INHIBITION OF TOPOISOMERASE-II BY ICRF-193, THE MESO ISOMER OF 2,3-BIS(2,6-DIOXOPIPERAZIN-4-YL)BUTANE - CRITICAL DEPENDENCE ON 2,3-BUTANEDIYL LINKER ABSOLUTE-CONFIGURATION

The bis(2,6-dioxopiperazine)s are a structurally and mechanistically u nique class of topoisomerase II inhibitors that do not bind DNA and th at do not stabilize topoisomerase II-DNA strand passing intermediates (''cleavable complexes''). The most effective topoisomerase II inhibit or in the bis(2,6-dioxopiperazine) series is ICRF-193 (meso or S, R* isomer), with a meso 2,3-butanediyl linker connecting the dioxopiperaz ine rings. The two enantiomeric diastereomers, (R,R) and (S,S), of ICR F-193 possessing the two optically active 2,3-butanediyl linkers have been prepared from their respective optically pure 2,4-diaminobutanes via 2,3-diaminobutane-N,N,N',N'-tetraacetic acid, esterification, and imide formation. Both in vivo and in vitro assays for catalytic inhibi tion of topoisomerase II were employed to show that the (S,S)- and (R, R)-isomers are almost inactive as topoisomerase II inhibitors. The dat a indicate that the meso stereo-chemistry of the alkanediyl linker is crucial for activity and provides additional evidence that the cytotox icity of the bis(2,6-dioxopiperazine)s is due to their ability to inhi bit topoisomerase II.