Inhibition of topoisomerase I function by nitidine and fagaronine

Abstract

The benzophenanthridine alkaloids nitidine and fagaronine were characterized as inhibitors of topoisomerase I function. In common with the antitumor agent camptothecin, both nitidine and fagaronine stabilized the covalent binary complex formed between calf thymus topoisomerase I and DNA. The effects of these compounds were readily apparent at 0.15-0.3 microM concentrations. Both nitidine and fagaronine inhibited the topoisomerase I-mediated relaxation of supercoiled pSP64 plasmid DNA more effectively than camptothecin; unlike camptothecin, both of these benzophenanthridine alkaloids also bound directly to and mediated the unwinding of B-form DNA. Nitidine and fagaronine were also studied in comparison with camptothecin to determine the sequence specificity of DNA breaks produced from a 32P-end-labeled duplex in the presence of topoisomerase I. All three compounds produced very similar cleavage patterns. The specificity of nitidine and fagaronine for inhibiting topoisomerase I function was studied by measuring the effects of the compounds on the unknotting of P4 DNA by calf thymus topoisomerase II. Moderate inhibition of topoisomerase II-mediated unknotting was obtained, but only in the presence of high (i.e., 40 microM) concentrations of nitidine and fagaronine. In comparison, doxorubicin inhibited topoisomerase II to the same extent as nitidine and fagaronine when it was employed at 2.5 microM concentration and was strongly inhibitory when employed at 10 microM concentration.

Synthesis, structure, antimycobacterial and anticancer evaluation of new pyrrolo-phenanthroline derivatives

“…On the other hand, phenanthroline, azaindolizine and phenanthridine derivatives were successful identified as DNA intercalating agents or possessing antimycobacterial activity 26,30,[40][41][42][43] . In the same time, benzo[c]phenanthridinium alkaloids as fagaronine and nitidine which showed antileukemic activity on rodents 44 and act as topoisomerase I and II inhibitors [45][46][47] , played the role of model compound for the development of new anticancer agents 14 . Having all these above consideration in mind and encouraged by our previous promising results in the field of anti-TB [25][26][27][28] and anticancer 29,30,32 derivatives with indolizine and/or phenanthroline skeleton, we have focused on the design of novel structures that contain four or five fused (hetero)cycles with pyrrolo[2,1-c] [4,7]phenanthroline skeleton (Scheme 3).…”

Inhibition of topoisomerase IIα and G2 cell cycle arrest by NK314, a novel benzo[c]phenanthridine currently in clinical trials

“…Fagaronine has been reported to be a DNA binding agent and inhibitor of topoisomerases (4,5). Nitidine has also been reported to be a topoisomerase I inhibitor (6). However, neither of these compounds was developed as an anticancer drug because of low potency.…”

“…Further study showed that NK109 was reduced to an inactive metabolite in vivo. To overcome this route of metabolic elimination, NK314 was synthesized by introducing a trimethylene group to N 5 -C 6 of NK109 (ref. 10; Fig.…”

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).…”