Towards the discovery of novel sigma receptor modulators: organolithium-methods based synthesis and biological evaluations

Marta Rui
2016 unpublished
My three-years-project has been focused on two main topics, Sigma Receptors (SRs) and Lithium carbenoids, as briefly summarized in the following paragraphs. 1. Sigma Receptors as novel targets for the cancer treatment. The driving force of my project work has been the need of finding "druggable" proteins as new molecular targets to treat cancer conditions. In the discovery of novel anticancer agents, able to guarantee a result with poor side effects, SRs modulators are fit for purpose. Briefly,
more » ... Sigma Receptors are involved in a large number of physiological functions including learning and memory processes, depression and anxiety, schizophrenia, analgesia and cancer. There are two subtypes of Sigma Receptors: S1R and S2R based on anatomical distribution, pharmacological and pathological activities. S1Rs are well known and several modulators have been identified so far. Particularly, S1R agonists are proved to exert neuroprotective and neuroplastic effects whereas S1R antagonists give rise to beneficial activities against neuropathic pain and cancer. Conversely, S2Rs still present enigmatic aspects, both from structural and pharmacological point of view. However, numerous experimental evidences show the overexpression of this molecular target in cancer cells and the scientific community strongly supports the idea that S2R modulators may have antiproliferative and proapoptotic effects. Accordingly, we spent some of our efforts in identifying new anticancer agents, acting via SR modulation. In detail, we generated a QSAR model, using the activity data published in literature and our in-house library. 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 an [...]
doi:10.25365/thesis.44900 fatcat:btmva6ti4nbrdkl3iu35ipsiue