Staff member

Carlo Matera

Postdoctoral Researcher
Nanoprobes and Nanoswitches
+34 934 031 127
Staff member publications

Matera, Carlo, Gomila-Juaneda, Alexandre, Camarero, Núria, Libergoli, Michela, Soler, Concepció, Gorostiza, Pau, (2018). A photoswitchable antimetabolite for targeted photoactivated chemotherapy Journal of the American Chemical Society Just Accepted Manuscript,

The efficacy and tolerability of systemically administered anticancer agents are limited by their off-target effects. Precise spatiotemporal control over their cytotoxic activity would allow improving chemotherapy treatments, and light-regulated drugs are well suited to this purpose. We have developed phototrexate, the first photoswitchable inhibitor of the human dihydrofolate reductase (DHFR), as a photochromic analog of methotrexate, a widely prescribed chemotherapeutic drug to treat cancer and psoriasis. Quantification of the light-regulated DHFR enzymatic activity, cell proliferation, and in vivo effects in zebrafish show that phototrexate behaves as a potent antifolate in its photoactivated cis configuration, and that it is nearly inactive in its dark-relaxed trans form. Thus, phototrexate constitutes a proof-of-concept to design light-regulated cytotoxic small molecules, and a step forward to develop targeted anticancer photochemotherapies with localized efficacy and reduced adverse effects.

Keywords: Photopharmacology, Photodynamic therapy, Antiproliferative, Arthritis, Psoriasis, Nanomedicine

Quadri, M., Matera, C., Silnovi, Pismataro, M. C., Horenstein, N. A., Stokes, C., Papke, R. L., Dallanoce, C., (2017). Identification of α7 nicotinic acetylcholine receptor silent agonists based on the spirocyclic quinuclidine-Δ2-isoxazoline scaffold: Synthesis and electrophysiological evaluation ChemMedChem XXIV National Meeting in Medicinal Chemistry (NMMC 2016) , Wiley Online Library (Perugia, Spain) 12, (16), 1335-1348

Compound 11 (3-(benzyloxy)-1′-methyl-1′-azonia-4H-1′-azaspiro[isoxazole-5,3′-bicyclo[2.2.2]octane] iodide) was selected from a previous set of nicotinic ligands as a suitable model compound for the design of new silent agonists of α7 nicotinic acetylcholine receptors (nAChRs). Silent agonists evoke little or no channel activation but can induce the α7 desensitized Ds state, which is sensitive to a type II positive allosteric modulator, such as PNU-120596. Introduction of meta substituents into the benzyloxy moiety of 11 led to two sets of tertiary amines and quaternary ammonium salts based on the spirocyclic quinuclidinyl-Δ2-isoxazoline scaffold. Electrophysiological assays performed on Xenopus laevis oocytes expressing human α7 nAChRs highlighted four compounds that are endowed with a significant silent-agonism profile. Structure–activity relationships of this group of analogues provided evidence of the crucial role of the positive charge at the quaternary quinuclidine nitrogen atom. Moreover, the present study indicates that meta substituents, in particular halogens, on the benzyloxy substructure direct specific interactions that stabilize a desensitized conformational state of the receptor and induce silent activity

Keywords: Agonists, Cycloaddition, Nitrogen heterocycles, Receptors, Spiro compounds