Dissertations / Theses on the topic 'Diazepine'

Cancer is a new growth that arises from abnormal and uncontrolled division of cells that may go on to invade and destroy surrounding tissues. The eukaryotic cell cycle consists of a complex sequence of events that regulates cell division and responses to DNA damage. These processes rely upon several key enzymes, including the cyclin dependent kinases (CDKs), checkpoint kinases (Chk2) and poly(ADP-ribose)polymerase-l (PARP-1). CDKs are a family of protein kinases that control progression of the cell cycle, and are themselves regulated by a complex network of activating and inhibitory mechanisms. The vital importance of CDKs in regulating of the cell cycle, emphasise their importance as anti-cancer drug targets. CDKs inhibitors compete with the natural substrate ATP in a competitive manner. Hymenialdisine and kenpaullone have been identified as novel and potent CDK inhibitors both containing an unusual azepinone scaffold. Checkpoint kinase 2 (Chk2) is a novel target for anti-cancer drug design. The enzyme mediates cell proliferation in response to DNA damage by inducing cell cycle arrest, which facilitates the DNA repair pathways. Chk2 inhibition has been recognised as a potential target for the chemopotentiation of current anti-cancer treatments. Few Chk2 inhibitors are known, kenpaullone has been identified as a novel and selective ATP competitive Chk2 inhibitor (IC ₅₀ = 0.8 µM). Debromohymenialdisine (DBH) also containing an azepinone scaffold has also been reported to inhibit Chk2. Poly(ADP-ribose)polymerase-l (PARP-1) is activated in response to DNA damage, and inhibition can potentiate cancer chemotherapy and radiotherapy. A PARP-1 inhibitor in combination with a cytotoxic agent should enhance drug activity by blocking the repair capabilities of PARP-1 in cancer cells. Although many types of inhibitors have been identified for each of these three enzymes, compounds containing a seven-membered lactam ring have been identified as key inhibitors for CDKs/Chk2/PARP-l. This study is entered upon developing the synthesis for a series of novel inhibitors of these three enzymes containing the essential lactam pharmacophore in their structures. The compounds synthesised in this study were assessed by a number of biological assays showing moderate or good growth or catalytic inhibitory activity against CDKs and PARP-1 respectively, while assays against Chk2 showed no inhibition.

The pyrrolo 2,1-c 1,benzodiazepines (PBDs) are a family of naturally occurring antitumour antibiotics which includes anthramycin, DC-81, tomaymycin and sibiromycin. They exert their biological activity through covalent binding to the exocyclic N2 group of guanine in the minor groove of DNA and block transcription in a sequence-specific manner. These PBD monomers span three DNA base pairs and have a preference for binding to purine-G-purine triplets. The PBDs have been used as a scaffold to attach other moieties, leading to novel sequence-selective DNA minor groove alkylating agents. In addition, as part of a rational approach to producing more efficient and selective DNA interstrand crosslinking agents, two PBD monomers have been linked together to form PBD dimers. The research in this thesis is a study of the molecular and cellular pharmacology of several series of novel PBD-containing agents including novel PBD dimers with different linker lengths, PBD-nitrogen mustard conjugates, PBD-polyamide conjugates and C2-aryl PBD monomers. Cytotoxicity in human tumour cell lines, efficiency of DNA interstrand crosslinking in naked linear plasmid DNA, and DNA sequence specificity were assessed. DNA interstrand crosslink formation and repair in cells were also measured. Resulting from this work Q2lQT-exo-unsaturated PBD dimers have been characterised to be highly cytotoxic and efficient in producing interstrand