5588
A. L. Ruchelman et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5585–5589
cells. The increased cytotoxic activity of 10a relative to
the ester 9a could also be partly attributed to the anti-
cipated increased stability of 10a relative to 9a in cell
culture media. The propyl homologue, 10b, had signifi-
cantly reduced TOP1-targeting activity and cytotoxicity
in these cell lines. It was also evident that both 10a and
10b, unlike 1, were substrates for the efflux transporters
MDR1 and BCRP, based upon their significantly
reduced toxicity in both KBV-1 and KBH5.0 cells rela-
tive to their parent cell line, KB3-1. As anticipated for
compounds that principally exert their cytotoxic activity
by targeting TOP1, these amide derivatives exhibited
decreased cytotoxic activity in CPT-K5 and P388/
CPT45 relative to their parent cell lines, RPMI8402
and P388, respectively.
Acknowledgements
This study was supported by Grant CA098127 (E.J.L.)
and Grant CA39662(L.F.L.) and Grant CA077433
(L.F.L.) from the National Cancer Institute.
References and notes
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