1. Unveiling the antiglioblastoma potential of harmicens, harmine and ferrocene hybrids
- Author
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Poje Goran, Šakić Davor, Marinović Marina, You Jiangyang, Tarpley Michael, Williams Kevin P., Golub Nikolina, Dernovšek Jaka, Tomašič Tihomir, Bešić Erim, and Rajić Zrinka
- Subjects
harmine ,β-carboline ,ferrocene ,hybrid compounds ,antiproliferative activity ,glioblastoma multiforme ,hsp90 ,dyrk1a ,antioxidant activity ,epr spectroscopy ,Pharmaceutical industry ,HD9665-9675 - 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 ., 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.
- Published
- 2024
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