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Design, synthesis, and biological evaluation with molecular dynamics study of novel pyrazolo[3,4-d]pyrimidine derivatives as anti-cancer agents

In continuation of our efforts to discover new structural chemotypes with significant chemotherapeutic activities, a novel series of pyrazolo[3,4-d]pyrimidine-based compounds linked to a piperazine ring, bearing different aromatic moieties, through different linkages was designed and synthesized as...

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Autores principales: Shaban, Rania M., Samir, Nermin, Nissan, Yassin M., Abouzid, Khaled A. M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10245091/
https://www.ncbi.nlm.nih.gov/pubmed/37293475
http://dx.doi.org/10.1039/d3ra00446e
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author Shaban, Rania M.
Samir, Nermin
Nissan, Yassin M.
Abouzid, Khaled A. M.
author_facet Shaban, Rania M.
Samir, Nermin
Nissan, Yassin M.
Abouzid, Khaled A. M.
author_sort Shaban, Rania M.
collection PubMed
description In continuation of our efforts to discover new structural chemotypes with significant chemotherapeutic activities, a novel series of pyrazolo[3,4-d]pyrimidine-based compounds linked to a piperazine ring, bearing different aromatic moieties, through different linkages was designed and synthesized as FLT3 inhibitors. All of the newly synthesized compounds were evaluated for their cytotoxicity on 60-NCI cell lines. Compounds with the piperazine acetamide linkage XIIa–f & XVI exhibited a remarkable anticancer activity among all of the tested compounds, especially against non-small cell lung cancer, melanoma, leukemia and renal cancer models. Furthermore, compound XVI (NSC no – 833644) was further screened with a 5-dose assay on nine subpanels and exhibited a GI(50) between 1.17 and 18.40 μM. On the other hand, molecular docking and dynamics studies were performed to predict the binding mode of the newly synthesized compounds in the FLT3 binding domain. Finally, through a predictive kinetic study, several ADME descriptors were calculated.
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spelling pubmed-102450912023-06-08 Design, synthesis, and biological evaluation with molecular dynamics study of novel pyrazolo[3,4-d]pyrimidine derivatives as anti-cancer agents Shaban, Rania M. Samir, Nermin Nissan, Yassin M. Abouzid, Khaled A. M. RSC Adv Chemistry In continuation of our efforts to discover new structural chemotypes with significant chemotherapeutic activities, a novel series of pyrazolo[3,4-d]pyrimidine-based compounds linked to a piperazine ring, bearing different aromatic moieties, through different linkages was designed and synthesized as FLT3 inhibitors. All of the newly synthesized compounds were evaluated for their cytotoxicity on 60-NCI cell lines. Compounds with the piperazine acetamide linkage XIIa–f & XVI exhibited a remarkable anticancer activity among all of the tested compounds, especially against non-small cell lung cancer, melanoma, leukemia and renal cancer models. Furthermore, compound XVI (NSC no – 833644) was further screened with a 5-dose assay on nine subpanels and exhibited a GI(50) between 1.17 and 18.40 μM. On the other hand, molecular docking and dynamics studies were performed to predict the binding mode of the newly synthesized compounds in the FLT3 binding domain. Finally, through a predictive kinetic study, several ADME descriptors were calculated. The Royal Society of Chemistry 2023-06-07 /pmc/articles/PMC10245091/ /pubmed/37293475 http://dx.doi.org/10.1039/d3ra00446e Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/
spellingShingle Chemistry
Shaban, Rania M.
Samir, Nermin
Nissan, Yassin M.
Abouzid, Khaled A. M.
Design, synthesis, and biological evaluation with molecular dynamics study of novel pyrazolo[3,4-d]pyrimidine derivatives as anti-cancer agents
title Design, synthesis, and biological evaluation with molecular dynamics study of novel pyrazolo[3,4-d]pyrimidine derivatives as anti-cancer agents
title_full Design, synthesis, and biological evaluation with molecular dynamics study of novel pyrazolo[3,4-d]pyrimidine derivatives as anti-cancer agents
title_fullStr Design, synthesis, and biological evaluation with molecular dynamics study of novel pyrazolo[3,4-d]pyrimidine derivatives as anti-cancer agents
title_full_unstemmed Design, synthesis, and biological evaluation with molecular dynamics study of novel pyrazolo[3,4-d]pyrimidine derivatives as anti-cancer agents
title_short Design, synthesis, and biological evaluation with molecular dynamics study of novel pyrazolo[3,4-d]pyrimidine derivatives as anti-cancer agents
title_sort design, synthesis, and biological evaluation with molecular dynamics study of novel pyrazolo[3,4-d]pyrimidine derivatives as anti-cancer agents
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10245091/
https://www.ncbi.nlm.nih.gov/pubmed/37293475
http://dx.doi.org/10.1039/d3ra00446e
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