Dissertations / Theses on the topic 'Quinazolinone synthesis'

Investigations into radical and palladium(0) cyclisations onto the C-2 position of the 3H-quinazolin-4-one moiety have been made. This has led to the syntheses of a number of biologically active quinazolinone natural products using alkyl, heteroaryl and acyl radical cyclisations. The reactions proceeded via a homolytic aromatic substitution mechanism. As such, fully rearomatised products were recovered. A C-2 radical 3H-quinazolin-4-one building block was also prepared. This turned out to have only limited synthetic applications. Radical cyclisations onto aryl groups were carried out using this building block.

Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1998.
Includes bibliographical references.
Several novel atropisomeric phosphine ligands have been synthesized and evaluated. The syntheses of 2-methyl-3-[2'-(diphenylphosphino)phenyl]-4(3H)- quinazolinone (la) and its methyl-substituted analogs lb and ic were achieved in good yield by coupling N-acetylanthranilic acid with the corresponding phosphinoanilines 4a-c. A practical resolution of ligands la-c was accomplished using the benzenesulfonylhydrazone derivative (10) of (1S)-(+)-camphorsulfonic acid as a novel resolving agent. Several catalytic reactions including palladium-catalyzed asymmetric allylic alkylation, phosphine-catalyzed [3+2] cycloaddition of N-tosylimines with 2,3- butadienoate, and asymmetric intramolecular Heck reaction were performed. The 2-methyl group of this ligand series could be activated into the olefin form in the presence of Rh(nbd)2C104. The rhodium complex was found to be able to catalyze conjugate addition of the Grignard reagent (n-BuMgBr) to enones. The synthesis of 3-[4',6'-dimethyl-2'-(diphenylphosphino)phenyl]-4(3H)- quinazolinone (id) was achieved by coupling 4H-3,1-benzoxazin-4-one (71) with 4,6- dimethyl-2-diphenylphosphinoaniline (4c). Ligand ld could be directly lithiated by lithium diisopropylamide (LDA). The hetero-substituted analogs le-g were synthesized in good yield by quenching the lithium anion of ligand id with electrophiles. Resolutions of ligands id and le were achieved using (-)-di-p-chloro-bis[(S)-dimethyl-(1- naphthylethyl)aminato-C 2 , N]dipalladium(II) (78) and (-)-di-ji-chloro-bis[(S)-dimethyl-(1- phenylethyl)aminato-C 2 , N]dipalladium(II) (7), respectively.
by Xuedong Dai.
Ph.D.

Diphtheria Toxin-like ADP-Ribosyltransferases The Human ADP-ribosyl transferases (ARTDs) are a group of poorly studied enzymes which are believed to be involved in e.g. DNA repair, protein degradation, transcription regulation and cell death. Medicinal chemistry programmes aimed at developing selective inhibitors of these ARTDs were initiated. A suitable starting compound for one of these enzymes, ARTD3, was found by screening a library of NAD-mimics using a thermal shift assay. A virtual screening protocol was instead developed in order to find novel inhibitors of ARTD7, 8, and 10. The hit compounds were then further developed into selective inhibitors of the corresponding ARTDs by systematically varying different structural features using a combination of synthetic organic chemistry, computational chemistry and structural biology. Compounds were initially characterized using differential scanning fluorimetry which was later replaced with an enzymatic assay to obtain IC50 values. Biotinylated analogs were also synthesized in an attempt to develop an AlphaScreen assay. A selective ARTD3 inhibitor was ultimately identified and found to delay DNA repair in cells after γ-irradiation. These compounds are potentially valuable tools for elucidating the biological role of the poorly characterized ARTD-family of proteins. Total Synthesis of Resveratrol Based Natural Products The polyphenolic natural product (-)-hopeaphenol was found to inhibit the type III secretion system present in certain gram-negative bacteria. (-)-Hopeaphenol is a tetramer of resveratrol and in order to investigate whether the entire structure was essential for inhibition two resveratrol dimers, ε-viniferin and ampelopsin B, were synthesized using a flexible and divergent synthetic route. Highlights of the synthetic strategy include the use of cyclopropylmethyl protecting groups, allowing an acid mediated three-step-one-pot deprotection-epimerization-cyclization of an advanced intermediate to form ampelopsin B. All previously reported syntheses of these two natural products include a dimerization of resveratrol which severly limits the possibilities to synthesize structural analogs. This new strategy enables the synthesis of a wide variety of analogs to ε-viniferin and ampelopsin B.
Populärvetenskaplig sammanfattning Små molekyler för att identifiera proteiners funktion Vår arvsmassa innehåller cirka 24000 gener som i sin tur innehåller information för hur de tusentals proteiner vi är uppbyggda av ska framställas. Många läkemedel fungerar genom att en molekyl interagerar med ett av dessa proteiner och hämmar dess funktion för att på så sätt framkalla en önskad effekt. Vi vet dock inte vilken funktion många av våra proteiner fyller vilket ofta gör utvecklingen av nya läkemedel svår eller omöjlig. Den första delen av denna avhandling beskriver en grupp proteiner kallade ARTDs och hur små molekyler kan framställas och systematiskt förbättras för att till slut helt kunna slå ut vissa av dessa ARTDs. Genom att sedan studera vilka effekter detta medför kan man ta reda på vilken funktion proteinet fyller. På längre sikt skulle denna kunskap sedan kunna användas för att utveckla nya läkemedel genom att till exempel slå ut de proteiner som orsakar en sjukdom. Totalsyntes av naturprodukter Naturprodukter defineras inom kemin som naturligt förekommande molekyler som produceras av levande organismer. De kan hittas i allt från mikroorganismer och växter till djur och kan vara en del av deras ämnesomsättning, en restprodukt eller ha någon annan funktion, känd eller okänd. Människor, och i vissa fall även andra djur, har sedan urminnes tider ovetandes använt dessa molekyler för en mängd olika syften, som gifter, färgämnen eller läkemedel. Penicillin är en av de mest kända, men mer än hälften av de nya läkemedel som godkänts de senaste trettio åren bygger på naturprodukter eller har inspirerats av dessa. De fortsätter således att vara viktiga för utvecklingen av nya läkemedel trots att vi idag har möjligheten att utveckla sådana från grunden. Att framställa naturprodukter på konstgjord väg kallas totalsyntes och är ofta en mycket svår och tidskrävande process. Vanligtvis rör det sig om mycket stora och komplexa molekyler och det finns sällan ett uppenbart sätt att genomföra totalsyntesen. För att bättre klara av detta måste nya metoder utvecklas. Den andra delen av denna avhandling beskriver nya metoder för att framställa komplexa molekyler kallade polyfenoler. Målet var att dessa metoder skulle vara så pass flexibla att de även kan användas för att framställa nya polyfenoler som aldrig tidigare existerat men som har förbättrade egenskaper.

Many heterocyclic compounds containing nitrogen, oxygen and sulfur show wide range of physiological activities and their synthesis has always been attracted the interest of chemists. The aim of this research is to develop new synthetic methodologies leading to the synthesis of new derivatives of isocoumarines, indoles, isoquinolines, benzodiazepinones and quinazolines, which have been found to show important biological activities. Starting from homophthalic acid and bishomophthalic acid the corresponding acyl azides were proposed to be synthesized, which then would be used for the synthesis of various heterocycles. The proposed diazide from homophthalic was not formed due to the tendency of the ortho-positioned acid to undergo cyclization. Instead, new unusual benzochromen and isocoumarin derivatives have been synthesized in a single step, for which reasonable mechanisms have been proposed. The half ester produced from homophthalic acid was an important key compound for the synthesis of new highly substituted indole derivatives, which are expected to be biologically active. The diisocyanate derived from was synthesized directly from ortho-bromo xylene was treated with alcohols and hydrazine to produce seven membered rings. Instead of the intramolecular cyclization reaction, they underwent polymerization to form new polymers. Furthermore, new synthetic method for the synthesis of pyrazoles has been developed.

