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Exploring evolutionary and chemical space using chemoinformatic tools and traditional methods in pharmacognosy
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi.ORCID iD: 0000-0002-9991-8406
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The number of new drugs coming to the market is declining while interest in lead discovery from natural resources is seeing a revival. Although methods for isolation and identification of natural products have advanced tremendously, methods for selection of potential leads have fallen behind. As part of the Marie Curie ITN “MedPlant: Phylogenetic exploration of medicinal plant diversity” this thesis contributed to the exploration of chemical diversity in angiosperms and the development of new tools to analyze and define the chemical potential of a plant.

In Paper I, it was demonstrated that physicochemical properties of selected specialized metabolites change in different plant groups. Changes in properties were assessed using ChemGPS-NP and diversity was quantified by calculating the volume occupied by the compounds in chemical space. By discussing the results against the background of possible underlying evolutionary mechanisms, it was concluded that evolutionary processes are reflected in chemical property space. These results hold great value for further studies on the evolution of chemical diversity and biochemical traits in plants. The methods developed can be used e.g. to define and predict the chemical diversity of related taxa, providing a strategy for a guided plant selection in search for new drug leads.

In Paper II, the scaffold and molecular diversity of over 5,200 sesquiterpene lactones (STLs) was investigated, using different chemoinformatic tools. Quantity and distribution of skeleton classes was determined and it was shown that different plant families possess specific sets of molecular frameworks, with considerable variation in their frequency. Clustering analysis enabled qualitative division of STLs into smaller groups with similar structural features, pointing out the differentiation of various plant groups. Including the study results, the dataset offers a compelling resource for chemosystematics, natural product research and drug lead discovery focused on STLs. It provides the basis for phylogenetic implementations due to the detailed taxonomic annotation. Since STLs display a source for new drugs, it is of high value for a guided search for plant derived drug leads.

In Paper III, Lindera benzoin was subjected to phytochemical and pharmacological investigations. Phytochemical investigations led to the isolation of three new sesquiterpenes. As Native American tribes used this shrub for various medicinal purposes, e.g. cold remedy or diaphoretic, the isolated compounds were evaluated in vitro for their anti-inflammatory activity. In cellular assays, they reduced pro-inflammatory prostaglandin E2 production in A549 cells in a dose-dependent manner, which may rationalize the traditional use of this plant.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2020. , p. 80
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 282
Keywords [en]
angiosperm chemistry, physicochemical properties of plant specialized metabolites, chemical diversity, chemical space, sesquiterpene lactones, scaffold diversity, molecular framework, cluster analysis, ECFP6, Lindera benzoin, sesquiterpenes, anti-inflammatory
National Category
Other Chemistry Topics Other Biological Topics
Research subject
Pharmacognosy
Identifiers
URN: urn:nbn:se:uu:diva-399068ISBN: 978-91-513-0843-2 (print)OAI: oai:DiVA.org:uu-399068DiVA, id: diva2:1382725
Public defence
2020-02-14, C4:305, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2020-01-23 Created: 2020-01-04 Last updated: 2020-03-05
List of papers
1. Charting Angiosperm Chemistry: Evolutionary Perspective on Specialized Metabolites Reflected in Chemical Property Space
Open this publication in new window or tab >>Charting Angiosperm Chemistry: Evolutionary Perspective on Specialized Metabolites Reflected in Chemical Property Space
2019 (English)In: Journal of Natural Products, ISSN 0163-3864, E-ISSN 1520-6025, Vol. 82, no 4, p. 798-812Article in journal (Refereed) Published
Abstract [en]

Plants possess an outstanding chemical diversity of specialized metabolites developed to adapt to environmental niches and increase fitness. The observed diversity is hypothesized to result from various evolutionary mechanisms, such as the continuous branching off and extension of existing biosynthetic pathways or enhanced levels of catalytic promiscuity in certain enzymes. In this study, ChemGPS-NP has been employed to chart the distribution and diversity of physicochemical properties for selected types of specialized metabolites from the angiosperms. Utilizing these charts, it is analyzed how different properties of various types of specialized metabolites change in different plant groups, and the chemical diversity from the volume they occupy in chemical property space is evaluated. In this context, possible underlying evolutionary mechanisms are discussed, which could explain the observed distribution and behavior in chemical property space. Based on these studies, it is demonstrated that evolutionary processes in plant specialized metabolism and the resultant metabolic diversification are reflected in chemical property space.

