Lead optimization of novel quinolone chalcone compounds by a structure–activity relationship (SAR) study to increase efficacy and metabolic stability

Abstract Many agents targeting the colchicine binding site in tubulin have been developed as potential anticancer agents. However, none has successfully made it to the clinic, due mainly to dose limiting toxicities and the emergence of multi-drug resistance. Chalcones targeting tubulin have been pro...

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Autores principales:	James Knockleby, Aïcha Dede Djigo, Indeewari Kalhari Lindamulage, Chandrabose Karthikeyan, Piyush Trivedi, Hoyun Lee
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/694e10661bf04f269dc3923c74b6cb41
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spelling	oai:doaj.org-article:694e10661bf04f269dc3923c74b6cb412021-11-08T10:53:53ZLead optimization of novel quinolone chalcone compounds by a structure–activity relationship (SAR) study to increase efficacy and metabolic stability10.1038/s41598-021-01058-z2045-2322https://doaj.org/article/694e10661bf04f269dc3923c74b6cb412021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-01058-zhttps://doaj.org/toc/2045-2322Abstract Many agents targeting the colchicine binding site in tubulin have been developed as potential anticancer agents. However, none has successfully made it to the clinic, due mainly to dose limiting toxicities and the emergence of multi-drug resistance. Chalcones targeting tubulin have been proposed as a safe and effective alternative. We have shown previously that quinolone chalcones target tubulin and maintain potent anti-proliferative activity vis-à-vis colchicine, while also having high tolerability and low toxicity in mouse models of cancer and refractivity to multi-drug resistance mechanisms. To identify the most effective anticancer chalcone compound, we synthesized 17 quinolone–chalcone derivatives based on our previously published CTR-17 and CTR-20, and then carried out a structure–activity relationship study. We identified two compounds, CTR-21 [((E)-8-Methoxy-3-(3-(2-methoxyphenyl)-3-oxoprop-1-enyl) quinolin-2(1H)-one)] and CTR-32 [((E)-3-(3-(2-ethoxyphenyl)-3-oxoprop-1-enyl) quinolin-2(1H)-one)] as potential leads, which contain independent moieties that play a significant role in their enhanced activities. At the nM range, CTR-21 and CTR-32 effectively kill a panel of different cancer cells originated from a variety of different tissues including breast and skin. Both compounds also effectively kill multi-drug resistant cancer cells. Most importantly, CTR-21 and CTR-32 show a high degree of selectivity against cancer cells. In silico, both of them dock near the colchicine-binding site with similar energies. Whereas both CTR-21 and CTR-32 effectively prevents tubulin polymerization, leading to the cell cycle arrest at G2/M, CTR-21 has more favorable metabolic properties. Perhaps not surprisingly, the combination of CTR-21 and ABT-737, a Bcl-2 inhibitor, showed synergistic effect in killing cancer cells, since we previously found the “parental” CTR-20 also exhibited synergism. Taken together, CTR-21 can potentially be a highly effective and relatively safe anticancer drug.James KnocklebyAïcha Dede DjigoIndeewari Kalhari LindamulageChandrabose KarthikeyanPiyush TrivediHoyun LeeNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q James Knockleby Aïcha Dede Djigo Indeewari Kalhari Lindamulage Chandrabose Karthikeyan Piyush Trivedi Hoyun Lee Lead optimization of novel quinolone chalcone compounds by a structure–activity relationship (SAR) study to increase efficacy and metabolic stability
description	Abstract Many agents targeting the colchicine binding site in tubulin have been developed as potential anticancer agents. However, none has successfully made it to the clinic, due mainly to dose limiting toxicities and the emergence of multi-drug resistance. Chalcones targeting tubulin have been proposed as a safe and effective alternative. We have shown previously that quinolone chalcones target tubulin and maintain potent anti-proliferative activity vis-à-vis colchicine, while also having high tolerability and low toxicity in mouse models of cancer and refractivity to multi-drug resistance mechanisms. To identify the most effective anticancer chalcone compound, we synthesized 17 quinolone–chalcone derivatives based on our previously published CTR-17 and CTR-20, and then carried out a structure–activity relationship study. We identified two compounds, CTR-21 [((E)-8-Methoxy-3-(3-(2-methoxyphenyl)-3-oxoprop-1-enyl) quinolin-2(1H)-one)] and CTR-32 [((E)-3-(3-(2-ethoxyphenyl)-3-oxoprop-1-enyl) quinolin-2(1H)-one)] as potential leads, which contain independent moieties that play a significant role in their enhanced activities. At the nM range, CTR-21 and CTR-32 effectively kill a panel of different cancer cells originated from a variety of different tissues including breast and skin. Both compounds also effectively kill multi-drug resistant cancer cells. Most importantly, CTR-21 and CTR-32 show a high degree of selectivity against cancer cells. In silico, both of them dock near the colchicine-binding site with similar energies. Whereas both CTR-21 and CTR-32 effectively prevents tubulin polymerization, leading to the cell cycle arrest at G2/M, CTR-21 has more favorable metabolic properties. Perhaps not surprisingly, the combination of CTR-21 and ABT-737, a Bcl-2 inhibitor, showed synergistic effect in killing cancer cells, since we previously found the “parental” CTR-20 also exhibited synergism. Taken together, CTR-21 can potentially be a highly effective and relatively safe anticancer drug.
format	article
author	James Knockleby Aïcha Dede Djigo Indeewari Kalhari Lindamulage Chandrabose Karthikeyan Piyush Trivedi Hoyun Lee
author_facet	James Knockleby Aïcha Dede Djigo Indeewari Kalhari Lindamulage Chandrabose Karthikeyan Piyush Trivedi Hoyun Lee
author_sort	James Knockleby
title	Lead optimization of novel quinolone chalcone compounds by a structure–activity relationship (SAR) study to increase efficacy and metabolic stability
title_short	Lead optimization of novel quinolone chalcone compounds by a structure–activity relationship (SAR) study to increase efficacy and metabolic stability
title_full	Lead optimization of novel quinolone chalcone compounds by a structure–activity relationship (SAR) study to increase efficacy and metabolic stability
title_fullStr	Lead optimization of novel quinolone chalcone compounds by a structure–activity relationship (SAR) study to increase efficacy and metabolic stability
title_full_unstemmed	Lead optimization of novel quinolone chalcone compounds by a structure–activity relationship (SAR) study to increase efficacy and metabolic stability
title_sort	lead optimization of novel quinolone chalcone compounds by a structure–activity relationship (sar) study to increase efficacy and metabolic stability
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/694e10661bf04f269dc3923c74b6cb41
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Lead optimization of novel quinolone chalcone compounds by a structure–activity relationship (SAR) study to increase efficacy and metabolic stability

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