A. R. Angeles et al. / Tetrahedron Letters 51 (2010) 6236–6239
6239
Taken together, the data described herein suggest that the
inhibitory activity of (+)-2 in vitro is enantiospecific and was there-
fore selected as one of the promising candidates for further evalu-
ation as an anti-cancer agent. Thus, the initial pharmacokinetic
properties of (+)-2 in rats were evaluated. Happily, the oral bio-
availability was 21% and the oral dosing of 50 mg/kg yielded an
AUC value of 3.9 lM h.
In summary, a highly convergent synthesis of (+)-2, a potent
and orally bioavailable anti-mitotic agent has been accomplished.
Furthermore, an improved method for the preparation of 2,3-
dihydrochroman-4-one derivatives that will serve as precursors
to structurally related compounds has been developed. This chem-
istry lends itself to the development of a SAR program that will be
reported in due course.
Acknowledgments
We thank Dr. Jesse Wong (Discovery Synthesis Group) for scale-
up support. We are indebted to Mr. Jason Hill for chiral separation
and purification of final compounds. We thank Drs. N.-Y. Shih and
John Piwinski for their encouragement and support.
Supplementary data
Supplementary data associated (CCDC 791341 contain the sup-
plementary crystallographic data for compound (ꢀ)-20b. This data
can be obtained free of charge from the Cambridge Crystallo-
with this article can be found, in the online version, at doi:10.
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Table 1
Biological data of compounds (+)-2 and 21a–c
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Compound
KSP IC50 (nM)
EC50 (p-HH3) (nM)
(+)-2
65
>3000
675
1.0
>1000
267
(ꢀ)-21a
(+)-21b
(ꢀ)-21c
23.0
28.0
pharmacodynamic marker, Histone H3 (p-HH3 EC50 = 1 nM), in
A2780 human ovarian carcinoma cells.