Adriana Gargano
| Discovery and Characterization of Natural Compounds for Cancer Therapy: A Combined Target-Based and Phenotypic Approach |
| Gargano Adriana1,2, Puerta Adrián3, González Bakker Aday3, Rocca Roberta1, Maggisano Valentina1, Bulotta Stefania1, Padrón José M.3 and Alcaro Stefano1,2 1Dipartimento di Scienze della Salute, Università “Magna Græcia” di Catanzaro, Campus Universitario “S. Venuta”, Viale Europa, 88100 Catanzaro, Italy; 2Associazione CRISEA – Centro di Ricerca e Servizi Avanzati per l’Innovazione Rurale, Località Condoleo, 88055 Belcastro (CZ), Italy; 3BioLab, Instituto Universitario de Bio-Orgánica “Antonio González”, Universidad de La Laguna, C/ Astrofísico Francisco Sánchez 2, 38206 La Laguna, Spain; |
| Abstract This PhD project identifies natural Mediterranean compounds endowed with pharmaceutical activity using both target-based drug discovery and phenotypic drug discovery approaches across five cancer-focused studies. The first project involved the synthesis of coumarin-lipophilic cation hybrids as selective inhibitors of mitochondrial Carbonic Anhydrases IX and XII. These showed potent, selective activity against various cancer cells, including multidrug-resistant models, via a “suicide inhibition” mechanism; phosphonium salts exert cytostatic effects, whereas guanidinium derivatives trigger apoptosis [1]. The second project investigated the modulation of the IL-20RA receptor, through a virtual screening of natural compounds and FDA-approved drugs, Ritonavir was identified as a potential inhibitor. Biological assays confirmed its dose-dependent efficacy, validated by IL-20RA silencing. [2]. The third and fourth projects targeted HDAC8 and Sphingosine Kinase 1 (SK1), respectively. Shape-based virtual screening identified a potent HDAC8 inhibitor that demonstrated high enzymatic inhibition (97.56% at 1 μM) and induced apoptosis in multiple cancer cell lines. For SK1, a pharmacophore-based screening identified 7 candidate ligands, currently undergoing enzymatic evaluation. Finally, the fifth project utilized a PDD approach to study two novel compounds from Argentinean Maytenus species: 20-α-hydroxyscutione and 15-α-hydroxytingenone [3]. Both compounds exhibited anti-migratory and pro-apoptotic effects on lung cancer cells without disrupting microtubule dynamics. Structural similarity searches identified related compounds in Mediterranean plants, such as Taraxacum officinale and Bituminaria bituminosa, providing a scientific basis for the design of a specialized botanical garden in collaboration with regional research centers. Overall, this work integrates computational modeling and biological validation to discover new therapeutic leads and supports the valorisation of Mediterranean botanical resources in drug discovery. |
| References [1] Fuentes-Aguilar, A.; González-Bakker, A.; Jovanović, M.; Stojanov, S.J.; Puerta, A.; Gargano, A.; Dinić, J.; Vega-Báez, J.L.; Merino-Montiel, P.; Montiel-Smith, S.; Alcaro, S.; Nocentini, A.; Pešić, M.; Supuran, C.T.; Padrón, J. M.; Fernández-Bolaños, J. G.; López, Ó. Coumarins-Lipophilic Cations Conjugates: Efficient Mitocans Targeting Carbonic Anhydrases. Bioorg Chem 2024, 145, 107168. [2] Maggisano, V.; Gargano, A.; Maiuolo, J.; Ortuso, F.; De Amicis, F.; Alcaro, S.; Bulotta, S. Rational Identification of Ritonavir as IL-20 Receptor A Ligand Endowed with Antiproliferative Properties in Breast Cancer Cells. Int J Mol Sci 2025, 26, 1285 [3] de Almeida, M.T.R.; Ríos-Luci, C.; Padrón, J.M.; Palermo, J.A. Antiproliferative Terpenoids and Alkaloids from the Roots of Maytenus Vitis-Idaea and Maytenus Spinosa. Phytochemistry 2010, 71, 1741 1748. |