| 摘要: | 在活性藥物成分及賦形劑中，異原子扮演了極重要的角色，根據等效性，或是生物等效性的觀點，這些異原子可以替換原先的碳炭脂肪族或雜環結構。其中雜環骨架被認為是不可或缺的存在，在諸多的藥物中，都能發現含氮雜環或其他類似之含氧或硫之五元及六元環之蹤跡。雜環結構的頻繁出現，與合成方法學的進步具有莫大的關聯性，例如，金屬偶聯反應及其他偶聯反應的發現，提供更況素有效合成雜環的途徑。在本篇研究中，設計並合成包含多樣化雜環且具有生物活性的四種不同系列化合物。第一系列為含有苯二氮平之異羥肟酸酯之設計與合成，並評估其對於改善血管性認知功能障礙(認知功能障礙的第二主因)之能力。本系列所合成之化合物對於不同亞型之組蛋白去乙醯酶皆具有抑制活性，根據乳酸脫氫酶呈色分析，選出化合物31作為後續試驗之後選藥物。在雙側頸總動脈閉塞之小鼠試驗中發現，化合物31能有效提升腦血流量並提升記憶力。此外，化合物31亦對海馬迴萎縮具有改善的功效，並提升慢性腦灌注不足小鼠皮質層及海馬迴之組蛋白乙醯化程度。
第二及第三系列則為設計及合成具有取代基之哌啶、嘧啶、吡啶、吲哚啉、喹啉、異噁唑、嗎啉及苯二氮平化合物，期許具有視黃醇結合蛋白4及Rho激酶具有抑制活性。第二系列及第三系列之化合物分別為黃斑部病變及青光眼之藥物開發。此二系列之化合物，利用多樣的取代反應、還原胺化反應、偶聯反應，如:鈴木偶聯反應利用硼酸類配位體及有機鹵代化合物以鈀金屬作為催化劑。第四系列為利用來那度胺作為泛素連接酶3配位體透過不同長度的鏈接結合兩種不同蛋白，設計並合成蛋白降解靶向嵌合体。此系列包含兩種不同類型的蛋白降解靶向嵌合体，其一為透過反苯環丙胺標的離胺酸去甲基酶1，另一類則為透過氯吉林來標的單胺氧化酶。本系列所合成之12個化合物分別對於其標的白做活性評估，目前試驗仍在進行中，然在本篇論文中收錄其合成相關資訊。
Heteroatoms comprise as a very common fragment of numerous active pharmaceutical
ingredients as well as excipients; from the point of view of significance, it is all the same if these are isosterically/bioisosterically replaced carbons/carbon substructures in aliphatic
structures or real heterocycles. The heterocyclic scaffolds are considered as privilege
structures. Most frequently, nitrogenous heterocycles or various positional combinations of
nitrogen, sulphur, and oxygen in five- or six-membered rings are found as a privilege core
structures in various drugs. The increasing presence of various heterocycles is related to
advances in synthetic methodologies, such as metal-catalyzed cross-coupling and heterocoupling
reactions, allows the rapid access to a wide variety of functionalized heterocycles.
In the present study, four different series of molecules containing various heterocycles have
been synthesized possessing different medicinal properties. The first series includes the
designing and synthesis of 10,11-dihydro-5H-dibenzo[b,f]azepine hydroxamates which were
also evaluated for their effects on amelioration of vascular cognitive impairment (the second
cause of dementia). Most of the compounds synthesized showed mixed inhibition against
different isoforms of HDACs. Amongst the series, compound 31 was identified as the
potential candidate by LDH cytotoxicity study and was selected for further investigations.
The treatment of BCCAO mice with compound 31 resulted in elevation of Cerebral Blood
Flow (CBF) values as well as improved the memory of mice. Compound 31 was also found
to improve hippocampal atrophy. Compound 31 also lead to increase the levels of histone
acetylation (H3K14 or H4K5) in the cortex and hippocampus of CCH mice.
The second and third series includes the designing and synthesis of piperidine, pyrimidine,
pyridine, indoline, quinoline, isoxazole, morpholine and diazepine substituted compounds
which are expected to possess antagonistic properties against Retinol Binding Protein 4
(RBP4) and ROCK inhibitory properties, respectively. The second series has been designed
to evaluate against Age Related Macular Degeneration (AMD) while the third series to be
evaluated against Glaucoma. The compounds have been synthesized utilising a number of
organic reactions like substitution reactions, reductive amination and cross-coupling reactions
such as suzuki reaction utilising the coupling partners namely boronic acid and an
organohalide and palladium(0) complex as a catalyst. The fourth and the last series describes
the designing and synthesis of PROTAC based molecules utilising lenalidomide (CRBN
ligand) as E3 ligand attached with two different types of protein of interest (POI) ligand via
carbon chain linker of varying lengths. This series consists of two kinds of PROTACs, one
consisting of tranylcypromine (TCPA), a LSD1 inhibitor as POI and other consisting of
2
clorgyline, a MAO-A inhibitor as POI. A total number of twelve compounds have been
synthesized for evaluation against various cancers as the role of LSD1 and MAO-A is well
known in the progression of various cancers. The evaluation of the compounds has not been
done yet but the synthesis is being complete with the collection of characterisation data (1H,
13C and mass spectras) which is presented in the thesis. |
