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Antioxidant screening by DPPH, ABTS, galvinoxyl, and FRAP methods showed no measurable radical scavenging or reducing activity, indicating that these compounds should not be described as antioxidants. Cytotoxic effects were evaluated in Ishikawa, HepG2, HT-29, MDA-MB-231, and Panc-1 cancer cell lines using the MTT assay, and compounds (3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl 4-(5-(1-methyl-2-phenyl-1H-indol-3-yl)thiophen-2-yl)-4-oxobutanoate (D1), synthesis of (3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i] isochromen-10-yl 4-(5-(1-methyl-2-pentyl-1H-indol-3-yl)thiophen-2-yl)-4-oxobutanoate (D2), and synthesis of (3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl 4-(5-(1-methyl-2-(p-tolyl)-1H-indol-3-yl)thiophen-2-yl)-4-oxobutanoate (D3) were found to exhibit significant cytotoxic activity. Compound D1 (EC50: 20.22 \u03bcM) showed activity similar to paclitaxel (EC50: 19.3 \u03bcM) in Ishikawa cells, while compounds D1 and D2 (EC50: 5.43 \u03bcM, EC50: 5.63 \u03bcM) showed comparable activity to the positive control (EC50: 4.5 \u03bcM) in HepG2 cells; compound D3 (EC50: 2.75 \u03bcM) showed a higher cytotoxic effect. No measurable cytotoxicity was observed in the healthy human endothelial (HUVEC) cell line for any of the tested compounds. Invasion assay showed that compounds D1 and D2 strongly inhibited cell invasion, particularly in HepG2 and Panc-1 cell lines. Annexin V\/PI assays and real-time PCR results showed that the compounds induced apoptosis, increasing the expression of BAX, P53, and caspase genes while suppressing Bcl-2 expression. Overall, the findings indicate that although the compounds studied in this work do not possess antioxidant properties, they exhibit selective cytotoxic, anti-invasive, and proapoptotic effects, warranting further investigation as potential anticancer agent candidates.<\/jats:p>","DOI":"10.1021\/acsomega.6c04482","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T04:59:11Z","timestamp":1785128351000},"page":"46670-46684","source":"Crossref","is-referenced-by-count":0,"title":["Synthesis and Biological\nEvaluation of Thiophene-Bridged\nIndole\u2013Artesunate Hybrids as Selective Anticancer Agents"],"prefix":"10.1021","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6161-2030","authenticated-orcid":true,"given":"Emrah","family":"Kavak","sequence":"first","affiliation":[{"name":"Necmettin Erbakan University, BITAM-Science and Technology Research and Application Center , ,","place":["Konya, Turkey, 42090"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dog\u0306an","family":"C\u0327etin","sequence":"additional","affiliation":[{"name":"Necmettin Erbakan University, BITAM-Science and Technology Research and Application Center , ,","place":["Konya, Turkey, 42090"]},{"name":"Van Yu\u0308zu\u0308ncu\u0308 Yil University , , ,","place":["Van, Turkey, 65080"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Metin","family":"Konus\u0327","sequence":"additional","affiliation":[{"name":"Van Yu\u0308zu\u0308ncu\u0308 Yil University , , ,","place":["Van, Turkey, 65080"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4770-2686","authenticated-orcid":true,"given":"Arif","family":"Kivrak","sequence":"additional","affiliation":[{"name":"Es\u0327kisehir Osmangazi University , , ,","place":["Eskis\u0327ehir, Turkey, 26040"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"2026081110180227800_cit1","doi-asserted-by":"publisher","first-page":"3511","DOI":"10.1080\/14786419.2020.1865954","article-title":"Design, synthesis\nand pharmacological evaluation of novel Artemisinin-Thymol","volume":"36","author":"Kavak","year":"2022","journal-title":"Nat. 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