crosslinks both in naked DNA and in cells that are not repaired up to 48 hours. Only two of the PBD-nitrogen mustard conjugates showed some interaction with DNA although several members of this group showed significant cytotoxicity. A PBD-tri-pyrrole conjugate was found to bind preferentially to the sequence 5'-AGATTATC. Novel C2-aryl PBD monomers were shown to bind selectively to 5'-purine-G-purine sequences and demonstrated significant cytotoxicity. In addition, a method utilizing fluorescently end-labelled oligonucleotides was developed and validated to screen libraries of PBD-containing molecules synthesised on beads by combinatorial chemistry. This method allowed the isolation and discrimination of beads containing compounds, which have a high affinity for specific DNA sequences.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
The present research describes new synthetic methodologies for the synthesis of new series of 2-aryl(heteroaryl)-4-trifluoro-4,5-dihydro-3Hpyrido[2,3-b][1,4]diazepin-4-ols and 2-aryl(heteroaryl)-3H-pyrido[2,3-b][1,4]diazepin-4(5H)-one analogs, in a single one-pot procedure or through on intermolecular cyclization reactions of the enaminoketones intermediates, where aryl = Ph, 4-MeC6H4, 4-OMeC6H4, 4-FC6H4, 4-ClC6H4, 4-BrC6H4, 4,4 -biphenyl, 1-naphtyl and heteroaryl = 2-furyl, 2-thienyl. The pyridodiazepinols were obtained from intramolecular cyclocondensation reactions of enaminoketones N3-[1-aryl(heteroaryl)-3-oxo-4,4,4-trifluorobut-1-en-1-yl]-2,3-diaminopyridines in methanol at temperature of 50 °C for 16 hours. In a one-pot reaction, these pyridodiazepinols can be obtained through reactions of 4-methoxy-1,1,1-trifluorobut-3-en-2-ones with 2,3-diaminopyridine, using methanol as solvent and a temperature of 55 to 60 ºC for 24 hours with yields of 56-68%. The attainment of the 2-aryl(heteroaryl)-3H-pyrido[2,3-b][1,4]diazepin-4(5H)-one analogs were obtained through the haloform intramolecular reactions, with the elimination of the trichloromethyl group, from the synthetic intermediate N3-[1-aryl(heteroaryl)-3-oxo-4,4,4-trichlorobut-1-en-yl]-2,3-diaminopyridines in methanol and a temperature of 65 °C for 20 hours with yield of 48-70%. Therefore, the respective pyridodiazepinones were obatined, in a one-pot reaction, reacting 4-aryl(heteroaryl)-4-methoxy-1,1,1-trichlorobut-3-en-2-ones with 2,3-diaminopyridine in more drastic conditions (methanol, 65 ºC and 24 hours) with yields of 48-70%. Under moderated conditions (methanol, 0 °C and 20 hours), regioselective synthesis between the 4-alkyl(aryl/heteroaryl)-4-methoxy-1,1,1-trihalobut-3-en-2-ones and 2,3-diaminopyridine, leads to the isolation of the respective N3-[1-aryl(heteroaryl)-3-oxo-4,4,4-trihalobut-1-en-1-yl]-2,3-diaminopyridines, through of addition - elimination reactions, in good yields. The N3-[1-aryl-3-oxo-4,4,4-trichlorobut-1-en-1-yl]-N2-[sulphonyl methano]-2,3-diaminopyridines were obtained by sulphonation reaction between the N3-[1-aryl-3-oxo-4,4,4-trichlorobut-1-en-1-yl]-2,3-diaminopyridines and methanesulfonyl chloride, at room temperature for 4 hours with yields of 53-66%. Finally, it was obtained a serie of N 3-[trifluoroacetyl-cycloalken-1-yl]-2,3-diaminopyridines through N-acilation reactions, involving cycloalkanones trifluoromethylated of 5, 7 or 8 members with 2,3-diaminopyridine in methanol at 0 ºC for 20 hours with yields of 65-69%. Subsequent reactions showed that, only under more drastic conditions (methanol, 50 °C e 24 hours), these cyclic enaminones underwent intramolecular cyclization, resulting the pyrido-imidazol as only product, independently of the cycloalkanone precursor. The compounds obtained in this research were identified by 1H and 13C NMR and analyzed by elemental analysis, being the N3-[1-aryl(heteroaryl)-3-oxo-4,4,4-trihalobut-1-en-1-yl]-2,3-diaminopyridines, also identified by X-ray diffraction.
