Synthesis And Studies Of NO Fluorescent Probe And AR Antagonist ODM-201 And Its Hydroximic Acid Analogues

This paper is divided into two parts:The first part is the design,synthesis and spectroscopy of nitric oxide fluorescent probes.In the past,NO was only considered as an atmospheric pollutant.With the in-depth study of NO in recent years,NO was found as an important biosignal molecule,which plays an extremely important role in many physiological and pathological activities,including nervous system,immune system,cardiovascular disease,and so on.Therefore,the development of high-sensitivity and high-selectivity fluorescent probes for detecting NO could greatly promote the understanding of the mechanism by which this important messenger molecule plays its role in vivo.In this paper,9,10-phenanthrenequinone was used as a raw material to react with terephthalaldehyde and ammonium acetate to give 4-（1H-phenanthro[9,10-d]imidazol-2-yl）benzaldehyde 1,1was reacted with ethyl acetoac etate and ammonium bicarbonate to form Diethyl 4-（4-（1H-phenanthro[9,10-d]imidazol-2-yl）phenyl）-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate 2,2 was reacted with methyl bromide to obtain NO fluorescent probe DHP-1.Along with the reaction of DHP-1 and NO,a blue fluorescence enhencement at 455 nm was observed with excitation wavelength at 343 nm.The second part is the synthesis of anti-prostate cancer drug ODM-201 and its hydroximic acid analogs.ODM-201 is a high affinity AR（androgen receptor）antagonist that inhibits testosterone-induced AR nuclear translocation and also blocks the activity of the test mutant AR（F876L）produced in response to anti-androgen therapy.SAHA（Vorinostat）is a hydroximic acid histone deacetylase（HDAC）inhibitor that works by competing with related substrate to bind to HDAC zinc chelation site.In this paper,we attempted to graft the hydroximic acid moiety in HDAC inhibitor SAHA to the ODM-201 core via an amide bond to obtain a bifunctional compound that could inhibit both AR and HDAC.At first 4-bromo-2-chlorobenzonitrile and 4-bromo-2-（trifluoromethyl）benzonitrile as the starting materials were reacted with 1-（tetrahydropyran-2-yl）-1H-pyrazole-5-boronic acid pinacol ester by Suzuki coupling,then treated with HCl/Et OH to obtain 2-chloro-4-（1-（tetrahydro-2H-pyran-2-yl）-1H-pyrazol-5-yl）benzonitrile 7 and2-（trifluoromethyl）-4-（1-（tetrahydro-2H-pyran-2-yl）-1H-pyrazol-5-yl）benzonitrile 37.Compound 7 and 37 were condensed with 1-（tert-butoxycarbonylamino）propan-2-yl methanesulfonate,and then treated with TFA/DCM to give（S）-4-（1-（2-aminopropyl）-1H-pyrazol-3-yl）-2-chlorobenzonitrile 10 and（S）-4-（1-（2-aminopropyl）-1H-pyrazol-3-yl）-2-（trifluoromethyl）benzonitrile 40 respectively.At last six compounds containing the hydroximic acid motif and ODM-201 core were synthesized from compound 10and 40 via one to three steps and their structures were confirmed by ¹H NMR and ¹³C NMR.Some of the compounds were tested for biological activity at the molecular and cellular levels.