530
J . Org. Chem. 2000, 65, 530-535
Im p r oved Syn th esis of Isogr a n u la tim id e, a G2 Ch eck p oin t
In h ibitor . Syn th eses of Did em n im id e C, Isod id em n im id e A,
Neod id em n im id e A, 17-Meth ylgr a n u la tim id e, a n d
Isogr a n u la tim id es A-C
Edward Piers,* Robert Britton, and Raymond J . Andersen
Departments of Chemistry and Earth and Ocean Sciences, 2036 Main Mall, University of
British Columbia, Vancouver, BC, Canada V6T 1Z1
Received September 16, 1999
A concise, improved synthesis of isogranulatimide (6), a naturally occurring substance with G2
checkpoint inhibition activity, is described. Also reported are the syntheses of didemnimide C (18),
isodidemnimide A (24), neodidemnimide A (36), 17-methylgranulatimide (9), and isogranulatimides
A (10), B (11), and C (12). Compounds 9-12, congeners of isogranulatimide (6), are now available
for biological evaluation.
Ch a r t 1
In tr od u ction
Cells use a series of checkpoints to temporarily halt
cell cycle progression in order to allow time for repair of
damaged DNA.1 The G1 checkpoint prevents damaged
DNA from being replicated in S phase and the G2
checkpoint prevents damaged chromosomes from being
segregated in mitosis. Many human cancers have genetic
defects in their p53 tumor suppressor gene. These p53-
cancers completely lack a G1 checkpoint and have
partially defective G2 checkpoints.2 It has been proposed
that combination therapy utilizing a specific inhibitor of
the G2 checkpoint and a DNA damaging agent would
selectively target p53- cancer cells relative to normal
p53+ cells.3 This approach to increasing the therapeutic
index of radiation or chemotherapy treatments seeks to
take advantage of a well-defined genetic abnormality
found in roughly half of all human cancers.
Two classes of G2 checkpoint inhibitors have been
discovered serendipitously. One class includes the purine
alkaloids caffeine (1) and pentoxifylline (2),4 and the other
includes the bisindolemaleimides staurosporine (3) and
UCN-01 (4)5 (Chart 1). In vitro experiments using a
variety of paired cell lines differing only in their p53
status have shown that caffeine, pentoxifylline, and
UCN01 induce greater sensitivity to DNA damage in
p53- cells than in p53+ cells, validating the potential
usefulness of this approach.6 However, staurosporine and
UCN01 are nonselective kinase inhibitors, and the purine
alkaloids have multiple pharmacological activities. Con-
sequently, none of the substances belonging to these
classes of compounds are sufficiently selective G2 check-
point inhibitors to test the principle of combination
therapy in vivo. Therefore, it is important to find new
selective G2 checkpoint inhibitors to further investigate
this promising approach to cancer treatment.
(1) (a) Hartwell, L.; Weinert, T.; Kadyk, L.; Garvick, B. Cold Spring
Harbor Symp. Quantum Biol. 1994, 59, 259. (b) Kaufmann, W. K.;
Paules, R. S. FASEB J . 1996, 10, 238.
(2) (a) Kastan, M. B.; Onyekwere, O.; Sidransky, D.; Vogelstein, B.;
Craig, R. W. Cancer Res. 1991, 51, 6304. (b) Paules, R. S.; Levedakalou,
E. N.; Wilson, S. J .; Innes, C. L.; Rhodes, N.; Tisty, T. D.; Galloway,
D. A.; Donehower, L. A.; Tainsky, M. A.; Kaufmann, W. K. Cancer Res.
1995, 55, 1763.
(3) (a) Murray, A. W. Nature 1992, 359, 599. (b) Weinert, T.; Lydall,
D. Cancer Biol. 1993, 4, 129. (c) Nurse, P. Cell 1997, 91, 865.
(4) (a) Busse, P. M.; Bose, S. K.; J ones, R. W.; Tolmach, L. J . Radiat.
Res. 1978, 76, 292. (b) Schlegel, R.; Pardee, A. B. Science 1986, 232,
1264. (c) Downes, C. S.; Musk, S. R. R.; Watson, J . V.; J ohnson, R. T.
J . Cell Biol. 1990, 110, 1855. (d) Andreassen, P. R.; Margolis, R.L. Proc.
Natl. Acad. Sci. U.S.A. 1992, 89, 2272.
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Wang, Q.; Fan, S.; Eastman, A.; Worland, P. J .; Sausville, E. A.;
O’Connor, P. M. J . Nat. Can. Inst. 1996, 88, 956.
Recently, we have used a novel high throughput assay
to screen marine natural product extracts for metabolites
(6) (a) Fan, S.; Smith, M. L.; Rivet, D. J .; Duba, D.; Zhan, Q.; Kohn,
K. W.; Firnace, J . A.; O’Connor, P. M. Cancer Res. 1995, 55, 1649. (b)
Russell, K. J .; Weins, L. W.; Demers, G. W.; Galloway, D. A.; Plon, S.
E. Groudine, M. Cancer Res. 1995, 55, 1639. (c) Powell, S. N.; DeFrank,
J . S.; Connell, P.; Eogan, M.; Preffer, F.; Dombkowski, D.; Tang, W.;
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10.1021/jo9914723 CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/29/1999