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Design, Synthesis and Biological Evaluation of Quinazolinamine Derivatives as Breast Cancer Resistance Protein and P-Glycoprotein Inhibitors with Improved Metabolic Stability

A series of twenty-two quinazolinamine derivatives showing potent inhibitory activities on breast cancer resistance protein (BCRP) and p-glycoprotein (P-gp) were synthesized. A cyclopropyl-containing quinazolinamine 22 was identified as a dual BCRP and P-gp inhibitor, while azide-containing quinazol...

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Autores principales: Cai, Chao-Yun, Teng, Qiu-Xu, Murakami, Megumi, Ambudkar, Suresh V., Chen, Zhe-Sheng, Korlipara, Vijaya L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9953095/
https://www.ncbi.nlm.nih.gov/pubmed/36830622
http://dx.doi.org/10.3390/biom13020253
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author Cai, Chao-Yun
Teng, Qiu-Xu
Murakami, Megumi
Ambudkar, Suresh V.
Chen, Zhe-Sheng
Korlipara, Vijaya L.
author_facet Cai, Chao-Yun
Teng, Qiu-Xu
Murakami, Megumi
Ambudkar, Suresh V.
Chen, Zhe-Sheng
Korlipara, Vijaya L.
author_sort Cai, Chao-Yun
collection PubMed
description A series of twenty-two quinazolinamine derivatives showing potent inhibitory activities on breast cancer resistance protein (BCRP) and p-glycoprotein (P-gp) were synthesized. A cyclopropyl-containing quinazolinamine 22 was identified as a dual BCRP and P-gp inhibitor, while azide-containing quinazolinamine 33 showed BCRP inhibitory activity. These lead compounds were further investigated in a battery of mechanistic experiments. Compound 22 changed the localization of BCRP and P-gp in cells, thus inhibiting the efflux of anticancer drugs by the two ATP-binding cassette (ABC) transporters. In addition, both 22 and 33 significantly stimulated the ATP hydrolysis of the BCRP transporter, indicating that they can be competitive substrates of the BCRP transporter, and thereby increase the accumulation of mitoxantrone in BCRP-overexpressing H460/MX20 cells. Azide derivative 33, exhibited a greater inhibitory effect on BCRP after UV activation and can serve as a valuable probe for investigating the interactions of quinazolinamine derivatives with BCRP. Notably, the dual BCRP and P-gp inhibitors 4–5, 22–24, 27, and BCRP inhibitor 33 showed improved metabolic stability compared to Ko143.
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spelling pubmed-99530952023-02-25 Design, Synthesis and Biological Evaluation of Quinazolinamine Derivatives as Breast Cancer Resistance Protein and P-Glycoprotein Inhibitors with Improved Metabolic Stability Cai, Chao-Yun Teng, Qiu-Xu Murakami, Megumi Ambudkar, Suresh V. Chen, Zhe-Sheng Korlipara, Vijaya L. Biomolecules Article A series of twenty-two quinazolinamine derivatives showing potent inhibitory activities on breast cancer resistance protein (BCRP) and p-glycoprotein (P-gp) were synthesized. A cyclopropyl-containing quinazolinamine 22 was identified as a dual BCRP and P-gp inhibitor, while azide-containing quinazolinamine 33 showed BCRP inhibitory activity. These lead compounds were further investigated in a battery of mechanistic experiments. Compound 22 changed the localization of BCRP and P-gp in cells, thus inhibiting the efflux of anticancer drugs by the two ATP-binding cassette (ABC) transporters. In addition, both 22 and 33 significantly stimulated the ATP hydrolysis of the BCRP transporter, indicating that they can be competitive substrates of the BCRP transporter, and thereby increase the accumulation of mitoxantrone in BCRP-overexpressing H460/MX20 cells. Azide derivative 33, exhibited a greater inhibitory effect on BCRP after UV activation and can serve as a valuable probe for investigating the interactions of quinazolinamine derivatives with BCRP. Notably, the dual BCRP and P-gp inhibitors 4–5, 22–24, 27, and BCRP inhibitor 33 showed improved metabolic stability compared to Ko143. MDPI 2023-01-30 /pmc/articles/PMC9953095/ /pubmed/36830622 http://dx.doi.org/10.3390/biom13020253 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
Cai, Chao-Yun
Teng, Qiu-Xu
Murakami, Megumi
Ambudkar, Suresh V.
Chen, Zhe-Sheng
Korlipara, Vijaya L.
Design, Synthesis and Biological Evaluation of Quinazolinamine Derivatives as Breast Cancer Resistance Protein and P-Glycoprotein Inhibitors with Improved Metabolic Stability
title Design, Synthesis and Biological Evaluation of Quinazolinamine Derivatives as Breast Cancer Resistance Protein and P-Glycoprotein Inhibitors with Improved Metabolic Stability
title_full Design, Synthesis and Biological Evaluation of Quinazolinamine Derivatives as Breast Cancer Resistance Protein and P-Glycoprotein Inhibitors with Improved Metabolic Stability
title_fullStr Design, Synthesis and Biological Evaluation of Quinazolinamine Derivatives as Breast Cancer Resistance Protein and P-Glycoprotein Inhibitors with Improved Metabolic Stability
title_full_unstemmed Design, Synthesis and Biological Evaluation of Quinazolinamine Derivatives as Breast Cancer Resistance Protein and P-Glycoprotein Inhibitors with Improved Metabolic Stability
title_short Design, Synthesis and Biological Evaluation of Quinazolinamine Derivatives as Breast Cancer Resistance Protein and P-Glycoprotein Inhibitors with Improved Metabolic Stability
title_sort design, synthesis and biological evaluation of quinazolinamine derivatives as breast cancer resistance protein and p-glycoprotein inhibitors with improved metabolic stability
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9953095/
https://www.ncbi.nlm.nih.gov/pubmed/36830622
http://dx.doi.org/10.3390/biom13020253
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