A novel strategy for the synthesis of thermally stable and apoptosis-inducing 2,3-dihydroazetes.
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.
St. Petersburg State University, Institute of Chemistry, 7/9 Universitetskaya nab., St. Petersburg, 199034, Russia. m.novikov@spbu.ru.
Ilia A
IA
Smetanin
St. Petersburg State University, Institute of Chemistry, 7/9 Universitetskaya nab., St. Petersburg, 199034, Russia. m.novikov@spbu.ru.
Mikhail S
MS
Novikov
St. Petersburg State University, Institute of Chemistry, 7/9 Universitetskaya nab., St. Petersburg, 199034, Russia. m.novikov@spbu.ru.
Anastasiya V
AV
Agafonova
St. Petersburg State University, Institute of Chemistry, 7/9 Universitetskaya nab., St. Petersburg, 199034, Russia. m.novikov@spbu.ru.
Nikolai V
NV
Rostovskii
St. Petersburg State University, Institute of Chemistry, 7/9 Universitetskaya nab., St. Petersburg, 199034, Russia. m.novikov@spbu.ru.
Alexander F
AF
Khlebnikov
Institute of Experimental Medicine, Russian Academy of Medical Sciences, ul. Acad. Pavlov 12, St. Petersburg, 197376, Russia.
Igor V
IV
Kudryavtsev
Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, pr. Torez 44, St. Petersburg, 194223, Russia.
Maxim A
MA
Terpilowski
Institute of Experimental Medicine, Russian Academy of Medical Sciences, ul. Acad. Pavlov 12, St. Petersburg, 197376, Russia.
Maria K
MK
Serebriakova
Institute of Experimental Medicine, Russian Academy of Medical Sciences, ul. Acad. Pavlov 12, St. Petersburg, 197376, Russia.
Andrey S
AS
Trulioff
Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, pr. Torez 44, St. Petersburg, 194223, Russia.
Nikolay V
NV
Goncharov