Staff View: Preparation and Preliminary Structure-Activity Relationship Studies of Schwarzinicine A Analogs as Vasorelaxant Agents

Preparation and Preliminary Structure-Activity Relationship Studies of Schwarzinicine A Analogs as Vasorelaxant Agents

Schwarzinicines A-D, a series of alkaloids recently discovered from Ficus schwarzii, exhibit pronounced vasorelaxant activity in rat isolated aorta. Building on this finding, a concise synthesis of schwarzinicines A and B has been reported, allowing further investigations into their biological prope...

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Main Authors:	Lee, Fong-Kai, Chan, Nathaniel Jia-Yoong, Krishnan, Premanand, Salam, Dayang Sharyati Datu Abdul, Chee, Xavier Wezen, Muhamad, Azira, Low, Yun Yee, Ting, Kang-Nee, Lim, Kuan-Hon
Format:	Article
Published:	American Chemical Society 2024
Subjects:	QD Chemistry RM Therapeutics. Pharmacology RS Pharmacy and materia medica
Online Access:	http://eprints.um.edu.my/45483/ https://doi.org/10.1021/acs.jnatprod.3c00707
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id	my.um.eprints.45483
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spelling	my.um.eprints.454832024-10-22T07:45:24Z http://eprints.um.edu.my/45483/ Preparation and Preliminary Structure-Activity Relationship Studies of Schwarzinicine A Analogs as Vasorelaxant Agents Lee, Fong-Kai Chan, Nathaniel Jia-Yoong Krishnan, Premanand Salam, Dayang Sharyati Datu Abdul Chee, Xavier Wezen Muhamad, Azira Low, Yun Yee Ting, Kang-Nee Lim, Kuan-Hon QD Chemistry RM Therapeutics. Pharmacology RS Pharmacy and materia medica Schwarzinicines A-D, a series of alkaloids recently discovered from Ficus schwarzii, exhibit pronounced vasorelaxant activity in rat isolated aorta. Building on this finding, a concise synthesis of schwarzinicines A and B has been reported, allowing further investigations into their biological properties. Herein, a preliminary exploration of the chemical space surrounding the structure of schwarzinicine A (1) was carried out aiming to identify structural features that are essential for vasorelaxant activity. A total of 57 analogs were synthesized and tested for vasorelaxant activity in rat isolated aorta. Both efficacy (E-max) and potency (EC50) of these analogs were compared. In addition to identifying structural features that are required for activity or associated with potency enhancement effect, four analogs showed significant potency improvements of up to 40.2-fold when compared to 1. Molecular dynamics simulation of a tetrameric 44-bound transient receptor potential canonical-6 (TRPC6) protein indicated that 44 could potentially form important interactions with the residues Glu509, Asp530, Lys748, Arg758, and Tyr521. These results may serve as a foundation for guiding further structural optimization of the schwarzinicine A scaffold, aiming to discover even more potent analogs. American Chemical Society 2024-03 Article PeerReviewed Lee, Fong-Kai and Chan, Nathaniel Jia-Yoong and Krishnan, Premanand and Salam, Dayang Sharyati Datu Abdul and Chee, Xavier Wezen and Muhamad, Azira and Low, Yun Yee and Ting, Kang-Nee and Lim, Kuan-Hon (2024) Preparation and Preliminary Structure-Activity Relationship Studies of Schwarzinicine A Analogs as Vasorelaxant Agents. Journal of Natural Products, 87 (4). pp. 675-691. ISSN 0163-3864, DOI https://doi.org/10.1021/acs.jnatprod.3c00707 <https://doi.org/10.1021/acs.jnatprod.3c00707>. https://doi.org/10.1021/acs.jnatprod.3c00707 10.1021/acs.jnatprod.3c00707
institution	Universiti Malaya
building	UM Library
collection	Institutional Repository
continent	Asia
country	Malaysia
content_provider	Universiti Malaya
content_source	UM Research Repository
url_provider	http://eprints.um.edu.my/
topic	QD Chemistry RM Therapeutics. Pharmacology RS Pharmacy and materia medica
spellingShingle	QD Chemistry RM Therapeutics. Pharmacology RS Pharmacy and materia medica Lee, Fong-Kai Chan, Nathaniel Jia-Yoong Krishnan, Premanand Salam, Dayang Sharyati Datu Abdul Chee, Xavier Wezen Muhamad, Azira Low, Yun Yee Ting, Kang-Nee Lim, Kuan-Hon Preparation and Preliminary Structure-Activity Relationship Studies of Schwarzinicine A Analogs as Vasorelaxant Agents
description	Schwarzinicines A-D, a series of alkaloids recently discovered from Ficus schwarzii, exhibit pronounced vasorelaxant activity in rat isolated aorta. Building on this finding, a concise synthesis of schwarzinicines A and B has been reported, allowing further investigations into their biological properties. Herein, a preliminary exploration of the chemical space surrounding the structure of schwarzinicine A (1) was carried out aiming to identify structural features that are essential for vasorelaxant activity. A total of 57 analogs were synthesized and tested for vasorelaxant activity in rat isolated aorta. Both efficacy (E-max) and potency (EC50) of these analogs were compared. In addition to identifying structural features that are required for activity or associated with potency enhancement effect, four analogs showed significant potency improvements of up to 40.2-fold when compared to 1. Molecular dynamics simulation of a tetrameric 44-bound transient receptor potential canonical-6 (TRPC6) protein indicated that 44 could potentially form important interactions with the residues Glu509, Asp530, Lys748, Arg758, and Tyr521. These results may serve as a foundation for guiding further structural optimization of the schwarzinicine A scaffold, aiming to discover even more potent analogs.
format	Article
author	Lee, Fong-Kai Chan, Nathaniel Jia-Yoong Krishnan, Premanand Salam, Dayang Sharyati Datu Abdul Chee, Xavier Wezen Muhamad, Azira Low, Yun Yee Ting, Kang-Nee Lim, Kuan-Hon
author_facet	Lee, Fong-Kai Chan, Nathaniel Jia-Yoong Krishnan, Premanand Salam, Dayang Sharyati Datu Abdul Chee, Xavier Wezen Muhamad, Azira Low, Yun Yee Ting, Kang-Nee Lim, Kuan-Hon
author_sort	Lee, Fong-Kai
title	Preparation and Preliminary Structure-Activity Relationship Studies of Schwarzinicine A Analogs as Vasorelaxant Agents
title_short	Preparation and Preliminary Structure-Activity Relationship Studies of Schwarzinicine A Analogs as Vasorelaxant Agents
title_full	Preparation and Preliminary Structure-Activity Relationship Studies of Schwarzinicine A Analogs as Vasorelaxant Agents
title_fullStr	Preparation and Preliminary Structure-Activity Relationship Studies of Schwarzinicine A Analogs as Vasorelaxant Agents
title_full_unstemmed	Preparation and Preliminary Structure-Activity Relationship Studies of Schwarzinicine A Analogs as Vasorelaxant Agents
title_sort	preparation and preliminary structure-activity relationship studies of schwarzinicine a analogs as vasorelaxant agents
publisher	American Chemical Society
publishDate	2024
url	http://eprints.um.edu.my/45483/ https://doi.org/10.1021/acs.jnatprod.3c00707
_version_	1814047567223193600
score	13.211869

Preparation and Preliminary Structure-Activity Relationship Studies of Schwarzinicine A Analogs as Vasorelaxant Agents

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