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三氟甲基烷基酮的生物活性及合成方法
Bioactivities and Synthesis of Trifluoromethyl Alkyl Ketones
三氟甲基烷基酮类化合物（TFMKs）具有独特的生理活性，三氟甲基能够增强化合物的亲脂性、代谢稳定性以及生物利用度。由于三氟乙酰基强烈的吸电子特性，TFMKs能够与目标水解酶形成稳定的半缩酮加合物，对生命体内多种活性酶起到抑制作用。最新的两个重要发现是TFMKs可以抑制SARS病毒和应用于眼科疾病，含氟原子数目、部位、有机碳链长度、不饱和度、其他官能团种类都是影响TFMKs作用的因素。TFMKs类化合物的合成方法，包括烃基金属试剂与三氟乙酸衍生物反应、使用三氟甲基化试剂TMS-CF3与羰基衍生物反应、三氟甲基仲醇氧化、羧酸与三氟乙酸酐/吡啶反应等方法。本文按照其作用的途径进行分类，归纳了三氟甲基烷基酮类化合物的药理活性，对现有的三氟甲基烷基酮类化合物合成方法进行了总结。
With high lipophicity and metabolic stability, trifluoromethyl alkyl ketones (TFMKs) act as important bioactive molecules, especially enzyme inhibitors. Besides, they are superior intermediates for pharmaceuticals and materials. Due to severe electrophilicity of trifluoromethyl, TFMKs form covalent hemiketal adducts targeting at many hydrolytic enzymes such as phospholipase A2 (PLA2) both in mammal and plant, human leukocyte elastase, oleamide hydrolase, human plasma kallikrein, pig liver esterase. TFMKs are inhibitors of human renin in the regulation of blood pressure and electrolyte homeostasis. Structure of chymotrypsin-trifluoromethyl ketone inhibitor complexes have been presented by XRD and NMR spectroscopy, this inhibition is depended on pH. TFMKs are also served as outstanding inhibitors of SARS-CoV 3CL protease. Diversity methods have been used in synthesis of TFMKs, involving the reactions of organometallic reagent like Grignard reagent or alkyl lithium with trifluoromethyl acid, acetate, or their salts, ester or amide react with TMSCF3 or Et3GeNa/PhSCF3 to generate nucleophilic trifluoromethylation, treatment of carboxylic acid chlorides with pyridine and trifluoroacetic anhydride, sulfone-mediated synthesis of TFMKs from alkyl and alkenyl bromides, oxidation of trifluoromethyl carbinols, catalytic aerobic oxidative decarboxylation of trifluoromethylhydroxy acids, conversion of trifluoroethyl amines by the treatment of NBS/DBU, conversion of enolizable carboxylic acids to TFMKs via enediolate trifluoroacetylation/decarboxylation, and ring opening of alkyl 2-siloxycyclopropanecarboxylates by triethylamine trihydrofluoride. Bioactive TFMKs on enzyme inhibition are summarized and synthesis methods are discussed in this paper, trend on both application and preparation are described.
Contents
1 Introduction
2 Possible mechanism and bioactivities of TFMKs
2.1 Inhibition on phospholipase A2(PLA2)
2.2 Inhibition on FAAH hydrolases
2.3 Inhibition on AChE
2.4 Inhibition on chymotrypsin
2.5 Inhibition on SARS-CoV 3CL
2.6 Inhibition on juvenile hormone esterase
2.7 Inhibition on other hydrolases
3 Synthesis of TFMKs
3.1 Organometallic reagent with trifluoromethyl acid, acetate, or their salts
3.2 Nucleophilic trifluoromethylation with TMSCF3 or Et3GeNa/PhSCF3
3.3 Carboxylic acid chlorides with pyridine and trifluoroacetic anhydride
3.4 Ethanolysis after condensation
3.5 Oxidation of trifluoromethylcarbinols
3.6 Trifluoroacetic ester/ketone exchange
3.7 Other methods
4 Conclusion and outlook
trifluoromethyl alkyl ketones
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