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

Abstract

A novel approach to indolo[3,2-c]isoquinoline and dibenzo[c,h][1,6]naphthyridine tetracyclic systems was discovered based on switchable reduction of 2-methoxy-3-(2-nitrophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid prepared via Castagnoli–Cushman reaction. Reduction with ammonium formate resulted in the expected selective transformation of the nitro group (thus providing access to substituted dibenzo[c,h][1,6]naphthyridine via cyclization and dehydrogenation). However, attempted reduction with sodium sulfide initiated a previously unknown reaction cascade including double reduction, cyclization, and decarboxylation, leading to formation of indolo[3,2-c]isoquinoline polyheterocycle in one synthetic step.

Discovery of Indolo[3,2-c]isoquinoline Derivatives as Novel Top1/2 Dual Inhibitors with Orally Efficacious Antitumor Activity and Low Toxicity

“…The key heteropolycyclic intermediate (10a) was prepared following the procedure established in a previous study, 35 and the method for synthesizing the other central scaffolds (10b−10g) was similar to that for synthesizing compound 10a. 9-Methoxy-6,11-dihydro-5H-indolo [3,2-c] 6.92 (dd, J = 8.8, 2.5 Hz, 1H), 4.04 (q, J = 6.9 Hz, 2H), 1.38 (t, J = 6.9 Hz, 3H).…”

“…The contrast of the antiproliferative activities of compounds 25−35 revealed that the antitumor activities of compounds 27 and 31 were more potent than those of the 4-methoxy (26), 5-ethoxy (29 and 33), 5difluoromethoxy (28 and 32), 5-isopropoxy (34), and 1,3dioxolane (30 and 35)-substituted analogues, suggesting that the 5-methoxy group on the indole ring was favorable for improving the antitumor activity. In addition, the replacement of the central scaffold of 11H-indolo [3,2-c]isoquinoline (35) by 6,11-dihydro-5H-indolo [3,2-c]isoquinolin-5-one (24) generates less-potent products, and the 1-chlorine substitution on the isoquinoline ring (27) decreases the antiproliferative activity of the compound (31). Among them, compound 31 represents the optimal agent, with IC 50 values of 0.53 μM against the HCT116 cancer cell line, and showed from 3.8-to In addition, the antitumor activities of the heterocyclicsubstituted indolo [3,2-c]isoquinoline derivatives were investigated (Table 3).…”

The Castagnoli–Cushman Reaction

“…The treatment of 2-methoxy-3-(2-nitrophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid ( 146 ) with sodium sulfide yields 147 , which is further transformed to indolo[3,2- c ]isoquinoline ( 148 ). On the other hand, the reduction of 146 with ammonium formate produces 149 which by cyclisation and dehydrogenation yields dibenzo[ c , h ][1,6]naphthyridine ( 150 ; Scheme 47 ) [ 87 ].…”