A novel strategy for the synthesis of thermally stable and apoptosis-inducing 2, 3-dihydroazetes. Issue 19 (19th April 2016)

• Record Type: Journal Article
• Authors: Smetanin, Ilia A.; Novikov, Mikhail S.; Agafonova, Anastasiya V.; Rostovskii, Nikolai V.; Khlebnikov, Alexander F.; Kudryavtsev, Igor V.; Terpilowski, Maxim A.; Serebriakova, Maria K.; Trulioff, Andrey S.; Goncharov, Nikolay V.
• Is Part Of: Organic & biomolecular chemistry. Volume 14:Issue 19(2016)
• Page Start: 4479
• Page End: 4487
• Publication Date: 2016-04-19
• Subjects: Chemistry, Organic -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1039/c6ob00588h
• Languages: English
• ISSNs: 1477-0520

Abstract

Abstract : Apoptosis-inducing 2, 3-dihydroazetes were prepared from 2-bromoazirines or 4-bromoisoxazoles by carbenoid-initiated ring opening followed by cyclization-hydrodebromination cascade. Abstract : A general and concise approach to thermally and hydrolytically stable alkyl 2, 3-dihydroazete-2, 3-di-/2, 2, 3-tricarboxylates from alkyl 2-bromoazirine-2-carboxylates or 4-bromo-5-alkoxyisoxazoles is reported. The synthesis involves the formation of 2-azabuta-1, 3-diene by the reaction of rhodium carbenoid with isoxazole or azirine followed by cyclization/hydrodebromination cascade. The latter reaction is the first example of the selective hydrodehalogenation of a valence isomer under equilibrium conditions. In vitro cytotoxicity tests on THP-1 cell line revealed that the 2, 3-dihydroazetes greatly differ in their ability to induce apoptosis and/or necrosis. To adequately describe and quantitatively assess these properties, the difference between the two areas under the curves of concentration dependency of apoptosis/necrosis induction within the concentration range was used. Trimethyl 4-phenyl-2, 3-dihydroazete-2, 2, 3-tricarboxylate was found to display the maximal apoptotic potential coupled with high cytotoxic and minimal necrotic potential.