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Novel 7-Deazapurine Incorporating Isatin Hybrid Compounds as Protein Kinase Inhibitors: Design, Synthesis, In Silico Studies, and Antiproliferative Evaluation

Cancer is a multifactorial disorder with extremely complex genetics and progression. The major challenge in cancer therapy is the development of cancer resistance and relapse. Conventional anticancer drugs directly target the DNA of the cell, while modern chemotherapeutic drugs include molecular-tar...

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Autores principales: Alanazi, Mohammed M., Alanazi, Ashwag S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10420662/
https://www.ncbi.nlm.nih.gov/pubmed/37570839
http://dx.doi.org/10.3390/molecules28155869
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author Alanazi, Mohammed M.
Alanazi, Ashwag S.
author_facet Alanazi, Mohammed M.
Alanazi, Ashwag S.
author_sort Alanazi, Mohammed M.
collection PubMed
description Cancer is a multifactorial disorder with extremely complex genetics and progression. The major challenge in cancer therapy is the development of cancer resistance and relapse. Conventional anticancer drugs directly target the DNA of the cell, while modern chemotherapeutic drugs include molecular-targeted therapy, such as targeting the abnormal cell signaling inside the cancer cells. Targeted chemotherapy is effective in several malignancies; however, the success has always been limited by drug resistance and/or side effects. Anticancer with multi-targeted actions simultaneously modulates multiple cancer cell signaling pathways and, therefore, may ease the chance of effective anticancer drug development. In this research, a series of 7-deazapurine incorporating isatin hybrid compounds was designed and successfully synthesized. Among those hybrids, compound 5 demonstrated a very potent cytotoxic effect compared to the reference anticancer drug against four cancer cell lines. Likewise, compound 5 inhibited the activity of four protein kinase enzymes in nanomolar ranges. Further analysis of the biological evaluation of compound 5 revealed the capability of compound 5 to arrest cell cycle progression and induce programmed cell death. Moreover, molecular simulation studies were performed to investigate the possible types of interactions between compound 5 and the investigated protein kinases. Finally, taking into consideration all the abovementioned findings, compound 5 could be a good candidate for further investigations.
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spelling pubmed-104206622023-08-12 Novel 7-Deazapurine Incorporating Isatin Hybrid Compounds as Protein Kinase Inhibitors: Design, Synthesis, In Silico Studies, and Antiproliferative Evaluation Alanazi, Mohammed M. Alanazi, Ashwag S. Molecules Article Cancer is a multifactorial disorder with extremely complex genetics and progression. The major challenge in cancer therapy is the development of cancer resistance and relapse. Conventional anticancer drugs directly target the DNA of the cell, while modern chemotherapeutic drugs include molecular-targeted therapy, such as targeting the abnormal cell signaling inside the cancer cells. Targeted chemotherapy is effective in several malignancies; however, the success has always been limited by drug resistance and/or side effects. Anticancer with multi-targeted actions simultaneously modulates multiple cancer cell signaling pathways and, therefore, may ease the chance of effective anticancer drug development. In this research, a series of 7-deazapurine incorporating isatin hybrid compounds was designed and successfully synthesized. Among those hybrids, compound 5 demonstrated a very potent cytotoxic effect compared to the reference anticancer drug against four cancer cell lines. Likewise, compound 5 inhibited the activity of four protein kinase enzymes in nanomolar ranges. Further analysis of the biological evaluation of compound 5 revealed the capability of compound 5 to arrest cell cycle progression and induce programmed cell death. Moreover, molecular simulation studies were performed to investigate the possible types of interactions between compound 5 and the investigated protein kinases. Finally, taking into consideration all the abovementioned findings, compound 5 could be a good candidate for further investigations. MDPI 2023-08-04 /pmc/articles/PMC10420662/ /pubmed/37570839 http://dx.doi.org/10.3390/molecules28155869 Text en © 2023 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
Alanazi, Mohammed M.
Alanazi, Ashwag S.
Novel 7-Deazapurine Incorporating Isatin Hybrid Compounds as Protein Kinase Inhibitors: Design, Synthesis, In Silico Studies, and Antiproliferative Evaluation
title Novel 7-Deazapurine Incorporating Isatin Hybrid Compounds as Protein Kinase Inhibitors: Design, Synthesis, In Silico Studies, and Antiproliferative Evaluation
title_full Novel 7-Deazapurine Incorporating Isatin Hybrid Compounds as Protein Kinase Inhibitors: Design, Synthesis, In Silico Studies, and Antiproliferative Evaluation
title_fullStr Novel 7-Deazapurine Incorporating Isatin Hybrid Compounds as Protein Kinase Inhibitors: Design, Synthesis, In Silico Studies, and Antiproliferative Evaluation
title_full_unstemmed Novel 7-Deazapurine Incorporating Isatin Hybrid Compounds as Protein Kinase Inhibitors: Design, Synthesis, In Silico Studies, and Antiproliferative Evaluation
title_short Novel 7-Deazapurine Incorporating Isatin Hybrid Compounds as Protein Kinase Inhibitors: Design, Synthesis, In Silico Studies, and Antiproliferative Evaluation
title_sort novel 7-deazapurine incorporating isatin hybrid compounds as protein kinase inhibitors: design, synthesis, in silico studies, and antiproliferative evaluation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10420662/
https://www.ncbi.nlm.nih.gov/pubmed/37570839
http://dx.doi.org/10.3390/molecules28155869
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