binding interactions and is therefore amenable to significant
structural modification. Although changes to this portion of
the molecule do not have a large impact on PKC affinity in
our binding assay, the effect of modifications to the A-ring
on isozyme selectivity and function are not known. Analogue
3 (Figure 1), with an aryl bromide substituent in the A-ring
region of the molecule, was designed to probe the effect of
structural changes in this region on isozyme affinity,
selectivity, and overall function.
The aryl bromide functionality was chosen as a diversi-
fication site that would allow analogue 3 to be rapidly
converted into new, systematically varied analogues with a
common core macrocycle and set of binding elements. The
general chemical stability of this group in addition to the
broad range of C-C, C-N, and C-O bond forming
processes described in the literature9 make this an attractive
functionality for late-stage diversification. The para disposi-
tion of the bromide substituent was chosen to minimize steric
issues that could impede the late-stage coupling reactions
and interfere with C1 domain binding.
Because our analogues are synthesized by coupling a top
“spacer” domain with a bottom “recognition” domain, the
generation of 3 required only the synthesis of a new spacer
domain which could be coupled with the preexisting recogni-
tion domain. Compared to the existing synthesis of the spacer
domain for analogue 2,8 a new and more step-economical
route was developed for the synthesis of analogue 3.
This synthesis was designed to exploit the pseudo-C2
symmetry present in bryostatin analogue spacer domains. The
fact that the C3 and C11 carbinols are symmetrically disposed
with respect to the axis that bisects the A-ring (Scheme 1)
Figure 1. Bryostatin 1 and synthetic analogues.
a treatment for cancer or neurological disease. To address
supply, performance, and mode of action issues, our group
has been involved in the design and synthesis of simplified
bryostatin analogues that can be produced in a practical
fashion and tuned for optimal therapeutic performance.
Representative of these efforts is analogue 1 (Figure 1),
which exhibits in vitro and in vivo biological activities
comparable to or better than bryostatin 1 in various assays.6,7
Analogue 2, with a phenyl group at C9, is representative of
a class of simplified analogues that lack an intact A-ring yet
retain single-digit nanomolar affinity for PKC.8
Scheme 1. Pseudo-C2 Symmetry of the Spacer Domain
Bryostatin is thought to act by modulating the activity and
cellular localization of various C1 domain-containing proteins
such as protein kinase C (PKC). In contrast to molecules
that target the ATP binding site of PKC and function only
as inhibitors, molecules that target the C1 domain can be
designed to inhibit or activate enzyme activity. In addition,
C1 domains are only present in a small subset of the large
family of kinases, offering selectivity in function. The PKC
family is divided into three subclasses: the conventional,
novel, and atypical isozymes. Of these three, bryostatin binds
only to the conventional and novel subclasses (eight isozymes
in total). A long-standing goal in the area of C1 domain
research is to design agents that can selectively regulate one
or a subset of these eight isozymes. Previous work in our
group indicates that the A-ring region of the bryostatin
scaffold is not directly involved in the key C1 domain
suggests that these two stereocenters could be set in a single
transformation through a double asymmetric reduction of a
diketone. This type of strategy has precedent in the work of
Schreiber et al. on the bidirectional synthesis of mycoticin
A.10
The synthetic route designed to take advantage of this
double asymmetric reduction strategy began with conjugate
(5) Lopanik, N.; Lindquist, N.; Targett, N. Oecologia 2004, 139, 131-
139.
(6) Wender, P. A.; Baryza, J. L.; Brenner, S. E.; Clarke, M. O.; Craske,
M. L.; Horan, J. C.; Meyer, T. Curr. Drug DiscoV. Technol. 2004, 1, 1-11.
(7) Wender, P. A.; Baryza, J. L.; Bennett, C. E.; Bi, F. C.; Brenner, S.
E.; Clarke, M. O.; Horan, J. C.; Kan, C.; LaCote, E.; Lippa, B. S.; Nell, P.
G.; Turner, T. M. J. Am. Chem. Soc. 2002, 124, 13648-13649.
(8) Wender, P. A.; Clarke, M. O.; Horan, J. C. Org. Lett. 2005, 7, 1995-
1998.
(9) For recent reviews, see: (a) de Meijere, A., Diederich, F., Eds. Metal-
Catalyzed Cross-Coupling Reactions, 2nd ed.; Wiley-VCH: Weinheim,
2004. (b) Hartwig, J. F. Synlett 2006, 1283-1294. (c) Schlummer, B.;
Scholz, U. AdV. Synth. Catal. 2004, 346, 1599-1626.
(10) Poss, C. S.; Rychnovsky, S. D.; Schreiber, S. L. J. Am. Chem. Soc.
1993, 115, 3360-3361.
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