Le travail décrit dans ce manuscrit de thèse est consacré au développement de nouvelles méthodes radicalaires et organométalliques permettant la synthèse de différentes classes de polycycles azotés. Nous avons étudié des cascades impliquant le motif N-acylcyanamide. Des précurseurs de type alkyle ont permis la synthèse de quinazolinones naturelles. L’utilisation de précurseurs vinyliques a permis de mettre à jour un processus de migration original, qui apporte de nouveaux éléments pour la compréhension du mécanisme de substitution aromatique homolytique. Enfin des radicaux aminyles ont pu être engagés dans ces cascades, conduisant à la première synthèse radicalaire de guanidines. Conscients de la nécessité de trouver des alternatives vertes pour la génération de radicaux, nous nous sommes intéressés à la catalyse photoredox en lumière visible. Nous l’avons utilisée pour la photo-génération de radicaux à partir d’époxydes et d’aziridines. D’autre part, le système catalytique palladium/norbornene a été employé pour la synthèse efficace de phenanthridines à partir d’iodures d’aryles et d’amines benzyliques. L’utilisation d’amide benzyliques nous a permis de mettre à jour la première exception à l’effet ortho. Des calculs DFT ont rationnalisé l’influence de la chélation sur la sélectivité de l’élimination réductrice à partir de l’intermédiaire Pd(IV) impliqué

Dans le cadre general des recherches effectuees au laboratoire autour des amidines heterocycliques, le travail presente dans ce memoire porte essentiellement sur la synthese et l'etude d'une serie d'imidazo(1,2-c) quinazolinones diversement substituees. Une reaction de tschitschibabin a partir d'amino-4-quinazolinone-2 constitue l'etape-cle de ces syntheses. Avec la bromo-3 phenyl propanedione-1,2, un second produit de reaction a pu etre identifie. C'est pourquoi nous avons porte un interet particulier a la phenomenologie de cette reaction en precisant l'influence de la nature de l'amidine heterocyclique mise en jeu, le solvant de reaction sur la composition du milieu obtenu. Le second aspect de ce travail porte sur l'interet des imidazo(1,2-c) quinazolinones diversement substituees en position 6. Ces composes se lient de maniere selective a une sous-classe de recepteurs aux benzodiazepines, dont le role physiologique reste encore tres mal connu. Ces recepteurs dits peripheriques (bzp) ou mitochondriaux, sont essentiellement presents dans les cellules gliales, cellules qui sont fortement impliquees dans le soutien et la protection du tissu nerveux. Certains de ces produits sont actuellement en cours d'etude pharmacologique (vasodilatateurs coronariens, immunomodulateurs)

The development of novel selective 5-HT6 and 5-HT7 receptor antagonists is an ever-growing area of interest among medicinal chemists. The potential of developing a therapeutic agent useful as an antipsychotic or antidepressant, as well as the possibility to develop a drug for Alzheimer’s disease and obesity has led to an increase in synthesis of possible lead compounds. The synthesis of unfused biheteroaryl derivatives is described within. The derivatives have been evaluated for binding affinity at 5-HT2A, 5-HT6 and 5-HT7 receptors. The most potent 5-HT6 receptor antagonists include a benzene ring, a hydrophobic group and a protonated nitrogen atom. The most potent and selective compound synthesized is 1-[3-butyl-5-(thienyl)phenyl]-4-methylpiperazine. The binding site of the 5-HT7 receptor is similar to that of the 5-HT6 receptor and the most selective and potent 5-HT7 receptor antagonist also contains a potonated nitrogen atom and a hydrophobic group. The difference in selectivity between the 5-HT6 and 5-HT7 receptor antagonists is the aromatic ring. The most potent 5-HT7 receptor antagonist synthesized contains a pyridine ring instead of benzene, as in the 5-HT6 receptor antagonist. The most potent and selective 5-HT7 receptor antagonist is 1-[4-(3-furyl)-6-methylpyridin-2-yl]-4-methylpiperazine. The need to increase selectivity for both 5-HT6 and 5-HT7 receptors has led to the synthesis of flexible-chain linked derivatives and the results are described within.

Since the first approved hepatitis C virus (HCV) NS3 protease inhibitors in 2011, numerous direct acting antivirals (DAAs) have reached late stages of clinical trials. Today, several combination therapies, based on different DAAs, with or without the need of pegylated interferon-α injection, are available for chronic HCV infections. The chemical foundation of the approved and late-stage HCV NS3 protease inhibitors is markedly similar. This could partly explain the cross-resistance that have emerged under the pressure of NS3 protease inhibitors. The first-generation NS3 protease inhibitors were developed to efficiently inhibit genotype 1 of the virus and were less potent against other genotypes. The main focus in this thesis was to design and synthesize a new class of 2(1H)-pyrazinone based HCV NS3 protease inhibitors, structurally dissimilar to the inhibitors evaluated in clinical trials or approved, potentially with a unique resistance profile and with a broad genotypic coverage. Successive modifications were performed around the pyrazinone core structure to clarify the structure-activity relationship; a P3 urea capping group was found valuable for inhibitory potency, as were elongated R6 residues possibly directed towards the S2 pocket. Dissimilar to previously developed inhibitors, the P1’ aryl acyl sulfonamide was not essential for inhibition as shown by equally good inhibitory potency for P1’ truncated inhibitors. In vitro pharmacokinetic (PK) evaluations disclosed a marked influence from the R6 moiety on the overall drug-properties and biochemical evaluation of the inhibitors against drug resistant enzyme variants showed retained inhibitory potency as compared to the wild-type enzyme. Initial evaluation against genotype 3a displayed micro-molar potencies. Lead optimization, with respect to improved PK properties, were also performed on an advanced class of HCV NS3 protease inhibitors, containing a P2 quinazoline substituent in combination with a macro-cyclic proline urea scaffold with nano-molar cell based activities. Moreover, an efficient Pd-catalyzed C-N urea arylation protocol, enabling high yielding introductions of advanced urea substituents to the C3 position of the pyrazinone, and a Pd-catalyzed carbonylation procedure, to obtain acyl sulfinamides, were developed. These methods can be generally applicable in the synthesis of bioactive compounds containing peptidomimetic scaffolds and carboxylic acid bioisosteres.

