Harmicens, Novel Harmine and Ferrocene Hybrids: Design, Synthesis and Biological Activity
| Autor: | Goran Poje, Marina Marinović, Kristina Pavić, Marija Mioč, Marijeta Kralj, Lais Pessanha de Carvalho, Jana Held, Ivana Perković, Zrinka Rajić |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Metallocenes
Organic Chemistry Antineoplastic Agents Apoptosis General Medicine Pharmacy Catalysis Computer Science Applications G2 Phase Cell Cycle Checkpoints Inorganic Chemistry Harmine Structure-Activity Relationship Chemistry Cell Line Tumor Humans Drug Screening Assays Antitumor Malaria Falciparum Physical and Theoretical Chemistry β-carboline harmine ferrocene hybrid amide triazole synthesis antiplasmodial antiproliferative Molecular Biology Biology Spectroscopy Carbolines Cell Proliferation |
| Zdroj: | International Journal of Molecular Sciences; Volume 23; Issue 16; Pages: 9315 International Journal of Molecular Sciences |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms23169315 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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