Discovery of harmiprims, harmine-primaquine hybrids, as potent and selective anticancer and antimalarial compounds.

Autor: Pavić K; University of Zagreb Faculty of Pharmacy and Biochemistry, A. Kovačića 1, 10000 Zagreb, Croatia. Electronic address: kristina.pavic@pharma.unizg.hr., Poje G; University of Zagreb Faculty of Pharmacy and Biochemistry, A. Kovačića 1, 10000 Zagreb, Croatia., Pessanha de Carvalho L; University of Tübingen, Institute of Tropical Medicine, Wilhelmstraße 27, 72074 Tübingen, Germany., Tandarić T; Department of Cell and Molecular Biology, Uppsala University, 75124 Uppsala, Sweden; Rudjer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia., Marinović M; University of Zagreb Faculty of Pharmacy and Biochemistry, A. Kovačića 1, 10000 Zagreb, Croatia., Fontinha D; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal., Held J; University of Tübingen, Institute of Tropical Medicine, Wilhelmstraße 27, 72074 Tübingen, Germany; German Center for Infection Research, Partner Site Tübingen, Tübingen, Germany., Prudêncio M; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal., Piantanida I; Rudjer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia., Vianello R; Rudjer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia., Krošl Knežević I; Rudjer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia., Perković I; University of Zagreb Faculty of Pharmacy and Biochemistry, A. Kovačića 1, 10000 Zagreb, Croatia., Rajić Z; University of Zagreb Faculty of Pharmacy and Biochemistry, A. Kovačića 1, 10000 Zagreb, Croatia. Electronic address: zrinka.rajic@pharma.unizg.hr.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2024 May 01; Vol. 105, pp. 117734. Date of Electronic Publication: 2024 Apr 23.
DOI: 10.1016/j.bmc.2024.117734
Abstrakt: Although cancer and malaria are not etiologically nor pathophysiologically connected, due to their similarities successful repurposing of antimalarial drugs for cancer and vice-versa is known and used in clinical settings and drug research and discovery. With the growing resistance of cancer cells and Plasmodium to the known drugs, there is an urgent need to discover new chemotypes and enrich anticancer and antimalarial drug portfolios. In this paper, we present the design and synthesis of harmiprims, hybrids composed of harmine, an alkaloid of the β-carboline type bearing anticancer and antiplasmodial activities, and primaquine, 8-aminoquinoline antimalarial drug with low antiproliferative activity, covalently bound via triazole or urea. Evaluation of their antiproliferative activities in vitro revealed that N-9 substituted triazole-type harmiprime was the most selective compound against MCF-7, whereas C1-substituted ureido-type hybrid was the most active compound against all cell lines tested. On the other hand, dimeric harmiprime was not toxic at all. Although spectrophotometric studies and thermal denaturation experiments indicated binding of harmiprims to the ds-DNA groove, cell localization showed that harmiprims do not enter cell nucleus nor mitochondria, thus no inhibition of DNA-related processes can be expected. Cell cycle analysis revealed that C1-substituted ureido-type hybrid induced a G1 arrest and reduced the number of cells in the S phase after 24 h, persisting at 48 h, albeit with a less significant increase in G1, possibly due to adaptive cellular responses. In contrast, N-9 substituted triazole-type harmiprime exhibited less pronounced effects on the cell cycle, particularly after 48 h, which is consistent with its moderate activity against the MCF-7 cell line. On the other hand, screening of their antiplasmodial activities against the erythrocytic, hepatic, and gametocytic stages of the Plasmodium life cycle showed that dimeric harmiprime exerts powerful triple-stage antiplasmodial activity, while computational analysis showed its binding within the ATP binding site of PfHsp90.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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