A series of
camptothecin open-ring
lactone tripartate conjugates were synthesized, in which
polyamine side chains with different architecture (ethane-1,2-diamine, spermidine, homospermidine, spermine, and 4,8,13,17-tetraza-icosane-1,20-diamine) are linked to the 21-carboxylic function through an amidic bond, while the 17-CH(2)OH is acetylated. The rationale for the synthesis of these compounds was to explore the influence of the
polyamine architecture on the activity of these
CPT conjugates into cells, since the positively charged
ammonium cations would favor interaction through electrostatic binding to the negatively charged
DNA backbone.
Topoisomerase I-mediated DNA cleavage assay was used to investigate the ability of these compounds to stimulate the DNA damage. The cleavage pattern was found to be similar to that of SN38 for all the new CPTs. The
CPT tripartates were tested for growth inhibition ability against the human
non-small-cell lung cancer carcinoma NCI-H460 cell line. Although these compounds were less potent than
topotecan, SN38, and
CPT after 1 h of treatment, the antiproliferative effects greatly increased after 72 h of exposure. The growth inhibition potency during long-term exposure is correlated with the number of charges of the 21-amide substituent. Both cleavage assay and in vitro effects support the interpretation that the compounds may have inhibitory activity also in the open-ring form. The architecture of the
polyamine moiety is important for antiproliferative activity, and a balance between the hydrophilic and lipophilic properties of the
polyamine is critical for
CPT potency.