inhibit or activate kinase activity.9 The PKC family of
isozymes is of additional importance because of its role in
numerous therapeutic indications.10
A major issue associated with the advancement of bryo-
statin toward therapeutic goals has been its limited supply
for clinical use and for mode of action studies. Low isolation
yields as well as environmental concerns make it impractical
to obtain clinically relevant amounts of material from its
natural ecosystem.11 Other sources have been identified, but
an arduous separation and cost are still serious concerns.12
Aquaculture has not proven cost effective thus far.13 Produc-
tion from the symbiont (Candidatus endobugula sertula) or
through genetics is promising but would still be limited to
bryostatin or its biosynthetic derivatives, agents neither
produced nor optimized in nature for human cancer chemo-
therapy.14 Total synthesis would provide greater flexibility
in achieving an optimized clinical candidate and impressive
progress has been made, but at over 70 total steps each, the
current syntheses have not impacted supply or advanced
investigations toward better candidates.15
To address the synthetic, biological, and medicinal chal-
lenges in this area, we set out to design simplified analogs
of bryostatin that could be synthesized in a practical fashion
and that could be tuned for superior clinical function.16 Initial
analog design, using a pharmacophoric model developed in
our group, has led to the synthesis of simplified analogs 1
and 2, which match and surpass, respectively, the potency
of the natural product and are synthesized in a highly
convergent and efficient fashion (Figure 1).17 These analogs
Figure 1. Bryostatin 1 and lead analogs.
can be accessed synthetically in under 30 steps, which makes
them viable clinical candidates given the remarkable potency
of bryostatin in human therapy (ca. 1.2 mg for a multiweek
treatment) and the finding that the analogs are even more
potent than bryostatin in cancer cell growth inhibition. A
key next objective in this area is the identification of analogs
with similarly high potencies but complementary target
selectivities. Toward this end, this study describes the
advancement of our convergent macrotransacetalization
strategy to the synthesis of B-ring modifications of our
designed leads and the initial disclosure of the role of this
modification in PKC binding and translocation.
Analogs 1 and 2, when docked to the proposed binding
site on the PKCδ-C1B domain in our homology model,18
have their C-rings deeply embedded in the binding cavity,
whereas the A- and B-rings are positioned over and away
from the enzyme, potentially interacting with other cellular
components, anchoring proteins, or other portions of the
enzyme upon binding and activation. As such, modifications
to this region of the analog would be expected to retain a
high degree of potency and could potentially be used to
modulate the dynamics of the interaction with receptors as
well as the ADME characteristics of the molecule. To test
this possibility, the predictive value of our homology model,
and the general utility of our synthetic approach, we set out
to make the first B-ring-modified analogs of our lead
compounds.
Recent work from our group has targeted variations to the
A-ring19 and the C20 ester.20 Analogs of the B-ring have
not yet been explored. It was envisioned that a five-
membered B-ring analog could be generated rapidly and
efficiently from 1,2-diols through a macrotransacetalization
with the known recognition domain17 used in the synthesis
of 2. Modeling performed with a conformer of the target
analog 10 (1.2 kcal/mol above the global minimum) showed
an exceptionally good overlay of the hypothesized pharma-
cophoric atoms (C1 carbonyl and C19 and C26 hydroxyls,
(9) Taylor, S. S.; Radzio-Andzelm, E. Curr. Opin. Chem. Biol. 1997, 1,
219-226.
(10) (a) Gavrielides, M. V.; Frijhoff, A. F.; Conti, C. J.; Kazanietz, M.
G. Curr. Drug Targets 2004, 5, 431-443. (b) Lahn, M.; Kohler, G.; Sundell,
K.; Su, C.; Li, S. Y.; Paterson, B. M.; Bumol, T. F. Oncology 2004, 67,
1-10. (c) Mackay, H. J.; Twelves, C. J. Endocr.-Relat. Cancer 2003, 10,
389-396. (d) da Rocha, A. B.; Mans, D. R. A.; Regner, A.; Schwartsmann,
G. Oncologist 2002, 7, 17-33. (e) Caponigro, F.; French, R. C.; Kaye, S.
B. Anti-Cancer Drugs 1997, 8, 26-33 and references therein.
(11) Schaufelberger, D. E.; Koleck, M. P.; Beutler, J. A.; Vatakis, A.
