Unveiling the antiglioblastoma potential of harmicens, harmine and ferrocene hybrids

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 <i>in vitro</i> and mechanism of action (inhibition of DYRK1A, Hsp90, anti-oxidative activity). The results have shown that triazole-type harmicens, namely <b>5</b>, with a ferrocene moiety in C-3 position of the β-carboline ring (<i>IC</i> ₅₀ = 3.7 ± 0.1 µmol L-1, SI = 12.6) and ., the C-6 substituted harmicene (<i>IC</i> ₅₀ = 7.4 ± 0.5 µmol L-1, SI = 5.8) exert remarkable activity and selectivity against human malignant glioblastoma cell line (U251) <i>in vitro</i>. On the other hand, amide-type harmicens <b>10</b>, <b>12</b>, and <b>14</b> exhibited strong, but non-selective activity, in the low micro-molar range. Mechanistic studies revealed that among active compounds, amide-type harmicens <b>12</b> and <b>14</b> inhibit DYRK1A and Hsp90 CTD, whereas compound <b>14</b> showed pronounced antioxidative activity. Therefore, the antiproliferative activity of harmicens might be a combination of complex molecular interactions.