Lopatriello, Annalisa (2020) Identification of bioactive natural products from plants and semi-synthetic modifications. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Lingua: English
Title: Identification of bioactive natural products from plants and semi-synthetic modifications
Creators:
CreatorsEmail
Lopatriello, Annalisaannalisa.lopatriello@unina.it
Date: 11 March 2020
Number of Pages: 177
Institution: Università degli Studi di Napoli Federico II
Department: Farmacia
Dottorato: Scienza del farmaco
Ciclo di dottorato: 32
Coordinatore del Corso di dottorato:
nomeemail
D'Auria, Maria Valeriamadauria@unina.it
Tutor:
nomeemail
Taglialatela-Scafati, OrazioUNSPECIFIED
Date: 11 March 2020
Number of Pages: 177
Uncontrolled Keywords: Natural products; drug discovery; organic chemistry; malaria transmission-blocking; phytocannabinoid; Cannabis sativa.
Settori scientifico-disciplinari del MIUR: Area 05 - Scienze biologiche > BIO/15 - Biologia farmaceutica
Area 03 - Scienze chimiche > CHIM/06 - Chimica organica
Date Deposited: 19 Mar 2020 11:28
Last Modified: 10 Nov 2021 09:52
URI: http://www.fedoa.unina.it/id/eprint/13084

Abstract

Natural products constitute an outstanding resource of lead compounds in drug discovery, due to their considerable structural diversity and their still not completely unraveled potential. Both marine and terrestrial plants contain an immense reservoir of secondary metabolites which could provide new and unique agents of immense therapeutic potential. Since less than 10% of the world biodiversity has been evaluated for potential biological activity, many more useful natural chemical entities are expected to be discovered. Considering the analysis of Food and Drug Administration (FDA) drug approvals in 2018, new drugs inspired by natural products correspond to approximately one-third compared to the other classes of drugs. In this context, the study reported in this Ph.D. addressed the research of new natural lead compounds, focusing on two main topics: - the investigation of the antimalarial potential of an African plant, Lophira lanceolata; - further exploration of the cannabinoid chemical space, through the isolation and semi-synthetic modifications of the secondary metabolites from a fiber cultivar of Cannabis sativa. A bioassay-guided screening of African plants for the identification of new transmission-blocking antimalarial leads indicated Lophira lanceolata (Ochnaceae) as the most promising plant. Specific life stages of the malaria parasite (Plasmodium sp.), responsible for the transmission of this desease were analyzed: gametocytes, occurring in the human host, and early sporogonic stages/ookinetes, developing in female mosquitoes of genus Anopheles (generally recognized as malaria vector). The phytochemical study of Lophira lanceolata led to the isolation of seven biflavonoids, including three previously unreported compounds, along with two known nitrile glycoside esters, lanceolins A and B. Among the isolated compounds, the biflavonoid lophirone E was identified as a potent gametocytocidal agent (IC50 = 0.14± 0.04 µM) with negligible cytotoxicity (selectivity index = 570), exhibiting a unique stage-specific activity profile, since it revealed to be about 100 times less active against P. falciparum asexual blood stages. Besides, the isolation of structural analogues allowed to draw preliminary structure-activity relationships, identifying the critical positions on the chemical scaffold of lophirone E. On the other hand, lanceolin B was proved to be a potent inhibitor of the development of the Plasmodium early sporogonic stages, indicating that the plant contains two different stage-selective antimalarial agents acting on transmissible stages in the human and mosquito host. This research work was supported by the Italian MIUR, PRIN2015, project 20154JRJPP “Towards multi-stage drugs to fight poverty related and neglected parasitic diseases: synthetic and natural compounds directed against Leishmania, Plasmodium and Schistosoma life stages and assessment of their mechanisms of action”. Parasite’s specific life stage assays (gametocytes and asexual stages) were carried out at the University of Milan, while early sporogonic stage and ookinete-stage (Ookinete Development Assay, ODA) at the School of Pharmacy at University of Camerino. Following a research topic investigated in our group for a long time, in the second part of my PhD, I studied the chemistry of Cannabis sativa. Despite the countless studies performed on different C. sativa chemotypes, its phytochemical content as well as the pharmacological potential of phytocannabinoids from C. sativa appear to be not exhaustively unravelled still today. For this reason, in this thesis the phytochemical content of a fiber hemp variety, as well as the chemistry of some isolated phytocannabinoids were analyzed and reported. The results of this study include the isolation and structure elucidation of a new phytocannabinoid, and the evaluation if its interaction with TRP channels. Besides, the analysis of the reactivity related to other known non-psychotropic phytocannabinoids, especially with iodine-based reagents, expanded the chemical space of cannabinoid chemotype, providing several new chemical entities, which were also pharmacologically evaluated. This work was financed by Italian MIUR (PRIN2017, Project 2017WN73PL, Bioactivity-directed exploration of the phytocannabinoid chemical space). The collaboration of the research groups of: • Prof. A. Habluetzel, School of Pharmacy, University of Camerino (ESS and ODA experiments); • Prof. D. Taramelli, University of Milan (Plasmodium asexual and gametocytes inhibition assays); • Prof. E. Muñoz, University of Córdoba (PPARs activity evaluation) • L. De Petrocellis, CNR, Naples (TRPs activity evaluation); • Prof. A. Kijjoa and Prof. J. A. Pereira, University of Porto (ECD computational calculation) is gratefully acknowledged.

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