Cassese, Hilde (2016) Design and Synthesis of heterocyclic molecules as novel agents for the treatment of chemo-resistant cancers. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Lingua: English
Title: Design and Synthesis of heterocyclic molecules as novel agents for the treatment of chemo-resistant cancers
Date: 31 March 2016
Number of Pages: 159
Institution: Università degli Studi di Napoli Federico II
Department: Farmacia
Scuola di dottorato: Scienze farmaceutiche
Dottorato: Scienza del farmaco
Ciclo di dottorato: 28
Coordinatore del Corso di dottorato:
D'Auria, Maria
Marinelli, LucianaUNSPECIFIED
Date: 31 March 2016
Number of Pages: 159
Uncontrolled Keywords: MCRs, BAX, SIRT6, Fz4
Settori scientifico-disciplinari del MIUR: Area 03 - Scienze chimiche > CHIM/08 - Chimica farmaceutica
Date Deposited: 11 Apr 2016 08:07
Last Modified: 31 Oct 2016 13:41


The drugs use in human medicine covers the whole range of chemical structure types, but the majority are heterocyclic small molecules or have heterocyclic structural components. In particular, anticancer drugs include rings in their structures. IUPAc gives the following definition of heterocyclic compounds : “cyclic compounds having as ring members atoms of at least two different elements” [1]. Heterocycles ring structures are in essence composed of elements other than carbon, where the most frequent substituents are oxygen, nitrogen and sulfur [2]. The discovery of novel multicomponent reactions enables new methodologies to synthesize known medicinally active compounds. Among all the multicomponent reactions presently known, the MCRs (multicomponent reactions) mediated by isocyanides are the most popular. The peculiar ability of the divalent carbon of isocyanides to react first with electrophiles and subsequently with nucleophiles, is key to the success of the multicomponent process. For this reason, the discovery of new electrophilic partners is a starting point for the development of novel multicomponent transformations. In this context, it is reported the usage of α-isocyanoacetamides along with (Z)-Aryl chlorides to give substituted 1,3-oxazol-2-oxime. However, since the final product is not stable, it can be hydrolized to give α-ketoamide amides. These molecules constitute useful scaffolds and intermediates for a variety of transformations in organic chemistry. As a continuation of this study, this work demonstrates that an electron deficient phenol could be a good nucleophiles third component in a reaction with (Z)- aryl chlorides and isocyanide to form a library of 41 aryloxyiminoamide derivates. The final product, namely aryloxyiminoamide, is an interesting compound because it can be used as intermediate for further synthetic transformations. The modern treatment of cancer involves surgery, radiotherapy and chemotherapy. However, the development of chemo-resistance, namely the lack of drugs response, is a persistent problem for the treatment of local and disseminated cancers. In fact, one of the hallmarks of human cancers is the ability to escape cell death, which is a major cause of treatment failures. In particular, the cancer cells block the apoptotic process by increasing the expression of anti-apoptotic BCL-2 members at the mitochondria and inactivate the effector arm of apoptosis, e.g. BAX, through mutations or inhibition. The recent discovery of the first small heterocyclic molecule BAM7 as BAX direct activator represents the starting point for a structure-based lead optimization program aimed at the discovery of new potent BAX activators. My work resulted in the discovery of BTC-8 which resulted 10 fold more potent than the lead BAM7. In vivo experiments have suggested that BAX direct activators may be considered as novel, effective anticancer drugs in a near future. Furthemore, some compounds ,which were synthesized as BAX direct activators, were included in the library of small molecules selected for acting as pharmacological chaperones on a misfolded mutant of the Frizzled4 (Fz4) receptor [3]. Fz4 is a key component of Wnt-β-catenin signalling and misregulation of Fz4 activity is involved in tumor proliferation and cencer stem cell genesis in many typer of malignancies, such as glioblastoma, colorectal and breast cancer. My work reported ,what are to our knowledge, the first small molecules that address the until-now-undruggable Fz4 receptor and inhibit Wnt signalling. This goal is achieved by using the potency of candidate molecules to rescue the misfolding mutant of the Fz4, as a readout in screening campaigns toward the identification of new ligands. V Another key aspect of cancer cells is an increase of aerobic glycolysis and an altered energy metabolism supporting continuous cell growth and proliferation. The epigenetic mechanisms involving covalent modifications of both DNA and histones have recently emerged as important players in the regulation of glucose metabolism. In particular, the sirtuin family of histone deacetylases are important regulators of diverse physiological and pathological events, including cancer metabolism. The most representative example is SIRT6, which is considered a promising pharmaceutical target for chemo-resistance cancers treatment. In this thesis, the identification of one heterocyclic compound which binds and inhibits the function of SIRT6 is reported. The result of this work, although very preliminary, may represent a starting point for the development of SIRT6 inhibitors.

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