A novel strategy for the synthesis of thermally stable and apoptosis-inducing 2,3-dihydroazetes

作者：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

来源：ORGANIC %26 BIOMOLECULAR CHEMISTRY, 2016, 14(19): 4479-4487.

DOI：10.1039/c6ob00588h

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-dihydroazete2,2,3-tricarboxylate was found to display the maximal apoptotic potential coupled with high cytotoxic and minimal necrotic potential.

• 出版日期2016