Les semiconducteurs organiques (OSC) tels que les composés organiques photovoltaïques (OPVs), les diodes électroluminescentes organiques (OLEDs) ou encore les transistors organiques à effet de champ (OFETs) constituent un domaine de recherche très attractif en raison de leur potentiel en tant que couches actives dans les dispositifs optoélectroniques. Les composés aromatiques polycycliques ainsi que les hétéroaromatiques sont considérés comme des matériaux prometteurs pour les OSC en raison de leurs conductivités électriques potentielles, de leurs propriétés optiques ainsi que de leurs assemblages géométriques. Ces deux systèmes et leurs propriétés photophysiques ont été étudiés dans les trois chapitres de cette thèse. Dans le premier chapitre, une étude sur un ensemble d'acènes linéaires, angulaires et condensés consistant en des liens hétéroatomes avec des agrégations uniques a été décrite et analysée. Les hétéroacènes N-fusionnés angulaires et π-étendus sont la classe principale étudiée dans le deuxième chapitre. Leurs synthèses sont basées sur la réaction de couplage de Suzuki-Miyaura et la réaction de Cadogan. Outre les acènes et les hétéroacènes N-fusionnés, les N-hétéroaromatiques ont fait l'objet d'une attention particulière dans le domaine de matériaux. L'un d'entre eux est la classe des quinazolines utilisées comme partie acceptrice d'électrons dans les structures push-pull pour le transfert de charge intramoléculaire (TCI). L'étude des relations entre les structures dérivées du motif quinazoline de type donneur d'électron-accepteur-donneur (D-A-D) et leurs propriétés de photoluminescence est le principal travail mentionné dans le troisième chapitre
Organic semiconductors (OSCs) are a highly attractive research field due to their potentials as active layers in optoelectronic devices such as organic field-effect transistors (OFETs), organic photovoltaic (OPVs) and organic light emitting diodes (OLEDs). Polycyclic aromatic compounds as well as heteroaromatics are considered as promising materials for OSCs due to their semi conductivity properties, optical properties and geometric structures. The mentioned systems and their photophysical properties were investigated in three chapters of my thesis. In the first chapter, a study on a set of linear, angular and condensed acenes consisting of heteroatom linkages with unique aggregations was described and analyzed. The angular and π-extended N-fused heteroacenes are the main class studied in the second chapter. Their synthesis is based on the Suzuki-Miyaura coupling and the Cadogan reactions. Besides acenes and N-fused heteroacenes, N-heteroaromatics have gained attention in material area. One of them is the quinazoline class that is known as an electron withdrawing unit in push-pull structures for intramolecular charge transfer (ICT). The investigation of the relationships between the electron donor-acceptor-donor (D-A-D) quinazoline-based structures and their photoluminescence properties is the main work mentioned in the third chapter

碩士
國立中正大學
化學所
95
Ent-fumiquinazoline G and its analogs contain unique structural motifs of quinazolinone and diketopiperazin-like skeletons. The key steps involved the intramolecular dehydration of a tripeptide derivative using triphenylphosphine, iodine, and DIEA and a final cyclization-upon-deprotection leading to the establishment of the desired products. Sixteen fumiquinazoline analogs were successfully prepared in our laboratory, the results reveal that piperazine motif of compounds having two side chains required longer reaction time than those having only one stereogenic center. In addition, the overall isolated yields are lower for those having two side chains. Circumdatin F and its analogspossess 3H-quninazolin-4-one as well as a 1,4-benzodiazepin-5-one. We have successfully developed the synthesis of circumdatin F and its analogs in our laboratory. The results suggest that much longer reaction time is required in the final cyclization step for amino acids having stereochemically hindred side chains. Val-and Ile-derived circumdatins are of most significance in this total synthesis. Using our experimental protocol, six circumdatin analogs have been prepared for the time being with overall satisfactory isolated yields. Adopting Fmoc method evidently avoids harsh conditions that are required for the Cbz method. Moreover, the Fmoc procedure gives desired products with higher yields.

博士
中國醫藥學院
藥物化學研究所
88
As part of our continuing search for potential anticancer candidates of 2-phenyl-4-quinazolinones and 2-phenyl-4-quinolones, two series of 6,7,2',3',4',5'-substituted 2-phenyl-4-quinazolinones and 6,2',3',4',5'-substituted 2,3-dihydro-2-phenyl-4-quinazolinones have been synthesized and evaluated for cytotoxicity and inhibition of tubulin polymerization. Through these biological screening, a preliminary structure-activity relationship has been established. On the whole, a good correlation was found between the two activities. Among them, 6-N,N-dimethylamino and 6-heterocyclic 2-phenyl-4-quinazolinones (56-60) showed potent cytotoxicity against a panel of human tumor cell lines with EC50 values in the low micromolar to nanomolar concentration ranges. 2-(3'-Methoxyphenyl)-6-(pyrrolidinyl)-4-quinazolinone (57) was especially the most potent. Moreover, compound 57 was also a potent inhibitor of tubulin polymerization with activity comparable to that of the antimitotic natural products such as colchicine, podophyllotoxin, and combretastatin A-4. Substituted 2-phenyl-4-quinazolinones and 2,3-dihydro-2-phenyl-4-quinazolinones also displayed highly selective cytotoxicity against the ovarian cancer (1A9) and vincristine-resistant epidermoid carcinoma of the nasopharynx (KB-VIN). On the other hand, a series of 4-alkoxy-2-phenylquinazolines and 4-alkoxy-2-phenylquinolines were synthesized respectively via alkylation of 2-phenyl-4-quinazolinones and 2-phenyl-4-quinolones, and their antiplatelet activities were evaluated. Among them, 4-ethoxy-2-phenylquinazoline (71), 4-methoxy-2-phenylquinoline (92), 4-ethoxy-2-phenylquinoline (93) and 7-fluoro-4-methoxy-2-phenylquinoline (98) showed very potent inhibitory effects on the platelet aggregation induced by arachidonic acid. Their activities were about ten to thirteen times more potent than aspirin. Compound 57 and 71, which exhibited strong cytotoxicity and antiplatelet activity respectively, were thus selected for further investigation of pharmaceutical mechanism.

碩士
國立臺灣大學
藥學研究所
88
This study is aimed to synthesize two series of compounds, namely, substituted arylpiperazinyl benzothiazinone 1,1-dioxide (A) and substituted arylpiperazinyl quinazolinone (B) derivatives for evaluation of α1A adrenoceptor selectivity and are considered to be potential for treatment of benign prostatic hyperplasia (BPH). The synthesis of compounds in A series started from esterification of 3,4-dimethoxyphenyl acetic acid (25) in methanol with a catalytic amount of concentrated sulfuric acid to give 3,4-dimethoxy-1-(carbomethoxymethyl)benzene (26). Then 26 underwent chloro-sulfonation with chlorosulfonic acid to afford 4,5-dimethoxy-2-carbomethoxymethylbenzenesulfonyl chloride (27). Compound 27 was treated with (2-methoxyphenyl)piperazinylalkyl amines (23a-c) and (2-pyrimidinyl)piperazinylalkyl amines (24a-c) to give N-((4-(2-methoxyphenyl)piperazinyl)alkyl)-4,5-dimethoxy-2-carbomethoxymethyl benzenesulfonamides (28a-c) and N-((4-(2-pyrimidinyl)piperazinyl) alkyl)-4,5-dimethoxy-2-carbomethoxymethylbenzenesulfonamides (31a-c), respectively. The hydrolysis of 28a-c and 31a-c with methanolic NaOH afforded N-((4-(2-methoxyphenyl)piperazinyl)alkyl)-4,5-dimethoxy-2-carboxymethylbenzenesulfonamides (29a-c) and N-((4-(2-pyrimidinyl)piperazinyl)alkyl)-4,5-dimethoxy-2-carboxymethylbenzene sulfonamides (32a-c), respectively. Compounds 29a-c and 32a-c were then treated with phosphorus oxychloride to provide N-((4-(2-methoxyphenyl)piperazinyl)alkyl)-6,7-dimethoxy-2H-1,2-benzothiazin-(4H)-3-one 1,1-dioxide (30a-c) and N-((4-(2-pyrimidinyl)piperazinyl)-alkyl)-6,7-dimethoxy-2H-1,2-benzothiazin-(4H)-3-one 1,1-dioxide (33a-c), respectively. For the synthesis of compounds in series B, 2-aminobenzophenone (36) and urea underwent condensation at 195 ℃ afford 4-phenyl quinazolin-2-one (37). The reaction of 37 reacted with p-methoxybenzyl chloride (38) gave 1-(p-methoxybenzyl)-4-phenyl- quinazolin-2-one (39) which was then treated with sodium cyanoborohydride to provide 1-(p-methoxy benzyl)-4-phenyl-3,4-dihydroquinazolin-2-one (40). 30a-c and 33c were subjected to different receptor binding assays. The preliminary results revealed that designed target compound 30a-c and 33c possess affinity toward α1A、α1B、 D1、 D2S、 D2L and 5-HT1A receptors. The different carbon chain length between the heterocycle moiety and arylpiperazine also affect the affinity and selectivity among different receptors. Among these compounds, compound 30b possess high affinity toward α1A receptors with IC50 = 107.2 pM and the selectivity ratio for α1B 、5-HT1A 、D1 、 D2S and D2L receptors is 118 、 12 、 6640 、 1538 and 6006, respectively.

