DEVELOPMENT OF ANTITUMOR DRUGS TARGETING TUMOR MARKERALDO-KETO REDUCTASES

五种醛酮还原酶（AKR1C1、AKR1C3、AKR1C21、AKR1B1和akr1b10）被认为是治疗多种癌症的诊断标志物和治疗靶点。我们寻找了酶的抑制剂，研究了抑制剂与酶结合的选择性决定因素，并合成了有效的选择性抑制剂。(1) AKR1C1抑制剂：根据该酶的晶体结构合成了有效的水杨酸类抑制剂。(2) AKR1C3抑制剂：在发现的抑制剂中，tolfenamic acid和baccharin分别是最有效和选择性最强的抑制剂。合成了一种具有高抑制效能和选择性的糖精衍生物。(3) AKR1C21抑制剂：胆酸及其衍生物是有效的抑制剂。(4) AKR1B1抑制剂：基于生物碱rhetsinine的结构合成了一种选择性强效抑制剂。(4) AKR1B10抑制剂：一些药物（如甲氧胺酸）和天然产物（山竹苷、墩墩果酸、咖啡酸苯乙酯）被发现是选择性抑制剂。合成了一种具有高抑制效能和选择性的咖啡酸苯乙酯衍生物。

Five aldo-keto reductases (AKR1C1, AKR1C3, AKR1C21, AKR1B1 andAKR1B10) are regarded as both diagnostic markers and therapeutic targets in the treatment of several types of cancer. We searched inhibitors of the enzymes, investigated selectivity determinants of the inhibitor-binding to the enzymes, and synthesized potent and selective inhibitors. (1) AKR1C1 inhibitor: Potent salicylic acid-based inhibitorswere synthesized based on the crystal structure of the enzyme. (2) AKR1C3 inhibitor: Among the inhibitors found, tolfenamic acid and baccharin were the most potent and selective inhibitors, respectively. A baccharin derivative with high inhibitory potency and selectivity was synthesized. (3) AKR1C21 inhibitor: Cholanic acid and its derivatives were found to be potent inhibitors. (4) AKR1B1 inhibitor: A selective and potent inhibitorwas synthesized based on the structure of an alkaloid rhetsinine. (4) AKR1B10 inhibitor:Some drugs (such as mefenamic acid) and natural products (mangostin, oleanolic acid,caffeic acid phenethyl ester) were found to be selective inhibitors. A caffeic acid phenethyl ester derivative with high inhibitory potency and selectivity was synthesized.