A facile hybrid 'flow and batch' access to substituted 3, 4-dihydro-2H-benzo[b][1, 4]oxazinones. Issue 37 (30th August 2016)

• Record Type: Journal Article
• Authors: Lin, Andrew J. S.; Russell, Cecilia C.; Baker, Jennifer R.; Frailey, Shelby L.; Sakoff, Jennette A.; McCluskey, Adam
• Is Part Of: Organic & biomolecular chemistry. Volume 14:Issue 37(2016)
• Page Start: 8732
• Page End: 8742
• Publication Date: 2016-08-30
• Subjects: Chemistry, Organic -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1039/c6ob01153e
• Languages: English
• ISSNs: 1477-0520

Abstract

Abstract : A simple flow chemistry approach to libraries of 2-substituted-phenylamino 3, 4-dihydro-2 H -benzo[ b ][1, 4]oxazine-6-carboxylates (12a–l and13a–l ) in 38–87% yields. Abstract : We describe a simple flow chemistry approach to libraries of ethyl 3-oxo-2-(substituted-phenylamino)-3, 4-dihydro-2 H -benzo[ b ][1, 4]oxazine-6-carboxylates (12a–l ) and N -ethyl-3-oxo-2-(substituted-phenylamino)-3, 4-dihydro-2 H -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 library13a–l was devoid of toxicity. Whereas the ester linked analogues12b, 12c, 12g, 12j and12l were highly cytotoxic with growth inhibition (GI50 ) values from 0.34 to >50 μM across all cell lines, with the 2-OH-Ph substituted12l 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 (GI50 32 to >50 μM) while the A2780 cells were highly sensitive (GI50 3.8–0.34 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.