碩士
國立中正大學
化學所
97
Abstract There are two project in this thesis. The first project is “ Lewis Acid-Mediated Total Synthesis of Quinazolinone Alkaloids and Their Analogs ” . The previously reported methodologies for preparation of quinazolinone analogous , either required a number of synthetic steps or proceed with long reaction hours and low to moderate yields. In this thesis, Lewis acid and microwaves were employed to assist double cyclizations of tripeptide precursors to afford the total synthesis of quinazolinone analogs. At first, sclerotigenin, a natural product, was selected as our target compound to optimize the reaction conditions, including Lewis acid, solvent and molar equivalent of Lewis acid , that efficiently facilitate the formation of the ring structure from its open-chain tripeptide precursor. This precursor was readily prepared in a straightforward manner. Finally, we afford the total synthesis of sixteen quinazoline analogs, including natural products sclerotigenin, circumdatin F, and asperlicin C, were achieved with good overall isolated yields (23－56%). The second project is “ Study toward DNA-Protein Interactions Using Functionalized Ionic Liquids ” . In this thesis, the technique for extraction of protein and oligo nucleotide has been established by combination of liquid-liquid extraction and molecular recognition. Basing on our previous studies, 6,7-dihydro-5H-pyrrolo[1,2a]imidazole based ionic liquids have been successfully constructed as extractant for affinity extraction. The results of SDS-PAGEs show the streptavidin can be captured into the ionic liquids layer for the strong interaction between streptavidin and biotin; the control protein, BSA, was unable to transfer into ionic layer. Further, the results of stoichiometry indicate that the stoichiometry of interaction of streptavidin-biotin-IL with biotin is approximately 1:4. Quartz crystal microbalance (QCM), a powerful tool for qualitative as well as quantitative analysis, was also used for investigating binding property in ionic liquids. The binding sensorgrams show the streptavidin and oligonucleotides irreversibly bind to biotinated-IL coated onto a gold electrode. These results indicate the interactions between protein / ligand and DNA / protein were well maintained in ionic liquids.

博士
國立中山大學
化學系研究所
103
In this thesis, there are two parts in this dissertation. Part I: we have designed and synthesized a series of new generation of protenial anti-cancer drugs containing two biologically active structure tetrahydroisoquinoline and quinazolone, CWO compounds. CWO series of compounds, especially in 0-CWO, which has the best of the anti-cancer activity for IC50 (0.26 μM in MDA-MB-231 breast adenocarcinoma cells), and was found in apoptosis experiments have the results of early and late apoptotic cells. In addition, I also have synthesized a series of hetero-atom aromatic rings for the nature product, evodiamine, in order to increase water solubility of the compounds. The second part of our successful discovery 3-hydroxypyridine in the presence of hypervalent iodine reagent which is in a mild condition, eco-friendly to give homocoupling products successfully. Finally, we use the bipyridine compounds for the application in the transition-metal-free catalytic reactions.

碩士
高雄醫學大學
醫藥暨應用化學研究所
100
Quinazoline derivatives have been found to possess a wide variety of biological activities. The aims of this thesis are to synthesize and evaluate a series of 4-substituted and 2-substituted-vinyl quinazoline derivatives. These 4-substituted and 2-substituted-vinyl quinazoline derivatives with various substituents at the C-4 position of quinazoline skeleton and at the vinyl moiety have been synthesized and evaluated for their antiproliferatve activities. Results indicated that most of these newly synthesized compounds exhibited potent activities against the growth of all the cancer cells tested including lung cancer cells (H460, H1299) and breast cancer cells (MB231) in which 4-anilino-2-(5-nitrofuran-2-yl)- vinyl quinazoline derivatives have been found to be the most potent in the growth inhibition of these cancer cell lines.

碩士
國立中正大學
化學工程所
93
2-Amino-4-chloro-6,7-dimethoxyquinazoline is a common key intermediate of some a-blocker anti-hypertension drugs including Prazosin, Doxazosin, and Terazosin. The preparation of 2-amino-4-chloro-6,7-dimethoxyquinazoline was first reported by Pfizer pharmaceutical company. Some modifications have been done in order to achieve economic scale-up and mass production towards those anti-hypertension drugs.

博士
靜宜大學
應用化學系
104
In this thesis, a series of 2-, 4-, 6, and 7-substituted quinazoline derivatives were designed and synthesized as well as their cytotoxicities againststomach cancer cell line AGS, lung cancer cell lines A549, hepatocellular liver carcinoma cell line HepG2, colon cancer cell line HT-29 andprostate cancer cell line PC-3 were evaluated. Target compounds 4a,b and 6a,b are 4-cyclohexylamino/cyclohexanemethylamino and 2-(substituted anilino) substituted quinazoline. Among them, 4b and 6a possess moderate inhibitory activity against HT-29. Introducing methoxy groups onto the 6- and 7-position of quinazoline, two series of com-pounds 10a-e and 12a-e exhibit cytotoxicity against HepG2 with GI50 values ranging at 2.7-3.35 M and 0.12-2.78 M, respectively, and 2-(halogen substituted anilino) compounds possess high cytotoxicity against HepG2 with GI50 values of 0.05 - 0.59 M. These results demonsatrate that introduction of methoxy group onto the 6 and 7 positions of quinazoline enhances the cancer cell inhibitory activity. Our results further showed the significant role to inhibitory activity of the 4-cyclohexanemethylamino substituent. Replacement of the 2-anilino group to 2-(pyridin-4-yl) group enhance the inhibitory activities against all tested cancer cell lines. Nevertheless, 2-(pyridin-2-yl) substituted compound showed no inhibitory activity.

碩士
國立陽明大學
生物藥學研究所
100
Cancerous inhibitor of PP2A (CIP2A) is a novel oncoprotein which could stabilize the c-Myc by inhibiting PP2A (protein phosphatase 2 A) activity toward c-Myc and promoting anchorage-independent cell growth and in vivo tumor formation. Particularly, overexpression of CIP2A on several solid- and non-solid tumors has been recorded on document, including human neck and head carcinomas, colon, breast, cervical, prostate cancer, and acute leukemia. Recent studies have shown that small molecules, such as Velcade and Tarceva, exhibited the ability to downregulate the expression of CIP2A and induce cell death. Based on the scaffold of Tarceva, we developed a series of mono- and di-substituted quinazoline and pyrimidine derivatives which have no EGFR inhibition. However, these molecules maintain the abilities to downregulate CIP2A in hepatocellular carcinoma cells. Di-substituted quinazoline derivatives showed more potent antiproliferative effect on HCC cells than mono-substituted quinazoline derivatives. Furthermore, downregulation of CIP2A by these molecules is correlated with cell proliferation; meanwhile, pAkt, the downstream signaling protein of CIP2A, was also been abolished. In summary, the substitution at 2’ position of quinazoline increase the bioactivity to against HCC. Therefore, this quinazoline structure is the great scaffold for synthesizing novel CIP2A ablating agents.

