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Molecular Design for Transition-State Analogue Enzyme Inhibitors

过渡态类似酶抑制剂的分子设计

基本信息

批准号：
03660141
负责人：
ETO Morifusa
金额：
$ 1.34万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1991
资助国家：
日本
起止时间：
1991 至 1992
项目状态：
已结题

项目摘要

Molecular designs for enzyme inhibitors were tried in order to find lead compounds of growth regulators for plants and insects by considering particularly transition-state analogues. Analogues of active intermediates, multi-substrates, and ground-state substrates were also considered.Inhibitors of the synthetase of tryptophan, an essential amino acid, must be effective as plant-growth regulators without deleterious mammalian effects. 3-(Substituted)-dihydroindoles potently inhibited the enzyme as putative transition-state analogues and retarded the growth of plants. Some thiols derived from substituted benzimidazoles, oxadiazoles, and triazoles also showed high activity to inhibit both tryptophan synthetase and plant-growth. Protection of the thiol group by acylation gave the good in vivo effect.Trifluoromethylketones and trifluoroacetate derivatives were designed for insect esterase inhibitors. Metamorphosis of silkworm larvae was suppressed by N-(p-phenoxyphenoxy-ethyl) trifluoroacetamide which was designed as a candidate inhibitor for insect juvenile hormone esterase. On the other hand, p-(N,N-diisopropylaminomethyl)trifluoroacetophenone inhibited acetylcholinesterase. 1,5-Disubstituted imidazoles were designed to inhibit cytochrome P450s which participate in the synteses of juvenile hormone in insects and of gibberellin in plants. Some imidazole derivatives induced precocious metamorphosis in silkworm larvae and some others retarded growth of plants.As multi-substrate analogue of glutathione-dependent enzymes S-substituted glutathiones were synthesized. S-(1-naphthylmethyl) glutathione inhibited glyoxalase I as well as glutathione S-transferase. Bicyclic phosphates with anti-GABA activity and octopamine related compounds were also studied.

为了寻找植物和昆虫生长调节剂的先导化合物，特别考虑过渡态类似物，尝试了酶抑制剂的分子设计。活性中间体的类似物、多底物和基态底物也被考虑。色氨酸合成酶的抑制剂是一种必需氨基酸，必须作为植物生长调节剂有效而不对哺乳动物产生有害影响。3-（取代）-二氢吲哚类化合物作为假定的过渡态类似物有效地抑制该酶，并延缓植物的生长。取代苯并咪唑、恶二唑和三唑衍生的硫醇类化合物也表现出很高的色氨酸合成酶抑制活性和植物生长抑制活性。通过酰化保护巯基，得到了较好的体内抑制效果。本文报道了昆虫保幼激素酯酶抑制剂N-（对苯氧基苯氧基乙基）三氟乙酰胺对家蚕幼虫变态的抑制作用。另一方面，对-（N，N-二异丙基氨基甲基）三氟苯乙酮抑制乙酰胆碱酯酶。设计了1，5-二取代咪唑类化合物，以抑制细胞色素P450，该酶参与昆虫保幼激素和植物赤霉素的合成。咪唑类化合物可诱导家蚕幼虫早熟变态，也可抑制植物生长。作为谷胱甘肽依赖酶的多底物类似物，合成了S-取代谷胱甘肽。S-（1-萘甲基）谷胱甘肽抑制谷胱甘肽酶I以及谷胱甘肽S-转移酶。还研究了具有抗GABA活性的双环磷酸酯和章鱼胺相关化合物。