M.; Alvarado, A. B.; Andrews, P.; Marzo, L. V.; Muschik, G. M.; Roacch,
J.; Ross, J. T.; Lebherz, W. B.; Reeves, M. P.; Eberwein, R. M.; Rodgers,
L. L.; Testerman, R. P.; Snader, K. M.; Forenza, S. J. Nat. Prod. 1991, 54,
1265-1270.
(12) Kamano, Y.; Zhang, H.-P.; Hino, A.; Yoshida, M.; Pettit, G. R.;
Herald, C. L.; Itokawa, H. J. Nat. Prod. 1995, 58, 1868-1875.
(13) Mendola, D. In Drugs from the Sea; Fusetani, N., Ed.; Karger:
Basel, 2000; pp 120-133.
(14) For a lead reference, see: Hildebrand, M.; Waggoner, L. E.; Liu,
H.; Sudek, S.; Allen, S.; Anderson, C.; Sherman, D. H.; Haygood, M. Chem.
Biol. 2004, 11, 1543-1552.
(15) (a) Evans, D. A.; Carter, P. H.; Carreira, E. M.; Charette, A. B.;
Prunet, J. A.; Lautens, M. J. Am. Chem. Soc. 1999, 121, 7540-7552. (b)
Kageyama, M.; Tamura, T.; Nantz, M. H.; Roberts, J. C.; Somfai, P.;
Whritenour, D. C.; Masamune, S. J. Am. Chem. Soc. 1990, 112, 7407-
7408. (c) Ohmori, K.; Ogawa, Y.; Obitsu, T.; Ishikawa, Y.; Nishiyama, S.;
Yamamura, S. Angew. Chem., Int. Ed. 2000, 39, 2290-2294.
(16) (a) Wender, P. A.; Cribbs, C. M.; Koehler, K. F.; Sharkey, N. A.;
Herald, C. L.; Kamano, Y.; Pettit, G. R.; Blumberg, P. M. Proc. Natl. Acad.
Sci. U.S.A. 1988, 85, 7197-7201. (b) Wender, P. A.; De Brabander, J.;
Harran, P. G.; Jimenez, J. M.; Koehler, M. F. T.; Lippa, B.; Park, C. M.;
Siedenbiedel, C.; Pettit, G. R. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 6624-
6629. (c) For other work on other simplified bryostatin analogs, see: Keck,
G. E.; Truong, A. P. Org. Lett. 2005, 7, 2153-2156. Hale, K. J.; Frigerio,
M.; Manaviazar, S.; Hummersone, M. G.; Fillingham, I. J.; Barsukov, I.
G.; Damblon, C. F.; Gescher, A.; Robert, G. C. K. Org. Lett. 2003, 5, 499-
502 and references therein.
(18) Wender, P. A.; Baryza, J. L.; Brenner, S. E.; Clarke, M. O.; Craske,
M. L.; Horan, J. C.; Meyer, T. Curr. Drug DiscoVery Technol. 2004, 1,
1-11.
(17) Wender, P. A.; Baryza, J. L.; Bennett, C. E.; Bi, C.; Brenner, S. E.;
Clarke, M. O.; Horan, J. C.; Kan, C.; Lacote, E.; Lippa, B.; Nell, P. G.;
Turner, T. M. J. Am. Chem. Soc. 2002, 124, 13648-13649.
(19) Wender, P. A.; Clarke, M. O.; Horan, J. C. Org. Lett. 2005, 7,
1995-1998.
(20) Wender, P. A.; Baryza, J. L. Org. Lett. 2005, 7, 1177-1180.
1894
Org. Lett., Vol. 8, No. 9, 2006