## - BRYO- STATIN 13 HSTR20## ______________________________________
Bryostatins, as a class of compounds, are known to be potent ligands for protein kinase C that function as partial antagonists (Lewin et al., Biochem. Pharmacol., 43, 2007-2014 (1992); Kraft et al., Proc. Natl. Acad. Sci. USA, 83, 1334-1338 (1986)). Because of the high affinity of bryostatins for protein kinase C and the central role of protein kinase C activity in the regulation of cellular function, bryostatins have been thought to exert an antineoplastic activity through protein kinase C.
In vitro, bryostatins activate individual protein kinase C isozymes to an extent similar to that of typical phorbol esters (Kazanietz et al., Mol. Pharmacol., 46, 374-379 (1994)). Biologically, however, bryostatins function as a partial antagonist for a subset of phorbol ester induced responses (Blumberg et al., in New Leads and Targets in Drug Research, Alfred Benzon Symposium 33, pp. 273-285 (Munksgaard, Copenhagen)). Multiple mechanistic differences have been proposed to contribute to their unique spectrum of biological response, including in vivo selectivity for the protein kinase C isozymes .delta. and .epsilon. (Szallasi et al., Mol. Pharmacol., 46, 840-850 (1994)); slow kinetics of protein kinase C translocation, and protection of protein kinase C-.delta. from down regulation at high doses (Szallasi et al., Mol. Pharmacol., 46, 840-850 (1994), Szallasi et al., J. Biol. Chem., 269, 2118-2124 (1994)). However, both the protection of protein kinase C-.delta. (Szallasi et al., supra J. Biol. Chem., (1994)), and the antagonism of phorbol ester action on Friend erythroleukemia cell differentiation (Dell'Aquilla et al., Cancer Res., 47, 6006-6009 (1987)) were demonstrated to be noncompetitive between bryostatin and phorbol ester. These two anomalies demonstrated that the working understanding of bryostatin mechanisms of action was incomplete. One possible explanation would be that bryostatins bind to receptors that phorbol esters do not bind in order to induce their antineoplastic effect. This explanation, if correct, would suggest that the antineoplastic target of bryostatins might not be protein kinase C. Similarly, results comparing the extent of arachidonic acid release induced in C3H10T1/2 cells by bryostatin analogs and phorbol esters suggested similar concepts (Dell'Aquilla et al., Cancer Res., 48, 3702-3708 (1988)). Nonetheless, the antineoplastic actions of bryostatin were still commonly thought to be mediated via the protein kinase C pathway because of a lack of affirmative data to the contrary.
A fairly detailed understanding of both phorbol ester and bryostatin interactions with the phorbol ester binding domain of protein kinase C exists. The structure-activity relations

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