O presente trabalho descreve novas metodologias sintéticas para obtenção de séries inéditas de 2-aril(heteroaril)-4-trifluor-4,5-diidro-3Hpirido[2,3-b][1,4]diazepin-4-óis e 2-aril(heteroaril)-3H-pirido[2,3-b][1,4]diazepin-4(5H)-onas análogas, em passo reacional único ou a partir de reações de ciclização intramoleculares de enaminocetonas intermediárias, sendo aril = Ph, 4-MeC6H4, 4-OMeC6H4, 4-FC6H4, 4-ClC6H4, 4-BrC6H4, 4,4 -bifenila, 1-naftila e heteroarila = 2-furila, 2-tienila. Os piridodiazepinóis foram obtidos a partir de reações de ciclocondensação intramolecular de enaminocetonas N3-[1-aril(heteroaril)-3-oxo-4,4,4-trifluorbut-1-en-1-il]-2,3-diaminopiridinas em metanol à 50 °C por 16 horas. Enquanto que, em passo reacional único, estes piridodiazepinóis foram obtidos a partir de reações de 4-metoxi-1,1,1-trifluorbut-3-en-2-onas com 2,3-diaminopiridina, utilizando metanol como solvente a uma temperatura de 55 à 60 °C por 24 horas com rendimentos mais satisfatórios que variam entre 56-68%. A obtenção das 2-aril(heteroaril)-3H-pirido[2,3-b][1,4]diazepin-4(5H)-onas análogas foi realizada através das reações de ciclocondensação intramolecular do tipo halofórmica, com eliminação do grupamento triclorometila, partindo dos intermediários sintéticos N3-[1-aril(heteroaril)-3-oxo-4,4,4-triclorobut-1-en-il]-2,3-diaminopiridinas em metanol à temperatura de 65 °C, por 20 horas com rendimentos não satisfatórios. No entanto, as respectivas piridodiazepinonas foram obtidas, em etapa reacional única, reagindo as 4-aril(heteroaril)-4-metoxi-1,1,1-triclorobut-3-en-2-onas com 2,3-diaminopiridina em condições mais drásticas, ou seja, utilizando metanol à temperatura de 65 °C por 24 horas com rendimentos que variam de 48-70%. Sob condições brandas (metanol, 0 °C e 20 horas), a síntese regioseletiva entre as 4-alquil(aril/heteroaril)-4-metoxi-1,1,1-trialobut-3-en-2-onas com 2,3-diaminopiridina, levou ao isolamento das respectivas N3-[1-aril(heteroaril)-3-oxo-4,4,4-trialobut-1-en-1-il]-2,3-diaminopiridinas, através de reações de adiçãoeliminação, com bons rendimentos. As N3-[1-aril-3-oxo-4,4,4-triclorobut-1-en-1-il]-N2-[sulfonil metano]-2,3-diaminopiridinas foram obtidas a partir de reações de sulfonação entre as N3-[1-aril-3-oxo-4,4,4-trialobut-1-en-1-il]-2,3-diaminopiridinas e cloreto de sulfonil metano, utilizando como solvente CH2Cl2 e um tempo reacional de 4 horas, à temperatura de 35 °C com rendimentos que variam de 53-66%. Finalmente, também foi mostrada as reações de ciclização derivadas de uma série de N3-[trifluoracetil-cicloalquen-1-il]-2,3-diaminopiridinas. Estas reações subseqüentes, mostraram que somente sob condições mais drásticas (metanol, 60 °C e 24 h), as enaminonas ciclo-derivadas ciclizam intramolecularmente, resultando como único produto um pirido-imidazol, independentemente da cicloalcanona precursora. Os compostos obtidos nesta tese foram identificados por RMN de 1H e 13C e analisados por análise elementar, sendo os compostos N3-[1-aril(heteroaril)-3-oxo-4,4,4-trialobut-1-en-1-il]-2,3-diaminopiridinas, identificados também por difração de Raios-X.

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Físicas e Matemáticas. Programa de Pós-Graduação em Química
Made available in DSpace on 2012-10-23T14:28:55Z (GMT). No. of bitstreams: 1 240358.pdf: 1103686 bytes, checksum: 4c410a7e99907ae4f7afa42254d4875d (MD5)
Ligantes N-doadores capazes de se coordenarem facialmente a íons metálicos divalentes são de interesse na síntese de complexos metálicos que mimetizem o ambiente de coordenação de sítios ativos de enzimas que contém resíduos de aminoácidos N-doadores.O ligante AAZ foi utilizado na preparação e caracterização de complexos mononucleares de CuII, ZnII e MnII, e na investigação preliminar da atividade de hidrolase para um complexo de CuII. Os cinco complexos obtidos foram sintetizados e caracterizados por análise de difratometria de raios X, espectroscopia no infravermelho, espectroscopia eletrônica e por ressonância magnética nuclear de H1, eletroquímica e titulação potenciométrica. Observou-se que o AAZ coordenou-se facialmente aos íons metálicos nos complexos 1, 2, 3 e 4, já no complexo 5 o ligante AAZ está coordenado de forma bidentada. Foi também observado nos complexos 1 e 2 a capacidade do AAZ em estabilizar as duas conformações possíveis do efeito Jahn Teller. O estudo eletroquímico do complexo 4 mostrou que o Mn2+ foi estabilizado de forma mais eficiente quando comparado ao complexo [Mn(tacn)2]2+. O ensaio cinético de hidrólise do BNPP com o complexo 5 mostrou um fator de acelereação da hidrólise de 2,1x105 em relação a reação não catalisada. A partir dessas observações, o AAZ apresenta-se como uma excelente opção para a preparação de ligantes de interesse bioinorgânicos.

