The Akt-mTOR signal is important for the survival and proliferation of cancer cells and has become an interesting drug target. In this study, five resveratrol derivatives were evaluated for anticancer activity and Akt/mTOR targeting activity in non-small lung cancer cell lines. The effects of resveratrol derivatives on cell proliferation were assessed by 2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, nucleus staining, and colony formation assay. Furthermore, the effect of resveratrol derivatives on proliferation-related protein expression was analyzed by immunofluorescence and Western blotting. For the structure–activity relationship (SAR), results reveal that two derivatives of resveratrol which are 4,4′-(ethane-1,2-diyl) bis(2-methoxyphenol) (RD2) and the 4-(3-hydroxy-4-methoxyphenethyl)-2-methoxyphenol (RD3) had very similar structures but exerted different cytotoxicity. The IC50 of RD2 and RD3 were 108.6 ± 10.82 and more than 200 µM in the A549 cell line and 103.5 ± 6.08 and more than 200 µM in H23 cells, respectively. RD2 inhibited cell proliferation and induced apoptosis when compared with the control, while RD3 caused minimal effects. Cells treated with RD2 exhibited apoptotic nuclei in a concomitant with the reduction of cellular p-Akt and p-mTOR. RD3 had minimal effects on such proteins. According to these results, molecular docking analysis revealed a high-affinity interaction between RD2 and an Akt molecule at the ATP-binding and the allosteric sites, indicating this RD2 as a potential Akt inhibitor. This study provides useful information of resveratrol derivatives RD2 for treating lung cancer via Akt/mTOR inhibition.

Akt is a key regulatory protein of cancer stem cells (CSCs) and is responsible for cancer aggressiveness and metastasis. Targeting Akt is beneficial for the development of cancer drugs. renieramycin T (RT) has been reported to have Mcl-1 targeting activity, and the study of the structure-activity relationships (SARs) demonstrated that cyanide and the benzene ring are essential for its effects. In this study, novel derivatives of the RT right-half analog with cyanide and the modified ring were synthesized to further investigate the SARs for improving the anticancer effects of RT analogs and evaluate CSC-suppressing activity through Akt inhibition. Among the five derivatives, a compound with a substituted thiazole structure (DH_25) exerts the most potent anticancer activity in lung cancer cells. It has the ability to induce apoptosis, which is accompanied by an increase in PARP cleavage, a decrease in Bcl-2, and a diminishment of Mcl-1, suggesting that residual Mcl-1 inhibitory effects exist even after modifying the benzene ring to thiazole. Furthermore, DH_25 is found to induce CSC death, as well as a decrease in CSC marker CD133, CSC transcription factor Nanog, and CSC-related oncoprotein c-Myc. Notably, an upstream member of these proteins, Akt and p-Akt, are also downregulated, indicating that Akt can be a potential target of action. Computational molecular docking showing a high-affinity interaction between DH_25 and an Akt at the allosteric binding site supports that DH_25 can bind and inhibit Akt. This study has revealed a novel SAR and CSC inhibitory effect of DH_25 via Akt inhibition, which may encourage further development of RT compounds for cancer therapy.

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 (4), a bis-tetrahydroisoquinolinequinone compound isolated from the Thai blue sponge (Xestospongia 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-O-(4′-pyridinecarbonyl) renieramycin T (11) compound exhibited high cytotoxicity with half-maximal inhibitory concentration (IC50) values of 35.27 ± 1.09 and 34.77 ± 2.19 nM against H290 and H460 cells, respectively. Notably, the potency of compound 11 was 2-fold more than that of renieramycin T (7) and equal to those of 4 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 11. Thus, the structure–cytotoxicity study of renieramycins was extended to facilitate the development of potential anticancer agents for NSCLC cells.