title: Synthesis and biological evaluation of fluorinated 1,5-diarylpyrrole-3-alkoxyethyl ether derivatives as selective COX-2 inhibitors endowed with anti-inflammatory activity.
abstract: A series of substituted 1,5-diarylpyrrole-3-alkoxyethyl ethers were previously synthesized and the potential anti-inflammatory and antinociceptive activities of these compounds were evaluated in vivo. The compounds displayed a very good activity against both carrageenan-induced hyperalgesia and oedema in the rat paw test. Therefore, in a very preliminary test, compounds (8a,b) showed antiproliferative activity in the HaCaT (aneuploid immortal keratinocyte from adult human skin) cell models. On these basis, our research continued with the synthesis of fluorinated derivatives (8c,d, 9b-d, and 10b-d) with the aim of improving the pharmacokinetic profile of the previous active compounds. Substitution of a hydrogen atom by a fluorine atom may change the conformational preferences of the molecules due to stereoelectronic effects and also fluorine atom may be able to exert the metabolic obstruction reducing the "first-pass effect". Compound 10b exhibited a prominent in vivo anti-inflammatory and antinociceptive activities, in addition its antiproliferative power in an in vitro model of human skin cancer is herein described.
authors.affiliation: Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Di Capua
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sticozzi
authors.affiliation: Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Brogi
authors.affiliation: Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Brindisi
authors.affiliation: Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cappelli
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano 49, I-80131, Napoli, Italy.
authors.forename: Lidia
authors.initials: L
authors.lastname: Sautebin
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano 49, I-80131, Napoli, Italy.
authors.forename: Antonietta
authors.initials: A
authors.lastname: Rossi
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano 49, I-80131, Napoli, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Pace
authors.affiliation: Department of Pharmacology Neuroscience, Psychology, Drug Research and Child Health - Neurofarba, Pharmacology and Toxicology Section, University of Florence, Viale G. Pieraccini 6, I-50139 Firenze, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
authors.affiliation: Department of Pharmacology Neuroscience, Psychology, Drug Research and Child Health - Neurofarba, Pharmacology and Toxicology Section, University of Florence, Viale G. Pieraccini 6, I-50139 Firenze, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Di Cesare Mannelli
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy; Department of Food and Nutrition, Kyung Hee University, Seoul, South Korea.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Valacchi
authors.affiliation: Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Giorgi
authors.affiliation: Rottapharm Biotech, Via Valosa di Sopra 7, 20052 Monza, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordani
authors.affiliation: Department of Chemical Studies and Technologies of Drugs, University of Rome "La Sapienza", Piazzale Aldo Moro 5, 00185 Roma, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Poce
authors.affiliation: Department of Chemical Studies and Technologies of Drugs, University of Rome "La Sapienza", Piazzale Aldo Moro 5, 00185 Roma, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Biava
authors.affiliation: Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy. Electronic address: maurizio.anzini@unisi.it.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Anzini
mesh_terms: D000328:Adult; D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D004487:Edema / Q000188:drug therapy; D054879:Halogenation; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy; D008958:Models, Molecular; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D051381:Rats; D012867:Skin / Q000187:drug effects / Q000473:pathology; D012878:Skin Neoplasms / Q000188:drug therapy / Q000473:pathology
chemical_list: D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D011758:Pyrroles; D051546:Cyclooxygenase 2
keywords: 1,5-diarylpyrrole derivatives; Anti-inflammatory agents; Antinociceptive agents; Antiproliferative activity; COX-2 inhibitors; Molecular modelling