La these a trait a la determination des constantes d'ionisation et a l'etude de la cinetique d'ouverture d'une thieno-1,2,4-triazolo-1,4-diazepine soluble dans l'eau, appelee conventionnellement nhptt. Les constantes d'ionisation du nhptt et de son produit d'ouverture le nhpto ont ete determinees en milieu aqueux par spectrophotometrie u. V. Et par ph-metrie. Les resultats experimentaux ont ete traites par curve-fitting. Les resultats montrent sans ambiguite que le noyau 1,2,4-triazole possede un caractere basique dans l'eau. Ce point avait echappe aux autres auteurs ayant etudie auparavant ces composes. Quelques unes des valeurs de pka n'ont pu (et ne peuvent) etre assignees en toute certitude a des sites (acido-basiques) bien definis etant donne le probleme des constantes microscopiques. La cinetique d'ouverture reversible du nhptt en nhpto a ete etudiee, en parallele, par polarographie et par spectrophotometrie u. V. . Les constantes sont issues, egalement, du traitement des donnees experimentales par curve fitting. Quelles que soient les conditions experimentales, la cinetique d'ouverture est du premier ordre. Le profil des valeurs des constantes d'ouverture et de fermeture en fonction du ph a ete etabli. Enfin, une relation entre constantes cinetiques apparentes, constantes cinetiques elementaires et constantes d'ionisation a ete etablie. Elle s'avere tres compliquee. Elle fait notamment intervenir les pka macroscopiques et microscopiques, ce qui justifie les etudes precedentes. Elle montre qu'il est impossible d'obtenir les constantes cinetiques elementaires autrement que sous forme de combinaisons lineaires. Les traitements par curve-fitting ont ete realises a l'aide de programmes que nous avons specialement concus suivant les problemes a traiter. Lorsque les domaines de ph l'ont permis, les problemes de force ionique ont ete pris en compte via l'introduction du concept d'activite

Made available in DSpace on 2014-06-11T19:35:12Z (GMT). No. of bitstreams: 0 Previous issue date: 2007-02-27Bitstream added on 2014-06-13T19:05:32Z : No. of bitstreams: 1 nascimento_js_dr_botfm.pdf: 722430 bytes, checksum: e2016c502b8c938e01734e5747ae7a04 (MD5)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Avaliar a qualidade da sedação e os efeitos sobre a frequencia cardiaca e a pressão arterial do midazolam e do diazepam associados ou nao a clonidina, em pacientes com suspeita de doenca coronariana. Métodos: Foi desenvolvido ensaio clinico prospectivo, duplo cego, randomizado, controlado, com 160 pacientes. Estes apresentavam teste ergometrico ou cintilografia positivos para isquemia miocardica e foram submetidos a cineangiocoronariografias diagnosticas eletivas, divididos em cinco grupos de 32 pacientes cada, de acordo com o farmaco utilizado: grupo C (clonidina 0,5 Êg.kg-1); grupo M (midazolam 40 Êg.kg-1); grupo MC (associacao do midazolam 40 Êg.kg-1 e da clonidina 0,5 Êg.kg-1); grupo D (diazepam 40 Êg.kg-1); grupo DC (associacao do diazepam 40 Êg.kg-1 e da clonidina 0,5 Êg.kg-1). A sedacao foi avaliada com base na escala de Ramsay e no consumo de meperidina (0,04 mg.kg-1) que foi utilizada nos pacientes que apresentaram agitacao ou ansiedade durante o procedimento. A PA invasiva, a FC e o escore de sedacao, foram analisados a cada 5 minutos em 4 diferentes momentos: M1 - inicio do exame; M2 - 5 minutos apos o inicio do exame; M3 - metade do tempo do exame e M4 - final do exame. Resultados: Os grupos foram homogeneos com relacao a PA, FC e sedacao no momento controle (M1). Os pacientes que utilizaram o midazolam apresentaram maiores escores de sedacao e variacao da FC e PA (p<0,05). Os que utilizaram o diazepam ou a clonidina exibiram menores e mais apropriados escores de sedacao para a realizacao do exame e apresentaram menor $ variacao da PA e da FC (p>0,05). A associacao com a clonidina potencializou de forma mais precoce e acentuada os efeitos sedativos do midazolam em relacao ao diazepam (p<0,05). O consumo de meperidina nao diferiu entre os grupos estudados (p>0,10)...
