Colorectal cancer (CRC) is a disease with high incidence and mortality, constituting the fourth most common cause of death from cancer worldwide. Naphthoquinones are attractive compounds due to their biological and structural properties. In this work, 36 naphthoquinone derivatives were synthesized and their activity evaluated against HT-29 cells. Overall, high to moderate anti-proliferative activity was observed in most members of the series, with 15 compounds classified as active (1.73 < IC50 < 18.11 μM). The naphtho[2,3-b]thiophene-4,9-dione analogs showed potent cytotoxicity, 8-hydroxy-2-(thiophen-2-ylcarbonyl)naphtho[2,3-b]thiophene-4,9-dione being the compound with the highest potency and selectivity. Our results suggest that the toxicity is improved in molecules with tricyclic naphtho[2,3-b]furan-4,9-dione and naphtho[2,3-b]thiophene-4,9-dione systems 2-substituted with an electron-withdrawing group. A 3D-QSAR study of comparative molecular field analysis (CoMFA) was carried out, resulting in the generation of a reliable model (r2 = 0.99 and q2 = 0.625). This model allowed proposing five new compounds with two-fold higher theoretical anti-proliferative activity, which would be worthwhile to synthesize and evaluate. Further investigations will be needed to determine the mechanism involved in the effect of most active compounds which are potential candidates for new anticancer agents.

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Purpose: Naphtho[2,3-b]furan-4,9-dione (Avicequinone B), a natural naphthoquinone isolated from the mangrove tree Avicennia alba, is recognized as a valuable synthetic precursor with anti-proliferative effect. However, the molecular mechanism involved in its bioactivity has not been investigated. This study aimed to determine the selectivity of avicequinone B against cancer cells and the transcriptomic changes induced in colorectal cancer (CRC). Methods: The cytotoxic effect against adenocarcinoma-derived cells or fibroblasts was evaluated using MTT assay. In addition, CRC cells were treated with avicequinone B in different settings to evaluate colony-forming ability, cell cycle progression, apoptosis/necrosis induction, and transcriptome response by RNA-seq. Results: Avicequinone B effectively reduced the viability of breast, colorectal, and lung adenocarcinoma cells with IC50 lower than 10 μM, while fibroblasts were less affected. The induction of G2/M arrest and necrosis-like cell death were observed in avicequinone B-treated HT-29 cells. Furthermore, RNA-seq revealed 490 differentially expressed genes, highlighting the reduction of interferon stimulated genes and proliferative signaling pathways (JAK-STAT, MAPK, and PI3K-AKT), as well as the induction of ferroptosis and miR-21 expression. Conclusion: In short, these results demonstrated the therapeutic potential of avicequinone B and paved the foundation for elucidating its mechanisms in the context of CRC.

Naphthoquinones are naturally occurring metabolites with recognized anti-cancer potential but limited clinical application. This study investigated the molecular mechanism of 8-hydroxy-2-(2-thenoyl)naphtho[2,3-b]thiophene-4,9-dione (1), a new candidate for colorectal cancer (CRC) treatment, using different experimental settings: MTT, clonogenic, wound healing, and cell cycle assays; as well as RNA sequencing. Naphthoquinone 1 selectively reduced the viability and migration of HT-29 cells by G2/M arrest and changes in their transcriptome signature with significant effect on cellular survival, proliferation, angiogenesis, response to interferon, oxidative stress, and immune response. Impact analysis identified ferroptosis and MAPK pathways as significantly affected. In summary, our results suggest that 1 induces the selective death of CRC cells by inducing oxidative stress, ferroptosis, and MAPK inhibition.