title: Synthesis and Biological Evaluation of 2-Methyl-4,5-Disubstituted Oxazoles as a Novel Class of Highly Potent Antitubulin Agents.
abstract: Antimitotic agents that interfere with microtubule formation are one of the major classes of cytotoxic drugs for cancer treatment. Multiple 2-methyl-4-(3',4',5'-trimethoxyphenyl)-5-substituted oxazoles and their related 4-substituted-5-(3',4',5'-trimethoxyphenyl) regioisomeric derivatives designed as cis-constrained combretastatin A-4 (CA-4) analogues were synthesized and evaluated for their antiproliferative activity in vitro against a panel of cancer cell lines and, for selected highly active compounds, interaction with tubulin, cell cycle effects and in vivo potency. Both these series of compounds were characterized by the presence of a common 3',4',5'-trimethoxyphenyl ring at either the C-4 or C-5 position of the 2-methyloxazole ring. Compounds 4g and 4i, bearing a m-fluoro-p-methoxyphenyl or p-ethoxyphenyl moiety at the 5-position of 2-methyloxazole nucleus, respectively, exhibited the greatest antiproliferative activity, with IC50values of 0.35-4.6 nM (4g) and 0.5-20.2 nM (4i), which are similar to those obtained with CA-4. These compounds bound to the colchicine site of tubulin and inhibited tubulin polymerization at submicromolar concentrations. Furthermore, 4i strongly induced apoptosis that follows the mitochondrial pathway. In vivo, 4i in a mouse syngeneic model demonstrated high antitumor activity which significantly reduced the tumor mass at doses ten times lower than that required for CA-4P, suggesting that 4i warrants further evaluation as a potential anticancer drug.
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, 44121 Ferrara, Italy.
authors.forename: Romeo
authors.initials: R
authors.lastname: Romagnoli
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, 44121 Ferrara, Italy.
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Baraldi
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, 44121 Ferrara, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Prencipe
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, 44121 Ferrara, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Oliva
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, 44121 Ferrara, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Baraldi
authors.affiliation: Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Campus de Cartuja s/n, 18071, Granada, Spain.
authors.forename: Maria Kimatrai
authors.initials: MK
authors.lastname: Salvador
authors.affiliation: Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Campus de Cartuja s/n, 18071, Granada, Spain.
authors.forename: Luisa Carlota
authors.initials: LC
authors.lastname: Lopez-Cara
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3NB, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3NB, UK.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Ferla
authors.affiliation: Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, USA.
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.affiliation: Dipartimento di Medicina Molecolare e Traslazionale Unità di Oncologia Sperimentale ed Immunologia, Università di Brescia, 25123 Brescia, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Ronca
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131 Padova, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Bortolozzi
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131 Padova, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Mariotto
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131 Padova, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Porcù
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131 Padova, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131 Padova, Italy.
authors.forename: Giampietro
authors.initials: G
authors.lastname: Viola
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D004249:DNA Damage / Q000187:drug effects; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D010080:Oxazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D055503:Protein Multimerization; D015398:Signal Transduction; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D010080:Oxazoles; D014404:Tubulin; D050257:Tubulin Modulators; D011065:Poly(ADP-ribose) Polymerases