Thesis(M.Sc. (Chemistry)) -- University of Limpopo, 2019
Imidazolyl-ethanamine Schiff base ligands of the N^N type were prepared by condensation reaction of histamine dihydrochloride with para-substituted aldehyde derivatives to yield: (E)-N-benzylidene-2-(1H-imidazol-4-yl)ethanamine 119a, 4-((E)(2-(1H-imidazol-4-yl)ethylimino)methyl)phenol 119b, E)-N-(4-fluorobenzylidene)-2(1H-imidazol-4-yl)ethanamine 119c and (E)-N-(4-nitrobenzylidene)-2-(1H-imidazol-4yl)ethanamine 119d, which were characterised by 1H and 13C-NMR, FTIR specroscopy and HRMS. 2D-NMR experiments (1H-1H COSY and 2D-HMBC) for representative ligand 119b were performed to qualify success in the condensation reaction. An attempted reaction to coordinate Schiff base ligand 119c to zinc chloride was carried out in an NMR tube and traces of the product were observed between 12 and 24 h monitoring using 1H-NMR. Iodine promoted cyclocondensation reaction of anthranilamide and para-substituted aldehyde derivatives afforded 2-aryl-quinazolin4(3H)-ones 120a-e and subsequent chloro-aromatisation reaction in SOCl2 afforded electrophilic C4-(Cl) 2-aryl-4-chloro-quinazolines 121a-e and the compounds were characterised by 1H and 13C-NMR and FTIR spectroscopic techniques. The 2-aryl-4chloro-quinazolines served as prerequisites for de-chloro amination on the C4-(Cl) position by 2-amino-3-nitropyridine to yield 2-aryl-N-(3-nitropyridin-2-yl)quinazolin-4amine derivatives 123a-e in good yield and the derivatives were characterised by 1H and 13C-NMR, FTIR and HRMS spectroscopic techniques. The C4-(Cl) position further allowed for Sonogashira cross-coupling with ethynylpyridine to yield 2-aryl-4(ethynylpyridine)quinazoline derivatives 125a-e which were characterised by 1H and 13C-NMR, FTIR and HRMS spectroscopic techniques. The 2-aryl-4(ethynylpyridine)quinazoline served as ligands for coordination to monomeric pcymene ruthenium(ll) which yielded (ɳ6-p-cymene)RuCl2-2-aryl-4(ethynylpyridine)quinazoline derivatives 126a-e in good yield. Compounds 126a-e were characterised by 1H and 13C-NMR, FTIR and HRMS spectroscopic techniques. 2D-HMBC NMR of representative ligands 126c and 126e showed long range couplings from 1JCH to 9JCH and this was confirmed by coordination induced shifts (CIS) ranging from 1 ppm to 11 ppm. Compounds 119a-d, 123a-e and 125a-e were inductively docked into the active receptors of tyrosine kinase (PDB:2SRC), glutamine synthetase (PDB:1HTO) and oxidoreductase (PDB:3F8P). The docking scores obtained gave hits ranging from -5 to -10 Kcal/mol. Compounds 119a-d, 121a-e, 123a-e, 125a-e and 126a-e were assayed employing the broth-dilution method which gave promising anti-Mycobaterium tuberculosis activity. Compound 125e gave good activity of <0.244 µg/mL over 7 day and 14 day sampling. Coordination of ligands 125a-e to Ru(ll) group resulted in loss of activity, notably for ligand 125e.
NRF and Sasol Inzalo Bursary

碩士
大仁科技大學
製藥科技研究所
102
The quinazoline (QA) is a heterocyclic compound with benzene fused to pyrimidine and is a well-leading structure for new drug development because it displays a wide spectrum of pharmacological activities such as neuron protective, anti-bacterial and anti-cancer properties. In this study, we have synthesized a series of novel QA derivatives and evaluated their anti-proliferative mechanisms. Firstly, QA series were subjected to MTT assay to examine the growth-inhibitory abilities against three human cancer cell lines, including nasopharyngeal cancer (NPC-TW01), leukemia (Jurkat), and lung carcinoma (NCI-H226). Among 23 compounds, 5e treatment showed dramatic growth-inhibitory effect on NPC-TW01 cells with IC50 of 4.7 μM. Furthermore, cell cycle analysis showed that 5e could cause TW-01 cells arrest in S phase. Detail anti-proliferation mechanisms of 5e against human NPC are actively investigated in our laboratory. In conclusion, 5e is a promising novel anti-proliferation drug and worthy of further investigation.

Yes
Vandetanib is an orally available tyrosine kinase inhibitor used in the treatment of cancer. The current synthesis proceeds via an unstable 4-chloroquinazoline, using harsh reagents, in addition to requiring sequential protection and deprotection steps. In the present work, use of the Dimroth rearrangement in the key quinazoline forming step enabled the synthesis of Vandetanib in nine steps (compared to the previously reported 12–14).
This work was supported by the Cancer Research UK-Cancer Imaging Centre (grant: C1060/ A16464), the Institute of Cancer Research and the University of Hull.

碩士
大仁科技大學
製藥科技研究所
103
The Quinazoline is a nitrogen-containing heterocyclic skeleton of benzene and pyrimidine being formed, many quinazoline compounds islated from porducts having broad pharmacological activity including neuronal protection, anti-bacterial and anti-tumor, and therefore subject to a considerable degree in drug development emphasis. In this study, we extend the results before continuing the synthesis of a series of oxime-containing, quinazolinone derivative of methyl oxime and amide and assess its antiproliferative activity in. The assessments were selected to seven human tumor cell lines, namely nasopharyngeal carcinoma (NPC-TW01), leukemia (Jurkat, HL 60, K562 and Molt 4), lung cancer (NCI-H226), and breast cancer (t-47D) cells, These 17 compounds evaluated by MTT-Microculture Tetrazolium analyzed. Among them, 2a shows anti-proliferative activity of the leukemia cells (HL 60) with an IC50 value of 14.10 μM; 3a the performance of the leukemia (HL 60, K562 and Molt 4) and breast cancer (t-47D)) have a more significant inhibitory activity with IC50 values between 10.80-15.50 μM. In addition, 3b and 3d for breast cancer cells also showed a slight inhibitory activity IC50 values were 18.92 and 17.91μM, respectively.

