Synthesis and Antitumor Properties of N-[2-(Dimethylamino)ethyl]carboxamide Derivatives of Fused Tetracyclic Quinolines and Quinoxalines:  A New Class of Putative Topoisomerase Inhibitors

Abstract

A series of tetracyclic quinoline- and quinoxalinecarboxamides were prepared, and their cytotoxicities were evaluated in a series of murine human tumor cell lines. Most of the quinoline derivatives were prepared by an adaptation of the Pfitzinger synthesis, followed by thermal decarboxylation and coupling with N,N-dimethylethylenediamine via a mixed anhydride method using isobutyl chloroformate. The quinoline analogues showed cytotoxicities broadly similar to those of the known tricyclic acridine-4-carboxamide mixed topoI/II inhibitor DACA, with thieno and indeno analogues being the most active. They showed little decrease in potencies against the Jurkat human leukemia topo II-resistant lines JLA and JLC, suggesting their cytotoxicity does not result primarily from inhibition of topo II. The quinoxaline analogues had more varied IC50 values, being on average less cytotoxic than the quinoline derivatives, but appeared to have a similar mode of action. Overall, this new class of compounds appear to be mixed topo I/II inhibitors, up to 3-fold more cytotoxic than DACA in the human leukemia cell lines studied, with in vivo activity in colon 38 comparable to that of DACA and doxorubicin.

Identification and Characterization of a Novel Class of c-Jun N-terminal Kinase Inhibitors

“…Several compounds with related indeno[1,2-b]quinoline and indolo [2,3-b]quinoxaline nuclei have been reported as inhibitors of topoisomerases I and II (Deady et al, 1997(Deady et al, , 1999Chen et al, 2000) and as cytotoxic compounds (Shibinskaya et al, 2010). However, the main effect of topoisomerase inhibitors is cytotoxicity, which was not found with our compounds and probably rules out topoisomerase inhibitory activity for these oxime quinoxalines.…”

Anti-Inflammatory Effects and Joint Protection in Collagen-Induced Arthritis after Treatment with IQ-1S, a Selective c-Jun N-Terminal Kinase Inhibitor

“…For example, several N-(11H-indeno [1,2-b]quinoxalin-11-ylidene)benzohydrazide derivatives with structures related to IQ-1S were recently reported as a-glucosidase inhibitors (Khan et al, 2014), and other structurally unrelated a-glucosidase inhibitors have been reported to have immunosuppressive and immunomodulatory properties (Willenborg et al, 1992;van den Broek et al, 1996). The indeno [1,2-b]quinoxaline nucleus of IQ-1S is a flat aromatic ring structure (Ghalib et al, 2010), and planar fused heterocyclic compounds can exhibit a wide variety of pharmacological activities, including DNA intercalation and inhibition of topoisomerases I/II (Deady et al, 1997;Moorthy et al, 2013). Although we did not evaluate potential DNAintercalating and topoisomerase-inhibiting properties of IQ-1S, this compound was noncytotoxic at high concentrations (Schepetkin et al, 2012), whereas many DNA intercalators (e.g., ellipticine) and topoisomerase inhibitors are cytotoxic (Cros et al, 1975).…”

Topoisomerase I inhibitors and drug resistance

“…Thus, there is an active effort to develop additional topoisomerase I inhibitors with structures and properties distinct from the camptothecins, such as benzophenanthridine alkaloids (nitidine and fagaronine) (Wang LK, 1993), coralyne and its analogues (Wang LK, 1996), intoplicine (Abigerges et al, 1996), Gl147211C (Besterman et al, 1996;Gerrits et al, 1996), quinolines and quinoxalines (Deady et al, 1997), benzimidazoles (Kim et al, 1996), an ellipticine-distamycin hybrid (Riou et al, 1995), and others (Funabashi et al, 1994;Gupta et al, 1995;Meikle et al, 1995;Boege et al, 1996;Cummings et al, 1996;Funayama et al, 1996;Makhey et al, 1996;Ray et al, 1996Ray et al, , 1997Rodriguez-Campos et al, 1996;Xie et al, 1996;Spicer et al, 1997). This promising class of anticancer drugs also exhibits antiviral activity (Priel et al, 1991).…”