title: Identification of new pyrrolo[2,3-d]pyrimidines as Src tyrosine kinase inhibitors in vitro active against Glioblastoma.
abstract: In the last few years, several pyrrolo-pyrimidine derivatives have been either approved by the US FDA and in other countries for the treatment of different diseases or are currently in phase I/II clinical trials. Herein we present the synthesis and the characterization of a novel series of pyrrolo[2,3-d]pyrimidines, compounds 8a-j, and their activity against Glioblastoma multiforme (GBM). Docking studies and MM-GBSA analysis revealed the ability of such compounds to efficiently interact with the ATP binding site of Src. Enzymatic assays against a mini-panel of kinases (Src, Fyn, EGFR, Kit, Flt3, Abl, AblT315I) have been performed, showing an unexpected selectivity of our pyrrolo[2,3-d]pyrimidines for Src. Finally, the derivatives were tested for their antiproliferative potency on U87 GBM cell line. Compound 8h showed a considerable cytotoxicity effect against U87 cell line with an IC50value of 7.1 μM.
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Genova, Viale Benedetto XV, 3, 16132 Genova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Musumeci
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Anna Lucia
authors.initials: AL
authors.lastname: Fallacara
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Genova, Viale Benedetto XV, 3, 16132 Genova, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Brullo
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Genova, Viale Benedetto XV, 3, 16132 Genova, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Grossi
authors.affiliation: Dipartimento di Farmacia, Università"Federico II" di Napoli, Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Botta
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Pierpaolo
authors.initials: P
authors.lastname: Calandro
authors.affiliation: Consiglio Nazionale delle Ricerche, Istituto di Fisiologia Clinica and Istituto Toscano Tumori, Core Research Laboratory, Via Fiorentina 1, 53100 Siena, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Chiariello
authors.affiliation: Consiglio Nazionale delle Ricerche, Istituto di Genetica Molecolare, IGM-CNR, Via Abbiategrasso 207, 27100 Pavia, Italy.
authors.forename: Miroslava
authors.initials: M
authors.lastname: Kissova
authors.affiliation: Consiglio Nazionale delle Ricerche, Istituto di Genetica Molecolare, IGM-CNR, Via Abbiategrasso 207, 27100 Pavia, Italy.
authors.forename: Emmanuele
authors.initials: E
authors.lastname: Crespan
authors.affiliation: Consiglio Nazionale delle Ricerche, Istituto di Genetica Molecolare, IGM-CNR, Via Abbiategrasso 207, 27100 Pavia, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Genova, Viale Benedetto XV, 3, 16132 Genova, Italy. Electronic address: schensil@unige.it.
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D015195:Drug Design; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D019061:src-Family Kinases
keywords: Glioblastoma; Kinase inhibitors; Pyrrolo-pyrimidines; Small molecules; Src