[ES] Se ha desarrollado un método de síntesis "verde" de compuestos metal orgánicos en medio acuoso, a temperatura y presión ambientes, fácilmente escalable y con tiempos de cristalización muy cortos (10 min). El método se ha aplicado con éxito a la síntesis de trimesatos de metales divalentes isoreticulares y con fórmula general M3(BTC)2·12 H2O (M = Ni2+, Co2+, Cu2+ y Zn2+; BTC = trimesato). La estructura de estos materiales presenta dos tipos de centros metálicos ("puente" y "ter-minales") en proporción 2 a 1, ambos con coordinación octaédrica y unidos a 4 moléculas de H2O y a dos oxígenos carboxilato del ligando. Usando este método de síntesis, se han preparado también series de compuestos bimetálicos isoreticulares de Co-Ni y Co-Zn en todo el rango de concentraciones, así como compues-tos de Mn-Ni con una concentración máxima de Mn2+ del 50%. Mediante la combinación de difracción de rayos X (en polvo y de monocristal) y microscopía EDX/SEM se ha demostrado que los compuestos bimetálicos forman verdaderas disoluciones sólidas (no meras mezclas de fases) y que los iones metálicos se dis-tribuyen homogéneamente en todo el cristal. Además, el análisis detallado de la variación de los parámetros de celda con la composición en compuestos Co-Ni y Co-Zn aporta fuertes evidencias de que los iones Co2+ ocupan preferentemente las posiciones "terminales". Se ha evaluado la actividad de los compuestos preparados como catalizadores para la oxidación aeróbica de cumeno (CM) a cumeno hidroperóxido (CHP). El com-puesto monometálico de Co2+, Co-BTC, presentó una elevada actividad, aunque la selectividad a CHP obtenida fue relativamente baja (69%), ya que los iones Co2+ catalizan también la descomposición del CHP formado. Una buena estrategia para optimizar esta selectividad consistió en aislar los iones Co2+ en una matriz de Ni-BTC (que es inerte tanto para la oxidación de CM como para la descomposición de CHP). Así, al disminuir la concentración de iones Co2+ en compuestos bimetálicos Co-Ni se observó un aumento de la selectividad a CHP de hasta el 91% para el material con un 5% de Co. Se ha calculado que estadísticamente el 73% de los iones Co2+ en este material se encuentran aislados, por lo que la des-composición/sobreoxidación del CHP se ve muy limitada. Usando una variación del método de síntesis, se han obtenido también compuestos isoreticulares de Co2+ en los que los ligandos trimesato se han reemplazado parcialmente por ligandos isoftálico o 5-aminoisoftálico. Al utilizar estos com-puestos como catalizadores para la oxidación aeróbica de CM, se ha observado que la introducción de este segundo ligando (y en particular del 5-aminoisoftálico) en la red metal-orgánica facilita la descomposición del CHP formado y aumenta la selectividad final a 2-fenil-2-propanol (PP). Esto se ha atribuido a la creación de defectos puntuales en la red del material, que presentan una mayor actividad para la descomposición de CHP. Siguiendo con la oxidación de CM como reacción modelo, se ha evaluado la actividad catalítica de compuestos isoreticulares de cobalto con ligandos bispirazolato funcionalizados con distintos grupos (CoBPZ, CoBPZ-NO2 y CoBPZ-NH2). En este caso se ha observado una clara influencia del ligando utilizado sobre la acti-vidad catalítica y la selectividad a CHP o PP del material. Mientras que el Co-BPZ presenta una baja conversión de CM y una elevada selectividad a CHP, Co-BPZ-NH2 presenta las características opuestas: una elevada velocidad de reacción pero una baja selectividad a CHP. En este último caso, el producto mayoritario forma-do es el PP. Por último, el estudio de MOFs de cationes divalentes como catalizadores de oxidación se ha completado con una reacción de síntesis de quinazolina mediante acoplamiento oxidativo de bencilamina y 2-aminoacetofenona usando TBHP co-mo oxidante. Como catalizadores para esta reacción se ha utilizado el trimesato de
[CAT] S'ha desenvolupat un mètode de síntesi "verda" de compostos metall orgànics en medi aquós, a temperatura i pressió ambients, fàcilment escalable i amb temps de cristal·lització molt curts (10 min). El mètode s'ha aplicat amb èxit a la síntesi de trimesats de metalls divalents isoreticular i amb fórmula general M3(BTC)2·12 H2O (M = Ni2+, Co2+, Cu2+ y Zn2+; BTC = trimesat). L'estructura d'aquests materials presenta dos tipus de centres metàl·lics ("pon" i "terminals") en una proporció de 2 a 1, ambdós amb coordinació octaèdrica i units a 4 molècules d'aigua i a 2 oxígens carboxilat del lligand. Emprant aquest mètode de síntesi, s'han preparat també sèries de compostos bimetàl·lics isoreticular de Co-Ni i Co-Zn en tot el rang de concentracions, així com compostos de Mn-Ni amb una concentració màxima de Mn2+ del 50%. Mitjançant l'ús combinat de difracció de raigs X (en pols i de monocristall) i microscòpia EDX/SEM s'ha demostrat que els compostos bimetàl·lics formen vertaderes dissolucions sòlides (no simples mescles de fase) i que els ions metàl·lics es distribueixen homogèniament en tot el cristall. A més, l'anàlisi detallat de la variació dels paràmetres de cel·la amb la composició de compostos Co-Ni i Co-Zn aporta fortes evidències de que els ions Co2+ ocupen preferentment les posicions "terminals". S'ha avaluat l'activitat dels compostos preparats com a catalitzador per a l'oxidació aeròbica de cumè (CM) a cumè hidroperòxid (CHP). El compost monometàl·lic de Co2+, Co-BTC, presenta una elevada activitat, encara que la selectivitat a CHP obtinguda és relativament baixa (69%), ja que els ions Co2+ catalitzen també la descomposició del CHP format. Una bona estratègia per optimitzar aquesta selectivitat consisteix en aïllar els ions Co2+ en una matriu de Ni-BTC (que és inert tant per a l'oxidació de CM com per a la descomposició de CHP). Així, a mesura que disminueix la concentració d'ions Co2+ en compostos bimetàl·lics Co-Ni s'observa un augment de la selectivitat a CHP de fins el 91% per al material amb un 5% de cobalt. S'ha calculat que estadísticament el 73% dels ions Co2+ d'aquest material es troben aïllats, de manera que la descomposició/sobreoxidació del CHP es veu molt limitada. Emprant una variació del mètode de síntesi, s'han obtingut també compostosisoreticulars de Co2+ en els que els lligands trimesat s'han reemplaçat parcialment per lligands isoftàlic o 5-aminoisoftàlic. Quan aquest compostos s'usen com a catalitzadors per a l'oxidació aeròbica de CM, sobserva que la introducció d'aquest segon lligand (i en particular del 5-aminoisoftàlic) en la xarxa metallorgànica es facilita la descomposició del CHP format i augmenta la selectivitat final a 2-fenil-2-propanol (PP). Això s'ha atribuït a la creació de defectes puntuals en la xarxa del material, que presenten una major activitat per a la descomposició del CHP. Seguint amb l'oxidació de CM com a reacció model, s'ha avaluat l'activitat catalítica de compostosisoreticulars de cobalt amb lligands bispirazolat funcionalitzats amb distints grups (CoBPZ, CoBPZ-NO2 i CoBPZ-NH2). En aquest cas s'ha observat una clara influència del lligand utilitzat sobre l'activitat catalítica i la selectivitat a CHP o PP del material. Mentre que el CoBPZ presenta una baixa conversió de CM i una elevada selectivitat a CHP, CoBPZ-NH2 presenta les característiques oposades: una elevada velocitat de reacció però una baixa selectivitat a CHP. En aquest últim cas, el producte majoritari format és el PP. Per últim, l'estudi de MOFs amb cations divalent como a catalitzadors d'oxidació s'ha completat amb una reacció de síntesi de quinazolina mitjançant acoblament oxidatiu de benzilamina i 2-aminoacetofenona emprant TBHP como a oxidant. Com a catalitzadors per aquesta reacció s'ha utilitzat el trimesat de coure, HKUST-1, així com materials isoreticular amb lligands mixtes obtinguts reemplaçant pa
[EN] A "green" synthesis method has been developed for the preparation of metal organic frameworks in aqueous media, which is easily scalable, at room tempera-ture, ambient pressure and very short crystallization times (10 min). This method has been successfully applied to the synthesis of isoreticular divalent metal trimesates of general formula M3(BTC)2·12 H2O (M = Ni2+, Co2+, Cu2+ y Zn2+; BTC = trimesate). The structure of these compounds features two types of metal centers ("bridging" and "terminal") in a 2 to 1 ratio, both with octahedral coordina-tion and linked to 4 water molecules and 2 carboxylate oxygens of the ligand. Using this method, two series of bimetallic isoreticular compounds of Co-Ni and Co-Zn have also been prepared in all range of compositions, as well as bimetallic Mn-Ni compounds up to a maximum concentration of 50% of Mn2+. A combined X-ray diffraction (powder and single crystal) and EDX/SEM has shown that these bimetallic compounds form true solid solutions (not simple mixture of phases) and that both ions distribute homogeneously throughout the crystal. A detailed analysis of the variation of cell parameters with the composition strongly sug-gests that Co2+ ions occupy preferentially the "terminal" positions of the frame-work. The materials obtained with the above method have been evaluated as catalysts for the aerobic oxidation of cumene (CM) to cumene hydroperoxide (CHO). The monometallic Co2+ compound, Co-BTC, showed a high catalytic activity, but a relatively low selectivity to CHP 69%), since the Co2+ ions can also catalyze the decomposition of the formed CHP. A good strategy to optimize the CHP selectivity consisted in isolating the Co2+ ions into a Ni-BTC (which is inert for both CM oxidation and CHP decomposition). In this way, as the concentration of Co2+ ions in the bimetallic Co-Ni compound decreases, a parallel increase of the CHP selec-tivity was observed, up to 91% for the material with 5% of Co. In this compound, 73% of the total Co2+ ions are statistically isolated, so that decomposi-tion/overoxidation of CHP is unlikely to occur. By using a variation of the above synthesis method, additional isoreticular Co2+ compounds have been prepared in which the trimesate ligands have been partially replaced by either isophthalic or 5-aminoisophthalic. When these compounds were used as catalysts for the aerobic oxidation of cumene, we observed that the introduction of this second ligand (in particular in the case of 5-aminoisophthalic) into the framework facilitates decomposition of CHP and in-creases the final selectivity to 2-phenyl-2-propanol (PP). This has been attributed to the progressive creation of point defects in the framework, having a higher activity for CHP decomposition. Following with the aerobic oxidation of CM as model reaction, we evaluated the catalytic activity of isoreticular cobalt compounds having bispyrazolate ligands bearing differnent functional groups (CoBPZ, CoBPZ-NO2 and CoBPZ-NH2). In this case, there is a clear influence of the ligand used on the catalytic activity of the material and the obtained selectivity to CHP or PP. While CoBPZ showed a low CM conversion and high CHP selectivity, the opposite properties are obtained for the Co-BPZ-NH2: i.e., a high reaction rate but a low CHP selectivity. In this latter case, the major product of the reaction was PP. Finally, the evaluation of divalent MOFs as oxidation catalysts has been complet-ed by addressing the synthesis of quinazoline through the oxidative coupling reaction of benzylamine and 2-aminoacetophenone using TBHP as oxidant. As catalysts for this reaction we have used a copper trimesate, HKUST-1, as well as isoreticular mixed-ligand compounds obtained by partially replacing trimesate ligands by 5-hydroxyisophthalic (OH-isophthalic).
Nowacka, AE. (2019). Divalent Metal Organic Frameworks as Heterogeneous Oxidation Catalysts [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/129872
TESIS

