Design and synthesis of harmiquins, harmine and chloroquine hybrids as potent antiplasmodial agents

Poje, Goran; Carvalho, Laís Pessanha de; Held, Jana; Moita, Diana; Prudêncio, Miguel; Perković, Ivana; Tandarić, Tana; Vianello, Robert; Rajić, Zrinka

doi:10.1016/j.ejmech.2022.114408

Cited by 20 publications

(16 citation statements)

References 56 publications

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“…Since both methods required starting building blocks based on harmine and ferrocene motifs, i.e., azides and alkynes or amines and carboxylic acids, extensive synthetic work was performed prior to the synthesis of the title compounds. In our previous work, we synthesized azides at the C-1 and C-3 ( 3 and 6 ), alkynes at the O-6, O-7, and N-9 ( 10 , 13 , and 16 ), and amines at the C-1, C-3, O-6, O-7, and N-9 positions of the β-carboline ring ( 4 , 7 , 11 , 14 , and 17 ) [ 31 , 32 , 33 , 35 ]. Here, we present the synthesis of alkynes at the C-1 and C-3 ( 2 , 9 ) and azides at the O-6, O-7, and N-9 ( 12 , 15, and 18 ) positions of the β-carboline ring.…”

Section: Resultsmentioning

confidence: 99%

“…Our previous work on harmine hybrids, i.e., harmicines, harmirins, and harmiquins, demonstrated that the development of hybrids is indeed a valid strategy for obtaining biologically active compounds that exhibit more pronounced activity than the parent compounds [ 31 , 32 , 33 , 34 , 35 ]. Encouraged by the literature data, which clearly show the potential of organometallic compounds as anticancer and antimalarial therapeutics [ 36 , 37 , 38 , 39 , 40 , 41 ], we set out to prepare harmicens—hybrids in which ferrocene is covalently bound to harmine/β-carboline ( Figure 1 ), and to investigate their antiproliferative and antiplasmodial activities.…”

Section: Introductionmentioning

confidence: 99%

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

Poje

Marinović

Pavić

et al. 2022

IJMS

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Poje

Marinović

Pavić

et al. 2022

IJMS

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“…β-carboline alkaloids are a remarkable family of natural and synthetic alkaloids with diverse pharmacological activities (Byun et al, 2022;Poje et al, 2022;Wu et al, 2020). Harmine, a classical small molecule β-carboline alkaloid (Figure 1a), is known for its biological and anti-cancer activities and has received a great deal of interest in cancer research (Dai et al, 2012;He et al, 2022;Nafie et al, 2021;Uhl et al, 2018;Wu et al, 2019;Zhang et al, 2014;Zhu et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Activation of endoplasmic reticulum stress by harmine suppresses the growth of esophageal squamous cell carcinoma

Fan

Wang

et al. 2023

Phytotherapy Research

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The worldwide overall 5‐year survival rate of esophageal squamous cell carcinoma (ESCC) patients is less than 20%, and novel therapeutic strategies for these patients are urgently needed. Harmine is a natural β‐carboline alkaloid, which received great interest in cancer research because of its biological and anti‐tumor activities. The aim of this study is to examine the effects of harmine on ESCC and its mechanism. We investigated the effects of harmine on proliferation, cell cycle, apoptosis, and tumor growth in vivo. RNA sequencing (RNA‐seq), real‐time PCR, and western blotting were used to detect the mechanism. Harmine inhibited ESCC cell growth in vitro and tumor growth in vivo. Differentially expressed genes in harmine‐treated ESCC cells were mainly involved in protein processing in the endoplasmic reticulum (ER). Real‐time PCR and western blotting confirmed harmine‐induced cellular ER stress. CRISPR‐Cas9 knockout of C/EBP homologous protein (CHOP) abolished harmine‐induced expression of death receptor 5 and apoptosis. Harmine also induced the expression of CHOP‐mediated sestrin‐2, which in turn contributes to autophagosome formation via suppressing the AMP‐activated protein kinase‐protein kinase B‐mammalian target of rapamycin signaling pathway. In conclusion, our results demonstrate that harmine inhibits the growth of ESCC through its regulation of ER stress, suggesting that it is a promising candidate for ESCC treatment.

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“…2 Since the discovery of quinine and the potent antipaludic activity of its quinolinic nucleus, significant efforts have been made to obtain new natural or synthetic structures containing this nucleus to provide novel treatment for the abovementioned problem. [3][4][5] As a privileged fragment, quinoline is a rigid, planar molecule, which is a pharmacophore present in the core of numerous physiologically active agents that display interesting therapeutic properties. 6 Structurally, quinoline can be readily modified with a broad range of substituents to provide the molecular diversity necessary to achieve a library of compounds, among which different members can show different biological effects.…”

Section: Introductionmentioning

confidence: 99%

Optimization of the synthesis, in silico ADME/Tox profiling studies, and evaluation of the antimalarial activity of (7-chloroquinolin-4-ylthio)alkylbenzoate derivatives

Gutiérrez

Fernández-Moreira

Acosta

et al. 2023

Journal of Chemical Research

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Optimized reaction conditions are developed to obtain a series of [(7-chloroquinolin-4-yl)sulfanyl] alcohol derivatives as intermediates to prepare a range of (7-chloroquinolin-4-ylthio) alkylbenzoate derivatives. The structures of all the synthesized compounds are confirmed from their infrared and nuclear magnetic resonance spectral data, and by elemental analysis. In silico ADME/Tox profiling studies of the synthesized molecules are undertaken, and the potential antimalarial activity of the products is determined. In vitro, all the prepared compounds significantly reduce heme crystallization with IC50 values of < 10 µM. In vivo, the reduction in parasitemia levels and survival time increases are marginal.

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Design and synthesis of harmiquins, harmine and chloroquine hybrids as potent antiplasmodial agents

Cited by 20 publications

References 56 publications

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

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

Activation of endoplasmic reticulum stress by harmine suppresses the growth of esophageal squamous cell carcinoma

Optimization of the synthesis, in silico ADME/Tox profiling studies, and evaluation of the antimalarial activity of (7-chloroquinolin-4-ylthio)alkylbenzoate derivatives

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