This dissertetion describes the relevance of natural products as building blocks for production of active pharmaceutical ingredients (API) and as lead compounds. Chapter 1 offers an introduction on the use of natural products as an effective therapeutic and its role on inspiring the discovery of new drugs. Chapter 2 focuses on the importance of natural products as lead compounds for active pharmaceutical ingredients (API) production. In the first part of this chapter the synthesis of vincamine, the major indole alkaloid presents in Vinca minor L., will be discussed. In particular the design of experiment (DOE) applied to the synthesis of vincamine starting from vincadifformine will be described. In the second part of this chapter the semi-synthesis of two lignan derivatives, oxomatairesinol and (-)-7-(R)-hydroxymatairesinol, will be reported. Chapter 3 will focus on the isolation and structural characterization of natural products. The first part describes the isolation and structural characterization of ten indole alkaloids from Voacanga africana (Apocynaceae) seeds. Then the semisynthesis of two cytisine derivatives, N-formyl and N-methyl cytisine, will be described. Chapter 4 describes the role of natural products as lead compounds. The first section illustrate a project that was performed in the laboratory of Prof. Karl-Heinz Altmann (ETH-Zurich, Switzerland) in the frame of COST Action CM1407 (Challenging Organic Synthesis Inspired By Nature: From Natural Product Chemistry To Drug Discovery). It is related to the synthesis of an analogue of the natural product doliculide, a 16-membered depsipeptide, that has been isolated in 1994 from the Japanese sea hare Dolabella auricularia. The second section will focus on the design and synthesis of hybrid compounds. Particularly it will describe the synthesis of pironetin-dumetorine hybrid compounds whose structures are representative of an optimizable lead scaffold for the discovery of new tubulin binders. Another topic here discussed will be the production of bivalent compounds linking two different units, a pironetin-dumetorine hybrid compound and a drug able to bind beta-tubulin, in order to have a duble action with the aim to limit the the protein-protein interaction between alfa and beta tubulin. Chapter 5 offers an overview on the role of natural products in drug discovery, in particular related to cancer stem cells (CSCs). In a recent review we summarized the natural products that demonstrate activity against CSCs. Forty-nine different natural products grouped into several structural classes (such as flavonoids, polyketides, terpenes, alkaloids and many others) will be described. Their structure diversity could suggest the synthesis of libraries of new compounds for a huge exploration of the chemical space of CSCs inhibitors.
NATURAL PRODUCTS AS BUILDING BLOCKS AND LEAD COMPOUNDS FOR API PRODUCTION / C. Marucci ; tutor: D. Passarella ; cotutor: M. Luzzani. - Milano : Università degli studi di Milano. DIPARTIMENTO DI CHIMICA, 2017 Mar 17. ((29. ciclo, Anno Accademico 2016.
|Titolo:||NATURAL PRODUCTS AS BUILDING BLOCKS AND LEAD COMPOUNDS FOR API PRODUCTION|
|Data di pubblicazione:||17-mar-2017|
|Parole Chiave:||natural products; API; hybrid compounds; cancer stem cell|
|Settore Scientifico Disciplinare:||Settore CHIM/06 - Chimica Organica|
|Citazione:||NATURAL PRODUCTS AS BUILDING BLOCKS AND LEAD COMPOUNDS FOR API PRODUCTION / C. Marucci ; tutor: D. Passarella ; cotutor: M. Luzzani. - Milano : Università degli studi di Milano. DIPARTIMENTO DI CHIMICA, 2017 Mar 17. ((29. ciclo, Anno Accademico 2016.|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.13130/marucci-cristina_phd2017-03-17|
|Appare nelle tipologie:||Tesi di dottorato|