碩士
國立臺灣大學
藥學研究所
90
Abstract This thesis is aimed to design and synthesize substituted arylquinazoline derivatives as potential non-peptide corticotropin-releasing hormone 1 (CRH1) receptor antagonists. According to the structure-activity relationship of a series of known CRH1 antagonists and the lead compound CP154526-1 (12), quinazoline core was intended to replace the pyrrolopyrimidine ring leading to the target compounds 8-aryl-4-(N-cyclopropylmethyl-N-propylamino)- 2-methylquinazol-ines (36-38, 40). 2-Bromoaniline (20) was the starting material to prepare 2-bromoisonitrosoacetamilide (21) which was cyclized by concentrated H2SO4 to give 7-bromoisatin (22). Accordingly, 22 was decarboxylated by hydrogen peroxide to afford 2-amino-3-bromobenzoic acid (23). Condensation of 23 with triphosgene and then treatment under basic condition gave 2-amino-3-bromobenzamide (25). 8-Bromo-2-methyl-3H- quinazolin-4-one (26) was formed by condensation of 25 and 2,4-pentadione with p-toluenesulfonic acid catalysis. Chlorination of 26 with phosphorus oxychloride gave the 8-bromo-4-chloro-2-methylquinazoline (27). The key intermediate, 8-bromo-4-(N-cyclopropylmethyl-N-propylamino)-2-methyl- quinazoline (19) was obtained by nucleophilic substitution of 27 by the corresponding amine. Palladium-catalyzed cross-coupling reaction was employed in the final step to afford the target compounds 4-(N-cyclopropylmethyl-N-propylamino)-8-mesityl-2-methylquinazoline (36)、4-(N-cyclopropylmethyl-N-propylamino)-8-(2,4-dimthoxyphenyl)-2-methylquinazoline (37)、8-(4-bromophenyl)-4-(N-cyclopropylmethyl-N-propylamino)-2- methylquinazoline (38) and 4-(N-cyclopropylmethyl-N-propylamino)-8- pyridyl-2-methylquinazoline (40). Preliminary results showed that target compounds 36 and 37 were selective CRH1 antagonists with Ki = 13 nM and Ki = 50 nM, respectively. The results demonstrated that designed targets 36 and 37 are potential non-peptide selective CRH1 antagonists.

碩士
國立臺灣大學
藥學研究所
88
Hepatitis C virus (HCV), a virus that infects some 170 million people worldwide, is causing rising rates of liver disease. The necessity of finding potent anti-HCV agents is an urgent task. Hydroxyurea was reported to possess antiviral and antitumor activities as the results of inhibiting DNA synthesis. It is also an analogue of hydroxamic acid, a well-known compound with high affinity for metal ions. These make it of value in the development of anti-HCV agents. In this investigation, a novel series of quinazolinone derivatives comprise of hydroxyurea moiety, such as 4-amino-1-(Nω-hydroxyureidoalkyl)-2-quinazolinone (2a-c), 4-amino-1-(N-carbamoyl-N-hydroxylaminoalkyl)-2-quinazolinone (3a-c), and 4-amino-1-(N-hydroxycarbamoylalkyl)-2-quinazolinone (4a-c), were designed and synthesized. From computer modeling it shows that these compounds bind with HCV helicase on the ATP binding site. This result indicates that quinazolinone derivatives possess the potentiality as HCV helicase inhibitors. In addition, their potential activities to inhibit HCV NS3 helicase are evaluated by ELISA.

