title: A facile hybrid 'flow and batch' access to substituted 3,4-dihydro-2H-benzo[b][1,4]oxazinones.
abstract: We describe a simple flow chemistry approach to libraries of ethyl 3-oxo-2-(substituted-phenylamino)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylates (12a-l) and N-ethyl-3-oxo-2-(substituted-phenylamino)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamides (13a-l) in 38-87% yields. This scaffold is poorly described in the chemical literature. Screening against a panel of 11 cancer and one normal cell line showed that the amide linked library 13a-l was devoid of toxicity. Whereas the ester linked analogues 12b, 12c, 12g, 12j and 12l were highly cytotoxic with growth inhibition (GI50) values from 0.34 to >50 μM across all cell lines, with the 2-OH-Ph substituted 12l analogue presenting with sub-micromolar potency against the A2780 (ovarian; 0.34 ± 0.04 μM), BEC-2 (glioblastoma; 0.35 ± 0.06 μM), MIA (pancreas; 0.91 ± 0.054 μM) and SMA (murine glioblastoma; 0.77 ± 0.029 μM) carcinoma cell lines. Interestingly, the U87 glioblastoma cell line showed inherent resistance to growth inhibition by all analogues (GI5032 to >50 μM) while the A2780 cells were highly sensitive (GI503.8-0.34 μM), suggesting that the analogues developed herein may be valuable lead compounds for the development of ovarian carcinoma specific cytotoxic agents. The differences in amide versus ester cytotoxicity was consitent with esterase cleaveage to release the cytotoxic warhead.
authors.affiliation: Chemistry, Centre for Chemical Biology, School of Environmental & Life Sciences, University of Newcastle, University Drive, Callaghan, NSW 2308, Australia. Adam.McCluskey@newcastle.edu.au.
authors.forename: Andrew J S
authors.initials: AJ
authors.lastname: Lin
authors.affiliation: Chemistry, Centre for Chemical Biology, School of Environmental & Life Sciences, University of Newcastle, University Drive, Callaghan, NSW 2308, Australia. Adam.McCluskey@newcastle.edu.au.
authors.forename: Cecilia C
authors.initials: CC
authors.lastname: Russell
authors.affiliation: Chemistry, Centre for Chemical Biology, School of Environmental & Life Sciences, University of Newcastle, University Drive, Callaghan, NSW 2308, Australia. Adam.McCluskey@newcastle.edu.au.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Baker
authors.affiliation: Chemistry, Centre for Chemical Biology, School of Environmental & Life Sciences, University of Newcastle, University Drive, Callaghan, NSW 2308, Australia. Adam.McCluskey@newcastle.edu.au and Chemical Engineering, Trine University, Angola, IN, 46703 USA.
authors.forename: Shelby L
authors.initials: SL
authors.lastname: Frailey
authors.affiliation: Department of Medical Oncology, Calvary Mater Newcastle Hospital, Waratah, NSW 2298, Australia.
authors.forename: Jennette A
authors.initials: JA
authors.lastname: Sakoff
authors.affiliation: Chemistry, Centre for Chemical Biology, School of Environmental & Life Sciences, University of Newcastle, University Drive, Callaghan, NSW 2308, Australia. Adam.McCluskey@newcastle.edu.au.
authors.forename: Adam
authors.initials: A
authors.lastname: McCluskey
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D048588:Benzoxazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic / Q000191:economics / Q000379:methods; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D054852:Small Molecule Libraries / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D048588:Benzoxazines; D054852:Small Molecule Libraries