TOWARDS THE DISCOVERY OF NOVEL SIGMA RECEPTOR MODULATORS: ORGANOLITHIUM-METHODS BASED SYNTHESIS AND BIOLOGICAL EVALUATIONS

My three-years-project has been focused on two main topics, Sigma Receptors (SRs) and Lithium carbenoids. Concerning SRs, we spent our efforts in identifying new anticancer agents, acting via SR modulation. In detail, we generated a QSAR model. This approach allowed to identify the structural features that guarantee a high affinity towards both SR subtypes. From this study emerged that compounds presenting a bulky aminic portion, i.e. 4-benzylpiperidine, possess pan-SR affinity. Therefore, we designed and synthetized a compound series of racemic and enantiomeric arylalkyl(alkenyl)-4-benzylpiperidine derivatives. On the bases of binding profile towards S1R and S2R and of its cytotoxic properties towards a panel of cancer cell lines, we select RC-106 as the most promising antiproliferative agent. Lastly, a biotin-pan-SR conjugate has been designed as pharmacological tool able to enhance the uptake of antiproliferative molecules in cancer cells, as well as to avoid side effects. Although several attempts have been carried out, up to now, the desired product has not been obtained. Regarding Lithium Carbenoids, their reactivity/stability has been studied toward enone substrates. The chemical profile of Carbenoids leads to consider these reagents as versatile homologating agents. The work presents herein is part of this scenario and it is a pursuance of the prior publication of Pace and co-workers, which developed a strategy to carry out a chemoselective 1,2-addition of LiCH2Cl to cyclic enones. Once the applicability of the lithium carbenoids towards these ketones has been confirmed, the reactivity/stability of these species has been investigated in depth. Therefore, we focused on the study of the parameters that may influence the behavior of monohalomethyllithium reagents, using a syringe pump instrument. Interestingly, from this work unexpected products emerged. Indeed, under particular conditions, a double homologation may occur, furnishing aldehydes. We analyzed this surprising reaction and disclosed the mechanism that took place.