| Summary: | The semisynthesis of renieramycin-type derivatives was achieved under mild and facile conditions by attaching a 1,3-dioxole-bridged phenolic moiety onto ring A of the renieramycin structure and adding a 4′-pyridinecarbonyl ester substituent at its C-5 or C-22 position. These were accomplished through a light-induced intramolecular photoredox reaction using blue light (4 W) and Steglich esterification, respectively. Renieramycin M (<b>4</b>), a bis-tetrahydroisoquinolinequinone compound isolated from the Thai blue sponge (<i>Xestospongia</i> sp.), served as the starting material. The cytotoxicity of the 10 natural and semisynthesized renieramycins against non-small-cell lung cancer (NSCLC) cell lines was evaluated. The 5-<i>O</i>-(4′-pyridinecarbonyl) renieramycin T (<b>11</b>) compound exhibited high cytotoxicity with half-maximal inhibitory concentration (IC<sub>50</sub>) values of 35.27 ± 1.09 and 34.77 ± 2.19 nM against H290 and H460 cells, respectively. Notably, the potency of compound <b>11</b> was 2-fold more than that of renieramycin T (<b>7</b>) and equal to those of <b>4</b> and doxorubicin. Interestingly, the renieramycin-type derivatives with a hydroxyl group at C-5 and C-22 exhibited weak cytotoxicity. In silico molecular docking and dynamics studies confirmed that the mitogen-activated proteins, kinase 1 and 3 (MAPK1 and MAPK3), are suitable targets for <b>11</b>. Thus, the structure–cytotoxicity study of renieramycins was extended to facilitate the development of potential anticancer agents for NSCLC cells.
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