Novel pyran-2-one based compounds for selective inhibition of tumor-related isoforms of human Carbonic Anhydrase hCA IX and XII. Synthesis, biological evaluation and docking studies.

Proponente Paolo Guglielmi - Ricercatore
Sottosettore ERC del proponente del progetto
Componenti gruppo di ricerca
Componente Categoria
Virginia Pontecorvi Dottorando/Assegnista/Specializzando componente non strutturato del gruppo di ricerca
Arianna Granese Componenti strutturati del gruppo di ricerca
Daniela Secci Componenti strutturati del gruppo di ricerca
Componente Qualifica Struttura Categoria
Simone Carradori Ricercatore Dipartimento di Farmacia, Università "Giovanni D'Annunzio"di Chieti-Pescara Altro personale aggregato Sapienza o esterni, titolari di borse di studio di ricerca

Carbonic Anhydrases (CAs, EC are ubiquitous metalloenzymes involved in the catalysis of the reversible hydration of carbon dioxide. Up to day, eight genetic CA families alpha, beta, gamma, delta, zeta, eta, theta, and iota-CAs, have been reported in organisms from across the phylogenetic tree. The fifteen human (h) isoforms of carbonic anhydrase (hCAs) belong to the alpha family and are involved in functions such as respiration, transport of carbon dioxide between metabolising tissues and lungs, pH homeostasis, electrolyte secretion in various tissues/ organs as well as biosynthetic reactions covering a pivotal role in a multitude of physiological functions. However, in some cases, these enzymes could contribute to pathological processes taking part in the complex machinery system developed by cells to face the hypoxic conditions of solid tumors and regulate intracellular pH. In particular the two isoforms of hCA IX and XII, called tumor-related isoforms, are overexpressed in different cancers. In this regard, the development of inhibitors that selectively bind and inhibit these two enzymes could be exploited for cancer treatment. The objective of this project is the development of novel and selective inhibitors of human carbonic anhydrase (hCAs) isoforms IX and XII, based on the pyran-2-one core, substituted at the position 5 with carboxamide linker bearing different (hetero)aromatic or aliphatic residues.
The novel compounds will be evaluated in in vitro assay against 4 isoforms of human carbonic anhydrase: the two off-targets hCA I and II and the two targets hCA IX and XII. The derivatives exhibiting the best profiles will be further investigated against proper tumor cell lines. Docking studies and molecular dynamics will be performed in order to assess the putative binding mode of the novel compounds.

LS7_4, PE5_11, PE4_5

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