National Category
Bioinformatics and Systems Biology Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-383876 (URN)10.1021/acs.jnatprod.8b00767 (DOI)000466442100014 ()30912945 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 606895-MedPlant
Available from: 2019-06-12 Created: 2019-06-12 Last updated: 2020-01-04Bibliographically approved
2. Structural classification and scaffold diversity of sesquiterpene lactones in the angiosperms
Open this publication in new window or tab >>Structural classification and scaffold diversity of sesquiterpene lactones in the angiosperms
(English)In: Phytochemistry, ISSN 0031-9422, E-ISSN 1873-3700Article in journal (Other academic) Submitted
Abstract [en]

Sesquiterpene lactones (STLs) present one of the largest groups of plant specialized metabolites with a wide range of biological activities. They are a valuable source for new plant derived drugs and drug leads since they contain several important chemical properties responsible for their versatile therapeutic potential.

The aim of this study was to analyze and compare the chemical diversity of all types of STLs in different plant groups, both qualitatively and quantitatively. For this purpose, over 5,200 STLs have been compiled and their plant origin has been recorded, resulting in a comprehensive dataset comprising over 8,600 entries. An overview of skeleton classes and their distribution among plant families was given by assigning the STLs to their major classes. An extensive scaffold diversity analysis was performed based on the molecular framework of these compounds using established metrics. Furthermore, molecular diversity and similarity was assessed via 2D fingerprint and clustering analysis.

The results highlighted significant differences in the degree of chemical diversity. It was demonstrated that the investigated plant families have tendencies to produce certain types of skeletons. The quantity and distribution of skeleton classes was determined per plant family and genus, as well as the proportions of skeleton classes to other STL producing families. Analyzing the scaffold diversity showed that they possessed specific sets of molecular frameworks with a considerable variation in their frequency of occurrence. Even if many plant families produce STLs belonging to the same skeleton class, their corresponding molecular frameworks differ. Clustering analysis confirmed the known large structural diversity and revealed similarities and differences of the compounds. The metrics employed enabled to qualitatively divide STLs into smaller groups with similar structural features, which reflected biologically and chemically different STLs and pointed out the differentiation of various plant groups, down to the taxonomic rank of the species.

Taken together, these analyses provided a comprehensive insight into scaffold and molecular diversity of STLs. Due to the detailed taxonomic annotation, the distinct distribution of different types of STLs was captured. This dataset represents the latest detailed compilation of STLs in the angiosperms, which can be used as a basis for further chemoinformatic or chemosystematic analyses. To provide an example of potential implementations, the results were utilized in a phylogenetic exploration of these metabolites.

Keywords
angiosperm chemistry, sesquiterpene lactones, chemical diversity, dataset, scaffold diversity, molecular framework, clustering analysis, ECFP6
National Category
Natural Sciences Other Chemistry Topics
Identifiers
urn:nbn:se:uu:diva-399075 (URN)
Available from: 2019-12-12 Created: 2019-12-12 Last updated: 2020-02-04Bibliographically approved
3. Bisabolane sesquiterpenes from the leaves of Lindera benzoin reduce prostaglandin E2 formation in A549 cells
Open this publication in new window or tab >>Bisabolane sesquiterpenes from the leaves of Lindera benzoin reduce prostaglandin E2 formation in A549 cells
Show others...
(English)In: Phytochemistry Letters, ISSN 1874-3900, E-ISSN 1876-7486Article in journal (Other academic) Submitted
Abstract [en]

Phytochemical investigation of leaves from the American shrub Lindera benzoin (L.) Blume (Lauraceae) resulted in the isolation of one pure compound (1) and a diastereomeric mixture of (2 and 3). The structures of these new bisabolane sesquiterpenes were elucidated via MS and extensive NMR measurements and identified as 6-(2-hydroxy-6-methylhept-5-en-2-yl)-3-(hydroxymethyl)-4-oxocyclohex-2-en-1-yl acetate (1) and 3-(hydroxymethyl)-6-(5-(2-hydroxypropan-2-yl)-2-methyltetrahydrofuran-2-yl)-4-oxocyclohex-2-en-1-yl acetate (2 and 3). The compounds were evaluated in vitro for their anti-inflammatory activity. In cellular assays, 1-3 reduced pro-inflammatory prostaglandin E2 production in A549 cells in a dose-dependent manner.

Keywords
Lindera benzoin, sesquiterpenes, structure elucidation, prostaglandin E2, anti-inflammatory
National Category
Natural Sciences Other Biological Topics Other Chemistry Topics
Identifiers
urn:nbn:se:uu:diva-399076 (URN)
Available from: 2019-12-12 Created: 2019-12-12 Last updated: 2020-02-04Bibliographically approved

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