Natural compounds are characterized by a considerable chemical and structural diversity alongside to be considered as the most valuable and prolific source of new drugs up to now. Not surprisingly, nature remains a key inspirational factor in the search for new therapeutic agents. In this frame, marine environment holds a central role furnishing several secondary metabolites which possess peculiar functionality groups on their backbone and a wide ranging of biological activities. Despite this promising potential, the main disadvantage of marine-derived compounds is represented by their limited availability. Therefore, always more frequently marine metabolites are useful not only as effective drugs but also as inspiration for countless synthetic drugs. During the PhD activity, the whole of my work was managed in two different topics: a) Structural and pharmacological characterization of novel secondary metabolites isolated from marine organisms. This task implied the extensive application of most spectroscopic (mainly NMR) and spectrometric techniques, often assisted by computational studies, as well as the development of efficient method for stereochemical assignment, including chemical derivatization and synthesis. The whole of these studies led to the isolation of two novel alkaloids, polyaurine A and B, from the Caribbean ascidian Polycarpa aurata featuring unusual structural moieties. Polyaurine A with its peculiar N-methylguanidine group resulted in the impairment of the development of eggs-laid by Schistosoma mansoni. The chemical investigation of the sesquiterpenoid quinones/hydroquinones-rich sponge Dysidea avara afforded the isolation of avarone and avarol. According to the substantiated redox properties of different quinones against Plasmodium and the similarities in physio-pathological processes of that protozoon and the blood fluke Schistosoma, these derivatives were evaluated against malaria and some neglected tropical diseases (i.e. schistosomiasis and leishmaniasis) since there is an urgent need of new therapeutic alternatives to keep up with the widespread parasite resistance. Moreover, my PhD activity was also focused in completing the configurational assignment of phosphoeleganin, an acyclic phosphorylated polyketide with inhibitory activity against protein tyrosine phosphatase 1B. The univocal stereochemical elucidation required the synthesis of the 8,9-anti stereoisomers of the tetradecan-5,8,9-triol as diastereoisomeric model compounds directed to the application of UDB concept. Accordingly, the widening of NMR database as useful support for stereostructural elucidation has encouraged the synthesis of several simplified analogues of the marine metabolite. b) Design and synthesis of quinone molecules inspired by bioactive marine natural products for antiparasitic and cytotoxicity screenings. Taking into account the antiplasmodial effects of some marine compounds endowed with the thiazinoquinone bicyclic moiety and also the antischistosomal properties of several effective antimalarials, a rationalized chemical library of thiazinoquinones has been synthesised inspired by the marine cytotoxic aplidinone A. The adopted synthetic scheme reflected the compelling priority of an efficient and inexpensive procedure for neglected diseases. Some requirements appeared crucial for the antiparasitic activity: a specific regiochemistry of the thiazinoquinone system strongly affected the antiparasitic potency whereas the nature of the side-chain substituents on the quinone moiety could address the selective toxicity against mammalian cells or specific developmental stages of parasites. Computational studies provided useful insights on putative mechanism of action exerted by thiazinoquinones supporting the one-electron reduction bioactivation step with subsequent formation of a toxic semiquinone radical species. Overall these data clearly point out the thiazinoquinone scaffold as potential new lead structure for neglected disease drugs discovery. To further exploit the versatility of the synthetic protocol, a small series of prenylated quinones and related thiazinoquinones has been prepared in order to broaden the knowledge on the antiproliferative effects of these compounds. Among these, a geranylquinone derivative exerted a cytostatic activity through G0/G1 cell-cycle arrest in BxPC-3 cells.

Exploitation of natural products in the search of drug-like molecules and leads: a fascinating resource

Marcello Casertano
2020

Abstract

Natural compounds are characterized by a considerable chemical and structural diversity alongside to be considered as the most valuable and prolific source of new drugs up to now. Not surprisingly, nature remains a key inspirational factor in the search for new therapeutic agents. In this frame, marine environment holds a central role furnishing several secondary metabolites which possess peculiar functionality groups on their backbone and a wide ranging of biological activities. Despite this promising potential, the main disadvantage of marine-derived compounds is represented by their limited availability. Therefore, always more frequently marine metabolites are useful not only as effective drugs but also as inspiration for countless synthetic drugs. During the PhD activity, the whole of my work was managed in two different topics: a) Structural and pharmacological characterization of novel secondary metabolites isolated from marine organisms. This task implied the extensive application of most spectroscopic (mainly NMR) and spectrometric techniques, often assisted by computational studies, as well as the development of efficient method for stereochemical assignment, including chemical derivatization and synthesis. The whole of these studies led to the isolation of two novel alkaloids, polyaurine A and B, from the Caribbean ascidian Polycarpa aurata featuring unusual structural moieties. Polyaurine A with its peculiar N-methylguanidine group resulted in the impairment of the development of eggs-laid by Schistosoma mansoni. The chemical investigation of the sesquiterpenoid quinones/hydroquinones-rich sponge Dysidea avara afforded the isolation of avarone and avarol. According to the substantiated redox properties of different quinones against Plasmodium and the similarities in physio-pathological processes of that protozoon and the blood fluke Schistosoma, these derivatives were evaluated against malaria and some neglected tropical diseases (i.e. schistosomiasis and leishmaniasis) since there is an urgent need of new therapeutic alternatives to keep up with the widespread parasite resistance. Moreover, my PhD activity was also focused in completing the configurational assignment of phosphoeleganin, an acyclic phosphorylated polyketide with inhibitory activity against protein tyrosine phosphatase 1B. The univocal stereochemical elucidation required the synthesis of the 8,9-anti stereoisomers of the tetradecan-5,8,9-triol as diastereoisomeric model compounds directed to the application of UDB concept. Accordingly, the widening of NMR database as useful support for stereostructural elucidation has encouraged the synthesis of several simplified analogues of the marine metabolite. b) Design and synthesis of quinone molecules inspired by bioactive marine natural products for antiparasitic and cytotoxicity screenings. Taking into account the antiplasmodial effects of some marine compounds endowed with the thiazinoquinone bicyclic moiety and also the antischistosomal properties of several effective antimalarials, a rationalized chemical library of thiazinoquinones has been synthesised inspired by the marine cytotoxic aplidinone A. The adopted synthetic scheme reflected the compelling priority of an efficient and inexpensive procedure for neglected diseases. Some requirements appeared crucial for the antiparasitic activity: a specific regiochemistry of the thiazinoquinone system strongly affected the antiparasitic potency whereas the nature of the side-chain substituents on the quinone moiety could address the selective toxicity against mammalian cells or specific developmental stages of parasites. Computational studies provided useful insights on putative mechanism of action exerted by thiazinoquinones supporting the one-electron reduction bioactivation step with subsequent formation of a toxic semiquinone radical species. Overall these data clearly point out the thiazinoquinone scaffold as potential new lead structure for neglected disease drugs discovery. To further exploit the versatility of the synthetic protocol, a small series of prenylated quinones and related thiazinoquinones has been prepared in order to broaden the knowledge on the antiproliferative effects of these compounds. Among these, a geranylquinone derivative exerted a cytostatic activity through G0/G1 cell-cycle arrest in BxPC-3 cells.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/806494
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