Background to evaluate the effects of midazolam, diazepam and associations with clonidine on heart rate (HR), blood pressure (BP) as well as its sedative effect on patients submitted to coronary angiography. Methods A randomized, controlled and double blind, prospective clinical trial was conducted on 160 patients submitted to an elective coronary angiography. All of them have ergometric test or miocardic cintilography positive to ischemia. They were divided into five groups with 32 patients each: C group (clonidine 0,5 ìg.kg-1); M group (midazolam 40 ìg.kg-1); DC group (midazolam 40 ìg.kg-1 and clonidine 0,5 ìg/kg associated); D group (diazepam 40 ìg/kg); DC group (diazepam 40 ìg/kg and clonidine 0,5 ìg.kg-1 associated). Sedation was evaluated based on the Ramsay Scale. Administration of a 0,04 mg.kg-1 dose of meperidine was given to the patients who were agitated or anxious during the procedure. The invasive BP, HR and sedation score based on Ramsay Scale were analyzed every five minutes and four different intervals were considered for the assessment: M1- at the start of the test; M2 5 minutes after the start of the test; M3 half time of the test; M4 at the end of the test. Results The groups were homogeneous in relation the BP, HR and sedation in the control moment (M1) and there was no difference regarding the weight, age and sex. The patients that used midazolam presented deeper sedation score and HR and BP variability (p<0,05). The patients that used diazepam or clonidine have superficial sedation score and better BP and HR stability. The association with clonidine showed the midazolam sedative effects earlier and $ deeper than diazepam (p<0,05). There was no difference in meperidine use (p>0,10) Conclusions The midazolam presented higher and deeper sedative and cardiovascular effect... (Complete abstract, click eletronic address below)

L'utilisation de peptides natifs en tant que medicaments se heurte a des inconvenients inherents a leur metabolisme et a leur manque de specificite. C'est dans le but de resoudre ces problemes que l'axe de recherche concernant les peptidomimetiques contraints a ete developpe. Nous avons synthetise des perhydrodiazepinones dont la structure s'apparente a celle des coudes presents dans certains peptides. Dans ce manuscrit, nous avons decrit differentes voies de synthese dont la principale implique une reaction de mitsunobu afin de realiser l'etape-clef de cyclisation. Cette strategie de synthese a ete adaptee sur supports (polyethylene glycol et resine de wang) dans le but d'obtenir un maximum d'outils utilisables en chimie combinatoire pour construire des librairies de ce type de molecules. Dans la derniere partie, nous avons augmente la diversite moleculaire de la structure en effectuant une synthese a partir d'un pool chiral permettant le controle de la chiralite de l'ensemble des carbones asymetriques.

