S. Narayan et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1630–1633
1633
IMR-90 human fibroblasts at concentrations up to 1
l
M. In these
access each analog, we were able to carry out a wide range of
chemistry on this highly complex scaffold. These side chain modi-
fications led to eribulin analogs that possess low- to sub-nM anti-
proliferative potency against both sensitive and resistant human
cancer cell lines in vitro. Furthermore, these compounds displayed
extremely low P-gp susceptibility as measured by differential anti-
proliferative activity against related sensitive and P-gp over-
expressing cell lines. Finally, in vivo activity in mouse xenograft
models was observed in case of some compounds.
studies, proliferation-independent nonspecific toxicity was not ob-
served (data not shown), indicating that the activity of the com-
pounds in this study is specific for proliferating cells.
Pharmacokinetic studies revealed that many compounds from
this series had good exposure levels in mice following intravenous
dosing. Specifically, compound concentration over 3–4 h after dos-
ing was found to be higher than the antiproliferative IC50 value
measured in cell culture (data not shown). Accordingly, a few can-
didate compounds were selected for in vivo evaluation in tumor
xenograft models.
Acknowledgments
Moderate in vivo antitumor activity was observed with several
analogs against LOX human melanoma xenografts in athymic mice.
For purposes of direct comparison, all compounds were tested at
0.1 mg/kg using the same Q1D Â 5[Â2] dosing schedule (once dai-
ly, five days a week for two weeks); that is, no attempt was made
to optimize the dose or the regimen for each compound. The data
for compounds 4 and 10 are shown in Figure 4. Overall, significant
inhibition of tumor growth by both compounds was observed,
although the levels of activity seen were somewhat less than that
of eribulin at the same dose. For compounds 4 and 10, tumor
growth was strongly inhibited as long as compound administration
continued, with tumor sizes increasing post dosing. No signs of
toxicity such as lowering of body weight or water uptake were evi-
dent. Although these in vivo data for non-amine-containing com-
We thank our colleagues in Andover’s section of Pharmaceutical
Science and Technology Core Function Unit (formerly Andover Pro-
cess Research and Chemical Development Departments) for the
supply of eribulin and other intermediates and many helpful
discussions.
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5
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Figure 4. Effect of compounds 4 and 10 on the growth of subcutaneous LOX
melanoma xenografts in athymic mice. Compounds were dosed intravenously once
daily, 5 days a week, for two weeks. Compounds 4, 10 and eribulin were dosed at
0.1 mg/kg; the positive control paclitaxel was dosed at 20 mg/kg.
25. Narayan, S. et al Bioorg. Med. Chem. Lett. 2011, 21, 1630.