DNA intercalation and poisoning topoisomerase I/II (topo I/II) are considered the mechanisms of action. (23) Indoloquinolines (backbone B in Chart 1) are known to induce apoptosis in cancer cells. Later, other possible targets have been identified, namely, sirtuins, (20,21) GSK3β, (18,19,22,23) and mitochondrial malate dehydrogenase. (1−17) Indolobenzazepines or paullones (backbone A in Chart 1), first synthesized in 1992, were discovered as potential inhibitors of cyclin-dependent kinases (Cdks) (7,18,19) with antiproliferative activity similar to that of flavopiridol, the first Cdk-inhibitor that reached clinical trials as an anticancer drug. Indolobenzazepines and indoloquinolines are fused heterocyclic scaffolds, which have gained a considerable interest in the field of medicinal chemistry. Furthermore, molecular modeling of the ligands and complexes showed a good fit to the binding pockets of these targets. HL 8 showed selective inhibition for the PIM-1 enzyme, while 8 revealed strong inhibition of five other enzymes, i.e., SGK-1, PKA, CaMK-1, GSK3β, and MSK1, from a panel of 50 kinases. In addition, the copper(II) complexes had higher affinity to DNA than their metal-free ligands. The lead compounds HL 4 and 4 as well as HL 8 and 8 induced apoptosis efficiently in Colo320 cells. The copper(II) complexes revealed low micro- to sub-micromolar IC 50 values with promising selectivity toward human colon adenocarcinoma multidrug-resistant Colo320 cancer cells as compared to the doxorubicin-sensitive Colo205 cell line. The structures of five compounds ( HL 6, ♽MF,, ♰.5H 2O, and Cl♲DMF) were elucidated by single crystal X-ray diffraction.

A series of latonduine and indoloquinoline derivatives HL 1– HL 8 and their copper(II) complexes ( 1–8) were synthesized and comprehensively characterized.

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