Unveiling the antiglioblastoma potential of harmicens, harmine and ferrocene hybrids

Poje, Goran; Šakić, Davor; Marinović, Marina; You, Jiangyang; Tarpley, Michael; Williams, Kevin P.; Golub, Nikolina; Dernovšek, Jaka; Tomašič, Tihomir; Bešić, Erim; Rajić, Zrinka

doi:10.2478/acph-2024-0033

Abstract

The poor prognosis of glioblastoma multiforme, inadequate treatment options, and growing drug resistance urge the need to find new effective agents. Due to the significant anti-cancer potential of harmicens, hybrid compounds which comprise harmine/β-carboline and ferrocene moiety, we investigated their antiglioblastoma potential in vitro and mechanism of action (inhibition of DYRK1A, Hsp90, anti-oxidative activity). The results have shown that triazole-type harmicens, namely 5, with a ferrocene moiety in C-3 position of the β-carboline ring (IC₅₀ = 3.7 ± 0.1 µmol L–1, SI = 12.6) and ., the C-6 substituted harmicene (IC₅₀ = 7.4 ± 0.5 µmol L–1, SI = 5.8) exert remarkable activity and selectivity against human malignant glioblastoma cell line (U251) in vitro. On the other hand, amide-type harmicens 10, 12, and 14 exhibited strong, but non-selective activity, in the low micro-molar range. Mechanistic studies revealed that among active compounds, amide-type harmicens 12 and 14 inhibit DYRK1A and Hsp90 CTD, whereas compound 14 showed pronounced antioxidative activity. Therefore, the antiproliferative activity of harmicens might be a combination of complex molecular interactions.

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Unveiling the antiglioblastoma potential of harmicens, harmine and ferrocene hybrids

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