Pierfrancesco Cinque
FPC1 – Pierfrancesco Cinque
University of Naples Federico II – Department of Pharmacy
pierfrancesco.cinque@unina.it
| Design and synthesis of molecular hybrids between drugs for dermatological disorders or wound healing and h2s donors |
| Pierfrancesco Cinque1, Giuseppe Caliendo1, Vincenzo Santagada1, Rosa Sparaco1, Vincenzo Calderone2, Valentina Citi2, Angela Ianaro1,Giuseppe Ercolano1, Barbara Maglione3 and Francesco Frecentese1. 1 Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy 2 Department of Pharmacy, University of Pisa, Via Bonanno, 6 ,56126, Pisa, Italy 3 Farmaceutici Damor Spa, Via Emilio Scaglione, 27, 80145 Napoli, Italy |
| Abstract The research project focuses on the development of molecular hybrids combining JAK kinase inhibitors, approved for dermatological diseases such as atopic dermatitis, psoriasis and vitiligo, with H₂S-releasing moieties able to mimic physiological hydrogen sulfide release [1]. These diseases are characterized by abnormal immune activation and chronic inflammation, with periods of clinical stability alternating with flare-ups. In this study, molecular hybrids based on JAK-STAT pathway inhibitors, such as Abrocitinib and Peficitinib, were designed and synthesized by conjugating the JAK-inhibiting pharmacophore with selected H₂S donors, namely TBZ, ADT-OH and HBTA. This strategy aims to combine the anti-inflammatory activity mediated by JAK-STAT pathway inhibition with the well-known biological properties of H₂S [2]. TBZ is commercially available, whereas ADT-OH and HBTA were prepared according to published procedures [3,4]. Compounds I–VI were evaluated for cytotoxicity in HaCaT keratinocytes at different concentrations ranging from 0.01 to 100 µM. Their H₂S-releasing profile was also assessed in the presence and absence of L-cysteine. In vitro pharmacological studies were performed at 5 µM, including scratch test assays to evaluate their wound healing potential. Overall, compounds I–VI showed promising results, with HBTA and ADT-OH derivatives, particularly compounds II, III, V and VI, displaying the best activity and promoting complete wound closure within 48–72 h. Further studies are ongoing to assess their anti-inflammatory activity and to confirm JAK-STAT pathway inhibition through molecular biology assays. |
| References [1] Samadi, A.; Nasrollahi, S. A.; Hashemi, A.; Nassiri Kashani, M.; Firooz, A. Janus Kinase (JAK) Inhibitors for the Treatment of Skin and Hair Disorders: A Review of Literature. J. Dermatol. Treat. 2017, 28 (6), 476–483. DOI: 10.1080/09546634.2016.1277179 [2] Magli, E.; Perissutti, E.; Santagada, V.; Caliendo, G.; Corvino, A.; Esposito, G.; Fiorino, F.; Migliaccio, M.; Scognamiglio, A.; Severino, B.; Sparaco, R.; Frecentese, F. H₂S Donors and Their Use in Medicinal Chemistry. Biomolecules 2021, 11 (12), 1899. DOI: 10.3390/biom11121899 [3] Wallace, J. L.; Caliendo, G.; Sparatore, A.; Santagada, V.; Fiorucci, S. Derivatives of 4- or 5-Aminosalicylic Acid. Patent WO2006125293, 2006. [4] Ercolano, G.; De Cicco, P.; Frecentese, F.; Saccone, I.; Corvino, A.; Giordano, F.; Magli, E.; Fiorino, F.; Severino, B.; Calderone, V.; Citi, V.; Cirino, G.; Ianaro, A. Anti-Metastatic Properties of Naproxen-HBTA in a Murine Model of Cutaneous Melanoma. Front. Pharmacol. 2019, 10, 66. DOI: 10.3389/fphar.2019.00066 |