ABSTRACT
A series of 4beta-[(4' '-benzamido)-amino]-4'-O-demethyl-epipodophyllotoxin derivatives (11-23) were designed to enhance DNA topoisomerase II inhibition, overcome drug resistance, and modulate water solubility of etoposide (1) analogues. The target compounds were synthesized and evaluated for their effects against DNA topoisomerase II and KB or 1-resistant KB-7d tumor cells in tissue culture. As compared with 1, most compounds showed superior inhibition against both KB and KB-7d cells. Nine compounds (13-18, 20-22) induced higher levels of cellular protein-linked DNA breaks than did 1. Ten compounds selected from these and related derivatives were further examined for their antitumor spectra and drug-resistance profiles. Like 1, these compounds selectively inhibited the growth of KB (nasopharyngeal) and 1A9 (ovarian) tumor cells. More notably, they retained inhibitory activity against etoposide-, camptothecin-, and paclitaxel-resistant KB or 1A9 subclones. In general, these C(4)-modified new derivatives exhibited superior activity profiles, particularly against drug-resistant cell lines, to those of 1. Preliminary metabolism studies on compounds 16 and 20 revealed that 20 was relatively resistant to metabolism by rat serum and liver enzymes, while 16 was metabolically unstable.
Subject(s)
Antineoplastic Agents/chemical synthesis , Benzamides/chemical synthesis , Podophyllotoxin/analogs & derivatives , Podophyllotoxin/chemical synthesis , Topoisomerase II Inhibitors , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzamides/chemistry , Benzamides/pharmacology , Cell Division/drug effects , Cell Line, Tumor , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Drug Stability , In Vitro Techniques , Microsomes, Liver/metabolism , Podophyllotoxin/chemistry , Podophyllotoxin/pharmacology , Rats , Serum , Solubility , Structure-Activity RelationshipABSTRACT
A new series of short pyrrole tetraamides are described whose submicromolar DNA binding affinity is an essential component for their strong antibacterial activity. This class of compounds is related to the linked bis-netropsins and bis-distamycins, but here, only one amino-pyrrole-carboxamide unit and an amidine tail is connected to either side of a central dicarboxylic acid linker. The highest degree of DNA binding, measured by compound-induced changes in UV melting temperatures of an AT-rich DNA oligomer, was observed for flat, aromatic linkers with no inherent bent, i.e., terephthalic acid or 1,4-pyridine-dicarboxylic acid. However, the antibacterial activity is critically linked to the size of the N-alkyl substiutent of the pyrrole unit. None of the tetraamides with the commonly used methyl-pyrrole showed antibacterial activity. Isoamyl- or cyclopropylmethylene-substituted dipyrrole derivatives have the minimum inhibitory concentrations in the submicromolar range. In vitro toxicity against human T-cells was studied for all compounds. The degree to which compounds inhibited cell growth was neither directly correlated to DNA binding affinity nor directly correlated to antibacterial activity but seemed to depend strongly on the nature of the N-alkyl pyrrole substituents.