Harmicens, Novel Harmine and Ferrocene Hybrids: Design, Synthesis and Biological Activity

Abstract

Cancer and malaria are both global health threats. Due to the increase in the resistance to the known drugs, research on new active substances is a priority. Here, we present the design, synthesis, and evaluation of the biological activity of harmicens, hybrids composed of covalently bound harmine/β-carboline and ferrocene scaffolds. Structural diversity was achieved by varying the type and length of the linker between the β-carboline ring and ferrocene, as well as its position on the β-carboline ring. Triazole-type harmicens were prepared using Cu(I)-catalyzed azide-alkyne cycloaddition, while the synthesis of amide-type harmicens was carried out by applying a standard coupling reaction. The results of in vitro biological assays showed that the harmicens exerted moderate antiplasmodial activity against the erythrocytic stage of P. falciparum (IC50 in submicromolar and low micromolar range) and significant and selective antiproliferative activity against the MCF-7 and HCT116 cell lines (IC50 in the single-digit micromolar range, SI > 5.9). Cell localization experiments showed different localizations of nonselective harmicene 36 and HCT116-selective compound 28, which clearly entered the nucleus. A cell cycle analysis revealed that selective harmicene 28 had already induced G1 cell cycle arrest after 24 h, followed by G2/M arrest with a concomitant drastic reduction in the percentage of cells in the S phase, whereas the effect of nonselective compound 36 on the cell cycle was much less pronounced, which agreed with their different localizations within the cell.

The anti‐breast cancer therapeutic potential of 1,2,3‐triazole‐containing hybrids

“…[181] The SAR revealed that the carbon spacer between 1,2,3-triazole and isatin as well as substituent at C-5 position of isatin moiety influenced the activity greatly, [181] and replacement of isatin moiety by pteridin-4(3H)-one or naphthalimide resulted in the loss of activity, [182,183] whereas replacement by 9H-pyrido [3,4-b]indole was tolerated as evidenced by that ferrocene-1,2,3-triazole-9H-pyrido [3,4-b]indole hybrids 142a,b (IC 50 : 3.7 and 6.8 µM, MTT assay) showed higher antiproliferative activity against MCF-7 breast cancer cells than harmine (IC 50 : 13.6 µM) and 5-fluorouracil (IC 50 : 23.9 µM). [184,185] In addition, 0.013-18.5 µM, MTT assay) exhibited considerable antiproliferative activity against MCF-7 breast cancer cells, and the SAR elucidated that electron-donating group especially methoxy group on the phenyl ring was favorable to the activity, and the number of methoxy groups was in positive correlation with the activity. [186] In particular, hybrids was one of the mechanisms of action.…”

“…[ 181 ] The SAR revealed that the carbon spacer between 1,2,3‐triazole and isatin as well as substituent at C‐5 position of isatin moiety influenced the activity greatly, [ 181 ] and replacement of isatin moiety by pteridin‐4(3 H )‐one or naphthalimide resulted in the loss of activity, [ 182,183 ] whereas replacement by 9 H ‐pyrido[3,4‐b]indole was tolerated as evidenced by that ferrocene‐1,2,3‐triazole‐9 H ‐pyrido[3,4‐b]indole hybrids 142a,b (IC 50 : 3.7 and 6.8 µM, MTT assay) showed higher antiproliferative activity against MCF‐7 breast cancer cells than harmine (IC 50 : 13.6 µM) and 5‐fluorouracil (IC 50 : 23.9 µM). [ 184,185 ] In addition, hybrids 142a,b (IC 50 : 46.5 and 43.0 µM) also displayed relatively low cytotoxicity towards normal HEK‐293T cells.…”

Research progress on the antitumor effects of harmine

“…designed and synthesized 18 novel compounds by combining harmine and ferrocene. Compound 36 exhibited a better antitumor activity than its parent compound in vitro ( 65 ).…”

Biological Activity of Amidino-Substituted Imidazo [4,5-b]pyridines

“…Working dilutions were freshly prepared on the day of testing. After 72 h of incubation, the cell growth rate was evaluated using the MTT assay as described previously [33]. Absorbance of the samples was measured at 570 nm, and OD values were used to calculate the 50% inhibitory concentration (IC 50 ).…”