Speaker
Descrizione
In this project we focused on the design, synthesis, and optimization of novel molecules of biomedical interest with particular relevance in the tumor microenvironment. [1] The developement of new strategies to counteract such a disease is of paramount importance. Among synthetic strategies known to date, the use of Multi-Target Directed Ligands (MTDLs) has emerged as particularly effective, and associated to benefits such as improved patient compliance, therapeutic outcomes and predictable pharmacokinetics and pharmacodynamics. [2] In this context, the project was carried out by the development of two different series of inhibitors, with the first targeting both Carbonic Anhydrases (CA) and Fibroblast Activation Protein (FAP), incorporating a radiolabeling chelator, and the latter obtained incorporating in the same compound the CA inhibition moiety and the radiolabeling chelator.
Carbonic Anhydrases (CA, EC 4.2.1.1) [3-4] are a superfamily of metalloenzymes encoded by eight unrelated gene families that reversibly catalyze the hydration of carbon dioxide to bicarbonate and protons. Among the eight CA families, 15 α-CA isoforms are expressed in humans. CAs are crucial in hypoxic tumors as are relevant to prevent too low intracellular pHs which in turn will trigger necrotic and apoptotic events. [5] The second target for this project is the Fibroblast activation protein-α (FAP-α; EC 3.4.14.5) [6], which is endowed with peptidase activity and expressed on the cell surface of cancer-associated fibroblasts (CAFs) in the tumor stroma. FAP plays a crucial role in tumor progression, growth and metastasis. [7] Although FAP is expressed in specific healthy tissues, [8] it is significantly upregulated in tumors. [9] In this project, two distinct series of derivatives were synthesized: The first bearing both pharmacophores and the chelating agent NOTA or DOTA; the second one bearing only the benzenesulfonamide moiety for the inhibition of carbonic anhydrases isoforms with the chelating agent NOTA.
References:
https://hdr.undp.org/system/files/documents/global-report-document/hdr2021-22reportenglish_0.pdf
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Puré E, et al. Oncogene. 2018 Aug;37(32):4343-4357.
Xin L, et al. Front Oncol. 2021 Aug 19;11:648187.