Orientadores: Luiz Manoel Aleixo, Oswaldo E. S. Godinho
Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Quimica
Made available in DSpace on 2018-07-23T06:59:49Z (GMT). No. of bitstreams: 1 Gomes_SandraTerezinhaMarques_D.pdf: 3400371 bytes, checksum: f579f07964f5142b6020fa1c3dd23fc8 (MD5) Previous issue date: 1997
Doutorado

Poly-(ADP-ribsoyl) Polymerases (PARPs) are a superfamily of enzymes comprised of 17 known isoforms. PARP inhibitors (PARPi) have shown success in clinical trials for the treatment of homologous recombination-deficient cancers. Though proven effective initially, tumors treated with PARPi eventually develop resistance. Combinatorial therapeutics targeting PARP and other pathways that may re-sensitize tumors to PARP inhibition, including PI3K/AKT/mTor pathway, and cell-cycle checkpoints (such as CDKs, CHK, and Wee) are being tested. In this context, the synthetic lethality of cyclin-dependent kinase 1 (CDK1) and PARP1 is known. Evaluation of PARP1 and CDK1 pharmacophores led to the development of the tetrahydro-arylazepinone (TAAP) scaffold as a potential dual PARP1/CDK1 inhibitor. We screened a handful of TAAP analogs against PARP1 in a cell-free assay that identified the low micromolar PARP1 inhibitor 1,2,3,4-tetrahydro-5H-benzo[e][1,4]-diazepin-5-one (TBAP), which served as the lead compound. The analogous 1,2,3,4-tetrahydro-5H-pyrido[2,3-e][1,4]-diazepin-5-one (TPAP) series showed a similar bioactivity profile. Satisfyingly, the N1-benzyl TPAP analogue showed activity in the low nanomolar range. The TAAP series (i.e., 6/7-membered scaffold) unfortunately lacked CDK1 inhibitory activity. Finally, many PARPi's show poor isoform-selectivity. The development of isoform-selective PARPi can clarify the specific function of each PARP isoform and may reduce the adverse side effects shown by PARPi. A handful of TAAP analogs were screened against 13 PARP isoforms, where some compounds demonstrated exquisite PARP1/2 selectivity. Concurrently, we discovered an inhibitor for PARP11, an isoform that lacks any known synthetic ligand. Future directions are suggested towards fine-tuning the structure-activity relationship of TAAP-isoform selective PARPi as well as developing a dual PARP1/CDK1 inhibitor.
Master of Science

Orientador: Eduardo Dias de Andrade
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba
Made available in DSpace on 2018-08-03T16:34:47Z (GMT). No. of bitstreams: 1 Abrahao_JoaoMigueldeBarros_D.pdf: 1096955 bytes, checksum: 5d94a7ca751633e0a5eaa63b6819accf (MD5) Previous issue date: 1994
Resumo: Este trabalho teve por objetivo avaliar os efeitos de uma tríade medicamentosa sobre os valores de pressão arterial sanguínea (PA) e frequência cardíaca (FC) em pacientes com indicação da exodontia de terceiros molares mandibulares inclusos. Para tanto foram selecionados 17 pacientes, de ambos os sexos, na faixa etária de 17 a 23 anos e normotensos, que foram tratados com o diazepam e a dexametasona, nas doses de 5 mg e 4 mg, respectivamente, 1 hora antes do procedimento cirúrgico, associadas à um anestésico local de longa duração (bupivacaína a 0,5% com adrenalina 1:200.000). As avaliações de PA e FC foram realizadas em 5 tempos distintos, ou seja, na semana anterior e no dia da cirurgia, com o paciente em repouso 60 minutos após a administração do diazepam e da dexametasona, 10 minutos após a injeção do anestésico local e após o término da intervenção cirúrgica. Os resultados mostraram que os valores médios da pressão arterial sanguínea (sistólíca e diastólica), bem como da frequência cardíaca, situaram-se dentro da faixa de normalidade biológica, durante todo o período experimental
Abstract: The aim of this study is to evaluate the effects of three drugs over blood pressure and heart rate in subjects submitted to impacted third molar removal. For this purpose, 17 patients, both sex, aged between 17 and 23 years, normotensive, were selected and treated with diazepan and dexametasone by single dose of 5mg and 4mg, respectively, one hour before the surgical procedure, associated a long-lasting local anaesthetic (bupivacaine 0.5% with epinephrine 1:200,000). The blood pressure and heart rate was measured in 5 different times, a week before, on the surgery day, with patient in rest position, 60 minutes after diazepan and dexametasone administration, 10 minutes after local anaesthetic injection, and at the end of the surgery. The results showed that the mean blood pressure (systolic and diastolic), heart rate within physiological values during the experimental phase
Doutorado
Farmacologia
Doutor em Ciências

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
This study demonstrated the sedative and anesthetic activity of the essential oil (EO) of Cymbopogon flexuosus in the silver catfish (Rhamdia quelen). The time for induction and recovery of this EO was compared with the EO of Aloysia triphylla, due to the similarity between their major components: α-citral (geranial) and β-citral (neral). Both EOs induced anesthesia at concentrations from 150 to 300 μL L-1 and sedation at 25 μL L-1. The EO of C. flexuosus was faster in inducing the initial stages of anesthesia, but there was no significant difference to reach deep anesthesia, and there was a significantly longer recovery time. Cooperative relations and the modulation of the benzodiazepine (BDZ) site of GABAa as a mechanism of action of both EOs was verified from the addition of diazepam and flumazenil to experiments (BDZ site of GABAa agonist and antagonist, respectively). The addition of diazepam (150 μM) induced potentiation in concentrations of 25, 150 and 300 μL L-1 both EOs without significant change in anesthesia recovery time. Flumazenil (10 μM) reversed the diazepam-induced anesthesia, but not the anesthesia induced by EOs at concentrations of 150 and 300 μL L-1, thus the EO of C. flexuosus induced effective sedation and anesthesia without short-term mortality and the modulation of the BDZ site of the GABAa in the anesthetic action mechanism of both EOs in this study was not demonstrated.
