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Synthesis and In Vitro Activity of Novel Melphalan Analogs in Hematological Malignancy Cells

Despite the continuous developments in pharmacology and the high therapeutic effect of new treatment options for patients with hematological malignancies, these diseases remain a major health issue. Our study aimed to synthesize, analyze in silico, and determine the biological properties of new melp...

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Autores principales: Poczta, Anastazja, Krzeczyński, Piotr, Tobiasz, Joanna, Rogalska, Aneta, Gajek, Arkadiusz, Marczak, Agnieszka
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8836188/
https://www.ncbi.nlm.nih.gov/pubmed/35163680
http://dx.doi.org/10.3390/ijms23031760
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author Poczta, Anastazja
Krzeczyński, Piotr
Tobiasz, Joanna
Rogalska, Aneta
Gajek, Arkadiusz
Marczak, Agnieszka
author_facet Poczta, Anastazja
Krzeczyński, Piotr
Tobiasz, Joanna
Rogalska, Aneta
Gajek, Arkadiusz
Marczak, Agnieszka
author_sort Poczta, Anastazja
collection PubMed
description Despite the continuous developments in pharmacology and the high therapeutic effect of new treatment options for patients with hematological malignancies, these diseases remain a major health issue. Our study aimed to synthesize, analyze in silico, and determine the biological properties of new melphalan derivatives. We obtained three methyl esters of melphalan having in their structures amidine moieties substituted with thiomorpholine (EM–T–MEL), indoline (EM–I–MEL), or 4-(4-morpholinyl) piperidine (EM–MORPIP–MEL). These have not yet been described in the literature. The in vitro anticancer properties of the analogs were determined against THP1, HL60, and RPMI8226 cells. Melphalan derivatives were evaluated for cytotoxicity (resazurin viability assay), genotoxicity (alkaline comet assay), and their ability to induce apoptosis (Hoechst33342/propidium iodide double staining method; phosphatidylserine translocation; and caspase 3/7, 8, and 9 activity measurements). Changes in mitochondrial membrane potential were examined using the specific fluorescence probe JC–1 (5,5′,6,6′-tetrachloro-1,1′,3,3′–tetraethylbenzimidazol carbocyanine). The EM–T–MEL derivative had the highest biological activity, showing higher cytotoxic and genotoxic properties than the parent drug. Moreover, it showed a high ability to induce apoptosis in the tested cancer cells. This compound also had a beneficial effect in peripheral blood mononuclear cells (PBMC). In conclusion, we verified and confirmed the hypothesis that chemical modifications of the melphalan structure improved its anticancer properties. The conducted study allowed the selection of the compound with the highest biological activity and provided a basis for chemical structure-biological activity analyses.
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spelling pubmed-88361882022-02-12 Synthesis and In Vitro Activity of Novel Melphalan Analogs in Hematological Malignancy Cells Poczta, Anastazja Krzeczyński, Piotr Tobiasz, Joanna Rogalska, Aneta Gajek, Arkadiusz Marczak, Agnieszka Int J Mol Sci Article Despite the continuous developments in pharmacology and the high therapeutic effect of new treatment options for patients with hematological malignancies, these diseases remain a major health issue. Our study aimed to synthesize, analyze in silico, and determine the biological properties of new melphalan derivatives. We obtained three methyl esters of melphalan having in their structures amidine moieties substituted with thiomorpholine (EM–T–MEL), indoline (EM–I–MEL), or 4-(4-morpholinyl) piperidine (EM–MORPIP–MEL). These have not yet been described in the literature. The in vitro anticancer properties of the analogs were determined against THP1, HL60, and RPMI8226 cells. Melphalan derivatives were evaluated for cytotoxicity (resazurin viability assay), genotoxicity (alkaline comet assay), and their ability to induce apoptosis (Hoechst33342/propidium iodide double staining method; phosphatidylserine translocation; and caspase 3/7, 8, and 9 activity measurements). Changes in mitochondrial membrane potential were examined using the specific fluorescence probe JC–1 (5,5′,6,6′-tetrachloro-1,1′,3,3′–tetraethylbenzimidazol carbocyanine). The EM–T–MEL derivative had the highest biological activity, showing higher cytotoxic and genotoxic properties than the parent drug. Moreover, it showed a high ability to induce apoptosis in the tested cancer cells. This compound also had a beneficial effect in peripheral blood mononuclear cells (PBMC). In conclusion, we verified and confirmed the hypothesis that chemical modifications of the melphalan structure improved its anticancer properties. The conducted study allowed the selection of the compound with the highest biological activity and provided a basis for chemical structure-biological activity analyses. MDPI 2022-02-03 /pmc/articles/PMC8836188/ /pubmed/35163680 http://dx.doi.org/10.3390/ijms23031760 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Poczta, Anastazja
Krzeczyński, Piotr
Tobiasz, Joanna
Rogalska, Aneta
Gajek, Arkadiusz
Marczak, Agnieszka
Synthesis and In Vitro Activity of Novel Melphalan Analogs in Hematological Malignancy Cells
title Synthesis and In Vitro Activity of Novel Melphalan Analogs in Hematological Malignancy Cells
title_full Synthesis and In Vitro Activity of Novel Melphalan Analogs in Hematological Malignancy Cells
title_fullStr Synthesis and In Vitro Activity of Novel Melphalan Analogs in Hematological Malignancy Cells
title_full_unstemmed Synthesis and In Vitro Activity of Novel Melphalan Analogs in Hematological Malignancy Cells
title_short Synthesis and In Vitro Activity of Novel Melphalan Analogs in Hematological Malignancy Cells
title_sort synthesis and in vitro activity of novel melphalan analogs in hematological malignancy cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8836188/
https://www.ncbi.nlm.nih.gov/pubmed/35163680
http://dx.doi.org/10.3390/ijms23031760
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