Dibenzo[c,h][1,5]naphthyridinediones as Topoisomerase I Inhibitors: Design, Synthesis, and Biological Evaluation

Abstract

Dibenzo[c,h][1,5]naphthyridinediones were prepared via a novel synthetic pathway. The compounds were designed as topoisomerase I (Top1) inhibitors based on the indenoisoquinoline series of drugs. The results of biological evaluation demonstrate that, unlike very closely related dibenzo[c,h][1,6]naphthyridinediones, dibenzo[c,h][1,5]naphthyridinediones retain the Top1 inhibitory activity of similarly substituted indenoisoquinolines.

Design and Synthesis of Indenoisoquinolines Targeting Topoisomerase I and Other Biological Macromolecules for Cancer Chemotherapy

“…Since the C-ring of the indenoisoquinolines does not offer attractive locations for the incorporation of nitrogen, it was expanded to a six-membered ring using an additional nitrogen atom. These studies were supported by the previously reported biological interest in nitidine chloride ( 14 ), topovale ( 70 ), and structurally related heterocyclic systems. , The resulting compounds had moderate biological activities, as represented by the dibenzo­[ c , h ]­naphthyridine systems 71 (Top1 ++, MGM 4.3 μM) and 72 (Top1 +++, MGM 3.3 μM). Although the overall MGM values for 71 and 72 were moderate, they retained potent anticancer activities in a number of cell lines.…”

“…The azaindenoisoquinolines were inspired by the results of the quantum mechanics calculations of indenoisoquinoline binding, since they emphasized the importance of π–π stacking in the ternary complexes. , The design of the inhibitors was complicated by the existence of opposing forces, since the incorporation of electronegative nitrogen atoms in the scaffold facilitates π–π stacking through increasing charge-transfer complex formation, but the electronegative nitrogens generally decrease the favorable dispersion contribution to π–π stacking, with the exception being the 7-aza compounds . That realization, along with the experimental biological results observed from rotating a nitrogen atom to all possible locations in the scaffold, ,,,,, led subsequent azaindenoisoquinoline design efforts exclusively down the 7-azaindenoisoquinoline pathway. , …”

“…40,41 The design of the inhibitors was complicated by the existence of opposing forces, since the incorporation of electronegative nitrogen atoms in the scaffold facilitates π−π stacking through increasing charge-transfer complex formation, but the electronegative nitrogens generally decrease the favorable dispersion contribution to π−π stacking, with the exception being the 7-aza compounds. 33 That realization, along with the experimental biological results observed from rotating a nitrogen atom to all possible locations in the scaffold, 24,32,33,35,72,73 led subsequent azaindenoisoquinoline design efforts exclusively down the 7-azaindenoisoquinoline pathway. 34,50 The fact that more than 700 indenoisoquinolines have already been synthesized and tested brings up the question of what more, if anything, can be done.…”

Rational Design of Benzylidenehydrazinyl-Substituted Thiazole Derivatives as Potent Inhibitors of Human Dihydroorotate Dehydrogenase with in Vivo Anti-arthritic Activity

“…The preparations of the esterified derivatives ( 22 , 23 ) are shown in Supplementary Scheme S4 . For these compounds, the esterification reactions of 2-formylbenzoic acid were firstly performed to obtain the methyl ester and ethyl esters without affecting the aldehyde group 58 . Thiazole hydrazine was obtained via the condensation of thiosemicarbazide and 2-bromo-1-phenylethanones in 1,4-dioxane at room temperature.…”

Two Annulated Azaheterocyclic Cores Readily Available from a Single Tetrahydroisoquinolonic Castagnoli–Cushman Precursor

“…Firstly, nitroso compounds have been established as intermediates in the reduction of nitroarenes with inorganic sulfides [28]. Decarboxylation of THIQ acids such as 5 is a known process occurring under similarly forcing conditions [29]. Decarboxylation of postulated intermediate A could be driven forward by the presence of the nearby nitroso functionality which, in turn, intercepts the carbanion generated upon the loss of CO 2 .…”