K. Lackey et al., WATER-SOLUBLE INHIBITORS OF TOPOISOMERASE-I - QUATERNARY SALT DERIVATIVES OF CAMPTOTHECIN, Journal of medicinal chemistry, 39(3), 1996, pp. 713-719
Eleven water soluble 7-substituted quaternary ammonium salt derivative
s of 10,11-(methylenedioxy)- and 10,11-(ethylenedioxy)-(20S)-camptothe
cin were synthesized via the Friedlander reaction followed by nucleoph
ilic displacement with an aromatic amine. All of these compounds were
more potent than camptothecin in the in vitro cleavable complex assay.
These inherently charged camptothecin derivatives were cytotoxic agai
nst three different human tumor cell lines (SKOV3, an ovarian adenocar
cinoma; SKVLB a multidrug resistant ovarian adenocarcinoma; and HT-29,
a colon carcinoma). A selected group of five compounds was evaluated
in the nude mouse HT-29 xenograft model. Two of these quaternary salts
(17 and 18) were more efficacious than Topotecan in delaying tumor gr
owth. In an extended in vivo model, 18 demonstrated tumor regression.