碩士
國立交通大學
應用化學系碩博士班
104
The first part is design and synthesis D- amino acid oxidase inhibitors (D-amino oxidase inhibitor, DAOI), the study found that patients with schizophrenia have brain excessive D- amino acid oxidase (D-amino oxidase, DAO) , thus suppressing excessive brain D- amino acid oxidase can be considered effective in the treatment of schizophrenia, and we found RS-D7 has good DAO inhibitory activity, therefore we used RS-D7 as the target compound, design and synthesis a series of RS-D7 analog and sent to test the biological activity and hoping that we can get more effective compound. On the other hand, in order to improve the poor solubility problems of RS-D7 , in which we have to modify its structure to improve the drawback. The second part : synthesis of benzazoles and quinazolinones is discovered by using iron pentacarbonyl as a reducing agent and solid carbon monoxide source under microwave irradiation. The reaction of substituted aryl iodides with o-amino/mercapto/hydroxyl nitrobenzenes and o-nitrobenzamides successfully delivered a wide variety of benzazoles and quinazolinones, respectively. The successive reactions proceed via iron pentacarbonyl mediated reduction of nitro to amine, carbonylative coupling of amines with aryl iodides followed by an intramolecular ring closure reaction. The diverse substrate scope with good to excellent yield makes this as a highly attractive strategy for the synthesis of benzazoles and quinazolinones.

Text in English
Specially prepared 2-amino-5-bromo-3-iodoacetophenone and 5-bromo-2-hydroxy-3 iodoacetophenone were subjected to Claisen-Schmidt aldol condensation with benzaldehyde derivatives followed by sequential and/or one-pot palladium catalyzed Sonogashira cross coupling and heteroannulation of the 3-alkynylated intermediates to afford indole-chalcones and benzofuran-chalcones, respectively. The indole-chalcones derivatives were, in turn, subjected to trifluoroacetic anhydride in tetrahydrofuran under reflux to afford the corresponding 3-trifluoroacetyl substituted indole-chalcone derivatives. The coupling constant values (Jtrans) of about 16.0 Hz for the chalcone derivatives corresponding to the vinylic protons confirmed the trans geometry of the α,β-unsaturated carbonyl framework in all the cases. Their trans geometry of the chalcone derivatives was further confirmed by single crystal X-ray diffraction (XRD) analyses. Further structural elaboration of the ambident electrophilic α,β unsaturated carbonyl (chalcone) moiety of the indole-chalcones and the analogous benzofuran chalcones with 2-aminothiophenol afforded novel benzothiezapine-appended indole and benzofuran hybrids, respectively. Sonogashira cross-coupling of 5-bromo-2-hydroxy-3 iodoacetophenone with terminal acetylenes followed by heteroannulation of the intermediate 3-alkynylated 5-bromo-2-hydroxyacetophenones afforded the corresponding 7-acetyl-2-aryl-5-bromobenzofurans in a single-pot operation. The oximes derived from the 7-acetyl–substituted 2-aryl-5-bromobenzofurans were subjected to Beckmann rearrangement with triflic acid in acetonitrile under reflux. We isolated the corresponding 7-amino-2-aryl-5 bromobenzofuran derivatives formed from hydrolysis in situ of the intermediate 7-acetamide 2-aryl-5-bromobenzofurans. Amino-dechlorination of the 4-chloroquinazoline derivatives with the 7-aminobenzofurans afforded novel benzofuran 4-aminoquinazoline hybrids. The prepared compounds were characterized using a combination of nuclear magnetic resonance (1H-NMR & 13C-NMR including 19F-NMR), infrared (IR) and mass spectroscopic techniques complemented with single crystal X-ray diffraction (XRD) analyses and/or density functional (DFT) method. The benzofuran-chalcone 203a–y derivatives were evaluated for anti-growth effect against the breast cancer (MCF-7) cell line by the MTT cell viability assay. Their mode of cancer cell death (apoptosis versus necrosis) was detected by Annexin V-Cy3 SYTOX staining and caspase-3 activation. The most cytotoxic compounds 203i and 203o were also evaluated for potential to inhibit tubulin polymerization and/or epidermal growth factor receptor-tyrosine kinase (EGFR-TK) phosphorylation. The experimental results were complemented with theoretical data from molecular docking into ATP binding site of the EGFR and colchicine binding site of tubulin, respectively. The benzofuran–4-aminoquinazoline hybrids 215a–j, on the other hand, were evaluated for antiproliferative propeties in vitro against the human lung cancer (A549), epithelial colorectal adenocarcinoma (Caco-2) and hepatocellular carcinoma (C3A) cell lines. The benzofuran-aminoquinazoline hybrids were also evaluated for potential to induce apoptosis and for their capability to inhibit EGFR-TK phosphorylation complemented with molecular docking (in silico) into the ATP binding site of EGFR. Mechanistic studies demonstrated that the benzofuran-appended aminoquinazoline hybrids 215d and 215j induced apoptosis via activation of caspase-3 pathway. Moreover, compounds 215d and 215j exhibited significant and moderate inhibitory effects against EGFR (IC50 = 29.3 nM and 61.5 nM, respectively) when compared to Gefitinib (IC50 = 33.1 nM). Molecular docking of compounds 215 into EGFR-TK active site suggested that they bind to the region of EGFR like Gefitinib does.
Chemistry
D. Phil. (Chemistry)

碩士
國立中正大學
化學所
97
In this thesis, metal triflates as Lewis acids and microwaves were employed to accelerate the dehydrocyclization reactions to efficiently construct natural and unnatural quinazolinones and a bicyclic imidazole. For the total synthesis of a small library of quinazolinones, two similar but reverse in peptide sequences synthetic approaches are incorporated to successfully construct asperlicin C and D, circumdatin F and sclerotigenin natural products, and other fused quinazolinones. Results of chiral resolution experiments clearly demonstrate that microwaves not only facilitated the double dehydrocyclization reactions but also minimized racemization during ring closing reactions. In previous studies, we have reported that the bicyclic imidazolium ionic liquid, bis(trifluoromethylsulfonyl)imide ([b-3C-im][NTf2]), excels than [bmim][PF6], [bdmim][PF6] and [bdmim][NTf2] in its chemical stability. Mainly due to their low overall isolated yields and multi-step synthesis in our previous preparations, herein we aim at preparing our bicyclic imidazole via a facile microwave-promoted one-pot synthesis with hope to improve overall isolated yield. Lastly, in this newly developed one-pot synthesis, a series of Lewis acids and solvents were attempted to optimize the reaction condition.

碩士
國立中正大學
化學所
96
Abstract Alkaloid pyrazino[2,1-b]quinazoline-3,6-diones contain structural motifs of quinazolinone and diketopiperazine-like skeletons. Some of which were found to have bioactivities. The last two steps in the organic synthesis of alkaloid pyrazino[2,1-b]quinazoline-3,6-diones involve the synthesis of peptides, which then undergo a cyclization-upon-deprotection reaction to form the final product. To perform peptide synthesis and cyclization-upon-deprotection, our and other laboratories have traditionally used liquid phase peptide synthesis and a combination of triphenylphosphine, iodine, and diisopropylethylamine (DIEA), respectively. Here we propose a new strategy to complete the synthesis of alkaloid pyrazino[2,1-b]quinazoline-3,6-diones. To successfully synthesize the required peptides, we demonstrate that a different technique named solid-phase-peptide synthesis (SPPS) may be used. To successfully perform the final step of cyclization, we found that various Lewis acids could be used, with the most efficient Lewis acid being Zn(OTf)2. Our results showed that Zn(OTf)2 shortened the cyclization from what would otherwise take normally a few days to hours to complete. By using our novel approach involving SPPS and Lewis acids, pyrazino[2,1-b]quinazoline-3,6-diones libraries may be established more rapidly and applied in bioactivity assays in the future.