Synthesis and Cytotoxic Activity of Fluorine-Containing 6,7-Dihydroindazolone and 6,7-Dihydrobenzisoxazolone Derivatives
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Pharmaceutical Chemistry Journal, Vol. 54, No. 7, October, 2020 (Russian Original Vol. 54, No. 7, July, 2020)
SYNTHESIS AND CYTOTOXIC ACTIVITY OF FLUORINE-CONTAINING 6,7-DIHYDROINDAZOLONE AND 6,7-DIHYDROBENZISOXAZOLONE DERIVATIVES T. S. Khlebnikova,1,* Yu. A. Piven’,1 V. G. Zinovich,1 A. V. Baranovskii,1 É. B. Rusanov,2 O. V. Panibrat,1 S. É. Ogurtsova,1 and F. A. Lakhvich1 Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 54, No. 7, pp. 21 – 26, July, 2020.
Original article submitted March 5, 2020. The oximes of fluorine-containing 6,7-dihydroindazole-4,5-diones and 6,7-dihydrobenzisoxazole-4-5-diones, 5-[3-fluorobenzoyloxy)imino)]-6,6-dimethyl-3-(3-fluorophenyl)-6,7-dihydrobenz[d]]isoxazol-4(5H)-one, and 5,5-dimethyl-7-phenyl-9-(4-fluorophenyl)-3,5,6,7-tetrahydro-2H-pyrazolo[4,3-f]quinoxaline were synthesized. The cytotoxic activity of these compounds against cell lines MCF-7 (human breast carcinoma) and HepG2 (human hepatocellular carcinoma) was determined. The fluorine-containing 6,7-dihydroindazolone derivatives synthesized here included substances with marked antiproliferative activity, the mechanism of which may be linked with induction of apoptosis due to impairment of the regular cell cycle, i.e., delayed of tumor cells in the G2/M phase. Keywords: 3-[fluoroalkyl(aryl)]-6,7-dihydroindazolone derivatives; 3-[fluoroalkyl(aryl)]-6,7-dihydrobenzisoxazolone derivatives, synthesis, cytotoxic activity.
Many heterocyclic compounds containing pyrazole and isoxazole rings (both alone and condensed with other monoor polycyclic systems) are used as the base structures for the design of numerous pharmacological agents [1, 2]. Derivatives of indazole [3] and benzisoxazole [4] have a wide spectrum of biological activity, including antitumor, anti-HIV, anti-inflammatory, analgesic, antipsychotic, and other activities. The main targets of the antitumor actions of indazole and benzisoxazole derivatives are protein kinases, as well as heat shock protein HSP90, which is involved in regulating the cell cycle; this can lead to the induction of apoptosis [5, 6]. An effective strategy for developing novel therapeutic agents consists of selective introduction of fluorine atoms and fluoroalkyl groups into biologically active molecules. This is illustrated by the continuing increase in the number of fluorine-containing drugs already approved for use and in 1 2 *
clinical trials [7]. Methods for synthesizing fluorine-containing heterocyclic structures as potential drugs are currently under intense development [8, 9]. The aim of the present work was to synthesize a group of novel 6,7-dihydroindazolone and 6,7-dihydrobenzisoxazolone derivatives, namely the oximes of fluorine-containing 6,7-dihydroindazole-4,5-diones and 6,7-dihydrobenzisoxazole-4-5-diones, as well as 5,5-dimethyl-7-phenyl-9-(4-fluorophenyl)-3,5,6,7-tetrahydro-2H-pyrazolo[4,3-f]-quinoxaline and 5-[3-fluorobenzoyloxy)imino)]-6,6-dimethyl-3-(3fluorophenyl)-6,7-dihydrobenz[d]]isoxazol-4(5H)-one, and to study their cytotoxic activities against cell lines MCF-7 (h
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