Unveiling the antiglioblastoma potential of harmicens, harmine and ferrocene hybrids : current recommendations and future perspectives

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

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 (IC$_{50}$ = 3.7 ± 0.1 µmol L$^{–1}$, SI = 12.6) and., the C-6 substituted harmicene (IC$_{50}$ = 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.

• Language: English
• Keywords: harmine, β-carboline, ferrocene, hybrid compounds, antiproliferative activity, glioblastoma multiforme, Hsp90, DYRK1A, antioxidant activity, EPR spectroscopy
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2024
• Number of pages: Str. 595-612
• Numbering: Vol. 74, iss. 4
• PID: 20.500.12556/RUL-166656
• UDC: 616-006.48
• ISSN on article: 1846-9558
• DOI: 10.2478/acph-2024-0033
• COBISS.SI-ID: 206354179
• Publication date in RUL: 21.01.2025

Record is a part of a journal

• Title: Acta pharmaceutica
• Shortened title: Acta pharm.
• Publisher: Croatian Pharmaceutical Society
• ISSN: 1846-9558
• COBISS.SI-ID: 3817585

Licences

• License: CC BY-ND 4.0, Creative Commons Attribution-NoDerivatives 4.0 International
• Link: http://creativecommons.org/licenses/by-nd/4.0/
• Description: Under the NoDerivatives Creative Commons license one can take a work released under this license and re-distribute it, but it cannot be shared with others in adapted form, and credit must be provided to the author.

Secondary language

• Language: Slovenian
• Keywords: harmin, β-karbolin, ferocen, hibridne spojine, antiproliferativno delovanje, multiformni glioblastom, Hsp90, DYRK1A, antioksidativna aktivnost, EPR spektroskopija, glioblastom