Poje, Goran; Šakić, Davor; Marinović, Marina; You, Jiangyang; Tarpley, Michael; Williams, Kevin P.; Golub, Nikolina; Dernovšek, Jaka; Tomašič, Tihomir; Bešić, Erim; Rajić, Zrinka (2024) Unveiling the antiglioblastoma potential of harmicens, harmine and ferrocene hybrids. Acta Pharmaceutica, 74 (4). pp. 595-612. ISSN 1846-9558
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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/beta-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 beta-carboline ring (IC50 = 3.7 +/- 0.1 mu mol L-1, SI = 12.6) and 9, the C-6 substituted harmicene (IC50 = 7.4 +/- 0.5 mu mol 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.
| Item Type: | Article | ||||||||||||
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| Uncontrolled Keywords: | harmine; β-carboline; ferrocene; hybrid compounds; antiproliferative activity; glioblastoma multiforme; Hsp90; DYRK1A; antioxidant activity; EPR spectroscopy | ||||||||||||
| Subjects: | NATURAL SCIENCES > Physics NATURAL SCIENCES > Chemistry BIOMEDICINE AND HEALTHCARE > Pharmacy |
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| Divisions: | Division of Physical Chemistry | ||||||||||||
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| Depositing User: | Jiangyang You | ||||||||||||
| Date Deposited: | 17 Apr 2025 12:48 | ||||||||||||
| URI: | http://fulir.irb.hr/id/eprint/9709 | ||||||||||||
| DOI: | 10.2478/acph-2024-0033 |
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