Design, Synthesis, and Biological Evaluation of Cytotoxic 11-Alkenylindenoisoquinoline Topoisomerase I Inhibitors and Indenoisoquinoline−Camptothecin Hybrids

Abstract

The indenoisoquinolines are a novel class of topoisomerase I (top1) inhibitors that are cytotoxic in cancer cell cultures and are therefore under development as potential anticancer agents. As inhibitors of the DNA religation reaction occurring after DNA cleavage by the enzyme, they are classified as top1 poisons, similar to the camptothecins. Two strategies were employed in order to further develop the structure-activity relationships of the indenoisoquinolines and enhance their therapeutic potential. The first strategy involved the synthesis of indenoisoquinoline-camptothecin hybrid molecules to take advantage of a proposed structural analogy between the indenoisoquinolines and camptothecin. The desired hybrids were synthesized by reaction of halogenated phthalides with a dihydropyrroloquinoline. The second strategy involved the attachment of various alkenyl substituents to the C-11 position of the indenoisoquinolines, which were assumed to project into the DNA minor groove. The required C-11-substituted indenoisoquinolines were synthesized by McMurry reactions of 11-ketoindenoisoquinolines with aldehydes, and the geometries of the resulting alkenes were established by nuclear Overhauser effect difference NMR spectroscopy. All of the new indenoisoquinolines were examined for cytotoxicity in human cancer cell cultures as well as for activity vs top1. Although the indenoisoquinoline-camptothecin hybrid molecules proved to be less cytotoxic and displayed less activity against top1, an analogue incorporating a 3'-aminoalkenyl substituent at the C-11 position of the indenoisoquinoline system was significantly more potent than the prototype indenoisoquinoline in both assays. These results indicate that C-11 aminoalkyl substituents that are assumed to project into the minor groove enhance the cytotoxicity and top1 inhibitory activity of the parent indenoisoquinoline system.

Cellular Topoisomerase I Inhibition and Antiproliferative Activity by MJ-III-65 (NSC 706744), an Indenoisoquinoline Topoisomerase I Poison

“…Non-CPT Top1 inhibitors such as the indolocarbazoles NB-506 and J-107088 are in clinical trials (Meng et al, 2003). More recently, indenoisoquinolines and minor groove binders (benzimidazoles) have been reported to be promising Top1 inhibitors (Strumberg et al, 1999;Cushman et al, 2000;Rangarajan et al, 2000;Jayaraman et al, 2002;Fox et al, 2003;Nagarajan et al, 2003). Preliminary screening of approximately 100 derivatives of our parent indenoisoquinoline compound NSC 314622 has identified MJ-III-65 (NSC 706744) to be a potent inhibitor of purified Top1 in biochemical assay (Cushman et al, 2000;Antony et al, (Ross et al, 1979;Kohn, 1991 .…”

“…Although not as potent as CPT, its chemical stability, unique Top1 cleavage sequence preference, and slower cleavage complex reversibility made NSC 314622 a good lead compound. By chemically modifying NSC 314622, we synthesized indenoisoquinoline derivatives to increase Top1 inhibition and cancer cell cytotoxicity (Strumberg et al, 1999;Cushman et al, 2000;Fox et al, 2003). As reported previously , one of the derivatives MJ-III-65 (NSC 706744), with an amino alcohol instead of a methyl at the N-6 position of the parent compound ( Fig.…”

Novel Indenoisoquinolines NSC 725776 and NSC 724998 Produce Persistent Topoisomerase I Cleavage Complexes and Overcome Multidrug Resistance

“…NSC 314622 served as a lead compound for the development of indenoisoquinolines to overcome some of the limitations of CPTs and to develop novel classes of Top1 inhibitors with different anticancer activity profiles. We have now synthesized and tested >300 indenoisoquinoline derivatives and found that some of them are both very potent Top1 poisons and exhibit antitumor activity in mouse models (10)(11)(12)(13). We have also obtained crystal structures of two different indenoisoquinolines within Top1 cleavage complexes (14)(15)(16).…”

Design, Synthesis, Biological Evaluation, and Molecular Docking Studies of Quinolone Derivatives as Potential Antitumor Topoisomerase I Inhibitors

“…Docking Simulations The pdb file about the crystal structure of DNA-Top I bound to SA315F (PDB code: 1T8I) 28,29) was obtained from the RCSB Protein Data Bank (http://www. pdb.org).…”