Design, Synthesis, and Biological Evaluation of Indenoisoquinoline Topoisomerase I Inhibitors Featuring Polyamine Side Chains on the Lactam Nitrogen

Abstract

The indenoisoquinolines are a class of noncamptothecin topoisomerase I inhibitors that display significant cytotoxicity in human cancer cell cultures. They offer a number of potential advantages over the camptothecins, including greater chemical stability, formation of more persistent cleavage complexes, and induction of a unique pattern of DNA cleavage sites. Molecular modeling has suggested that substituents on the indenoisoquinoline lactam nitrogen would protrude out of the DNA duplex in the ternary cleavage complex through the major groove. This indicates that relatively large substituents in that location would be tolerated without compromising biological activity. As a strategy for increasing the potencies and potential therapeutic usefulness of the indenoisoquinolines, a series of compounds was synthesized containing polyamine side chains on the lactam nitrogen. The rationale for the synthesis of these compounds was that the positively charged ammonium cations would increase DNA affinity through electrostatic binding to the negatively charged DNA backbone, and the polyamines might also facilitate cellular uptake by utilization of polyamine transporters. The key step in the synthesis involved the condensation of Schiff bases, containing protected amine side chains, with substituted homophthalic anhydrides, to afford cis-3-aryl-4-carboxy-1-isoquinolones. These isoquinolones were then converted to indenoisoquinolines with thionyl chloride. Although monoamines were much more potent than the lead compound, no significant increase in potency was observed through incorporation of additional amino groups in the side chain. However, one of the monoamine analogues, which features a bis(2-hydroxyethyl)amino group in the side chain, proved to be one of the most cytotoxic indenoisoquinoline synthesized to date, with a GI50 mean-graph midpoint (MGM) of 0.07 microM in the NIH human cancer cell culture screen, and topoisomerase I inhibitory activity comparable to that of camptothecin.

Activity of Indenoisoquinolines against African Trypanosomes

“…The disproportionately low poisoning activity and lack of coincidence between poisoning and cytotoxicity suggest that the stabilization of topoisomerase IB-DNA complexes is not the sole determinant of killing. Perhaps the direct interaction of indenoisoquinolines with DNA (30,35) prevents the topoisomerase from binding to its substrate, thus abrogating their effectiveness as poisons. This phenomenon was previously demonstrated with minor groove binders and mammalian topoisomerase IB (25).…”

“…Some of the indenoisoquinolines have the ability to bind and intercalate into DNA in the absence of the enzyme (30,35,36), and others may even interact directly with the mammalian topoisomerase IB protein at high drug concentrations (29). We have evaluated a battery of indenoisoquinolines (26)(27)(28)30) against T. brucei and we find that they have potent antitrypanosomal activities in vitro, inhibit nucleic acid synthesis in the parasite, act as topoisomerase poisons within the cell, and show preliminary evidence of efficacy in mice challenged with trypanosomes.…”

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 .…”

Intramolecular cyclization of N-(3-oxoalkenyl)phenylacetamides: synthesis of 3-phenyl-2(1H)-pyridones

“…[1][2][3][4][5][6][7] Further, a significant number of compounds with a 2(1H)-pyridinone motif exhibit interesting activities against a number of biological targets, and are used as scaffolds in drug discovery. [8][9][10][11] Methods for 2(1H)-pyridinone ring formation can be based on bi-and multicomponent reactions, intramolecular cyclizations and transformation of other hyterocycles.…”

“…Scheme 1. Base-catalyzed intramolecular cyclization of o-acylaminophenones (1), N-(3-oxoalkyl)amides (2) and N- (3-oxoalkenyl)amides (3).…”