Stereoselective Catalytic Processes for the Synthesis of Polycyclic Aromatic Compounds

In this PhD-thesis, two methodologies for enantioselective intramolecular ring closing reaction on indole cores are presented. The first methodology represents a highly stereoselective alkylation of the indole N1-nitrogen, leading to 3,4-dihydro-pyrazinoindol-1-ones – a structural class which is known for its activity on the CNS and therefore of high pharmacological interest concerning related diseases. In this approach, N-benzyl cinchona-alkaloids were used for the efficient catalysis of intramolecular aza-Michael reactions. Furthermore, computational studies in collaboration with the research group Prof. Andrea Bottoni (Department of Chemistry “G. Ciamician”, Bologna) were accomplished in order to get insight into the key interactions between catalyst and substrate, leading to enantiomeric excesses up to 91%. The results of the calculations on a model system are in accordance with the experimental results and demonstrate the high sensibility of the system towards structural modifications. The second project deals with a metal catalyzed, intramolecular Friedel-Crafts (FC)-reaction on indolyl substrates, carrying a side chain which on its behalf is furnished with an allylic alcohol unit. Allylic alcohols are part of the structural class of “π-activated alcohols” – alcohols, which are more easily activated due to the proximity to a π-unit (allyl-, propargyl-, benzyl-). The enantioselective intramolecular cyclization event is catalyzed efficiently by employment of a chiral Au(I)-catalyst, leading to 1-vinyl- or 4-vinyl-tetrahydrocarbazoles (THCs) under the formation of water as byproduct. This striking and novel process concerning the direct activation of alcohols in catalytic FC-reactions was subsequently extended to similar precursors, leading to functionalized tetrahydro-β-carbolines. These two methodologies represent highly efficient approaches towards the synthesis of scaffolds, which are of enormous pharmaceutical interest and amplify the spectra of enantioselective catalytic functionalisations of indoles.

Nuovi processi catalitici per la sintesi di prodotti ad attività farmacologica

The transition metal-catalyzed allylic alkylation (Tsuji-Trost type reaction) is a powerful tool for C-C, C-N, and C-O bond formation, which has been widely applied to organic chemistry over the last decades. Typical substrates for this transformation are activated allylic compounds such as halides, esters, carbonates, carbamates, phosphates, and so on. However, use of these substrates is associated with the disadvantage of generating a stoichiometric amount of chemical waste. Furthermore, these starting materials have to be prepared in an extra step from the corresponding allylic alcohol. Thus, ideal substrates would be the allylic alcohols themselves, with water being the only byproduct in this case. However, the scarse propensity of the hydroxyl moiety to act as good leaving group has significantly limited their use so far. During the last decade significant efforts have been made in order to develop more atom-economical and environmentally-friendly allylic alkylation protocols by employing allylic alcohols directly. In this PhD dissertation two main projects addressing this topic are presented. “Project 1” deals with the development of new metal-catalyzed intramolecular Friedel-Crafts (FC) allylic alkylations of electron-rich (PAPER A), as well as challenging electron-poor arenes (PAPER B) with alcohols. In “Project 2”, gold(I)-catalyzed intramolecular and stereoselective allylic alkylation reactions are reported. In particular, a FC alkylation of indole-containing allylic alcohols is presented in PAPER C. While, an O-alkylation of aminol-containing allylic alcohols is reported in PAPER D. To the best of knowledge, these reports represent the first example of gold(I)-catalyzed stereoselective alkylations with alcohols.

Cancer and aging: a multidisciplinary medicinal chemistry approach on relevant biological targets such as proteasome, sirtuins and interleukin 6

It is well known that ageing and cancer have common origins due to internal and environmental stress and share some common hallmarks such as genomic instability, epigenetic alteration, aberrant telomeres, inflammation and immune injury. Moreover, ageing is involved in a number of events responsible for carcinogenesis and cancer development at the molecular, cellular, and tissue levels. Ageing could represent a “blockbuster” market because the target patient group includes potentially every person; at the same time, oncology has become the largest therapeutic area in the pharmaceutical industry in terms of the number of projects, clinical trials and research and development (R&D) spending, but cancer remains one of the leading causes of mortality worldwide. The overall aim of the work presented in this thesis was the rational design of new compounds able to modulate activity of relevant targets involved in cancer and aging-related pathologies, namely proteasome and immunoproteasome, sirtuins and interleukin 6. These three targets play different roles in human cells, but the modulation of its activity using small molecules could have beneficial effects on one or more aging-related diseases and cancer. We identified new moderately active and selective non-peptidic compounds able to inhibit the activity of both standard and immunoproteasome, as well as novel and selective scaffolds that would bind and inhibit SIRT6 selectively and can be used to sensitize tumor cells to commonly used anticancer agents such gemcitabine and olaparib. Moreover, our virtual screening approach led us also to the discovery of new putative modulators of SIRT3 with interesting in-vitro and cellular activity. Although the selectivity and potency of the identified chemical scaffolds are susceptible to be further improved, these compounds can be considered as highly promising leads for the development of future therapeutics.