| Abstract
| - The synthesis, characterization, inhibitory activity againsttopoisomerase I, and biologicalevaluation of a series of 14 camptothecin derivatives ofpolypyrrolecarboxamide (lexitropsin)conjugates of two structural classes: (A)camptothecin−NHCO−lexitropsin 44−51 and(B)camptothecin−CONH−lexitropsin 38−43 aredescribed. All 16 compounds tested, 14 conjugatesplus two functionalized camptothecin controls, inhibit topoisomerase Iin the concentrationrange 1.12−16.6 μM that divide into three distinct categories basedon activity. The mostactive enzyme inhibitors belong to structure class A with eithercationic dimethylaminium orneutral amide end groups. Generally class B conjugates are lesseffective in inhibitingtopoisomerase I. Cytotoxic potencies of the drugs was testedagainst four representative humantumor cell lines: SKOV3, SKLVB, HT29, and KB. All 16 drugs gavemeasurable IC50 valuesagainst the KB cell line and fell into two categories withIC50 values of 0.049−0.66 μM (largelystructure class B) and 1.0−48 μM (largely class A). Thus theclass B conjugates, while lesspotent against the enzyme, contain two of the most potent drugs,38 and 39, against KB celllines. In contrast, in the case of the cell lines SKOV3 and HT29there was a general correlationbetween the better topoisomerase inhibitors and their cellcytotoxicities.
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