Este estudo demonstrou as atividades sedativa e anestésica do óleo essencial (OE) de Cymbopogon flexuosus em jundiás (Rhamdia quelen). Os tempos de indução e recuperação relatados para esse OE foram comparados com o OE de Aloysia triphylla devido à semelhança entre os seus principais componentes: α-citral (geranial) e β-citral (neral). Ambos os OEs induziram anestesia nas concentrações de 150 a 300 μL L-1 e sedação a partir de 25 μL L-1. O OE de C. flexuosus induziu mais rapidamente fases iniciais da anestesia, mas não houve diferença significativa para alcançar o estágio de anestesia profunda, além de induzir um tempo de recuperação significativamente mais longo. As relações cooperativas e a modulação do site benzodiazepínico (BDZ) do receptor GABAa como mecanismo de ação de ambos OEs foram testados a partir da adição de diazepam e flumazenil aos experimentos (agonista e antagonista do site BDZ do GABAa, respectivamente). A adição de diazepam (150 μM) potencializou o efeito de ambos os OEs nas concentrações de 25, 150 e 300 μL L-1, sem induzir alteração significativa nos tempos de recuperação anestésica. O flumazenil (10 μM) reverteu a anestesia induzida pelo diazepam, mas não a anestesia induzida pelos OEs nas concentrações de 150 e 300 μL L-1, portanto o OE de C. flexuosus induziu sedação e anestesia efetivas sem mortalidade a curto prazo e a modulação do site BDZ do GABAa como mecanismo de ação anestésica de ambos OEs não ficou demonstrada neste estudo.

Made available in DSpace on 2013-08-07T19:07:01Z (GMT). No. of bitstreams: 1 000436763-Texto+Completo-0.pdf: 467410 bytes, checksum: f234f7135286713fce26da90200be9a5 (MD5) Previous issue date: 2011
Objective : compare the therapeutic efficacy of intramuscular midazolam (IM-MDZ) and intravenous diazepam (IV-DZP) to 529treat seizures in children. Methods : Randomized controlled study enrolling children (2months-14years) presenting seizures admitted to the Pediatric Emergency Department of the Hospital Universitário de Santa Maria between August 2010-August 2011; being randomized to receive IV-DZP or IM-MDZ as initial treatment. The groups were compared regarding the length of time to start medication, to interrupt seizures after being medicated and the total length of time to achieve the seizures interruption. Results : Venous access was not obtained in 4 minutes in 4 patients (20%) assigned to the IV-DZP. 32 children completed the study (16 in each group). IV-DZP compared to the IM-MDZ, presented the longest interval to cease seizures (10. 6 x 7. 3min; p=0. 006). Two children of each group (12. 5%) the seizures did not stop after 10 minutes, being 3 children transferred to the PICU after tracheal intubation: 1 belonging to the IM-MDZ (6. 25%0 and 2 in the IV-DZP group (12. 5%). There were not differences regarding adverse effects between the groups (p=0. 171): one child in the IM-MDZ presented hypotension (6. 3%) and 5 (31%) presented hyperactivity or vomit after receiving IV-DZP. Conclusion : Intramuscular midazolam presented lower interval to cease seizures than IV diazepam. Intrauscular midazolam demonstrate be ans excellent o treat seizures in children as a result of its efficacy, facility and fast administration.
Objetivo : Comparar a eficácia terapêutica da administração de Midazolam Intramuscular (MZ-IM) e do Diazepam Endovenoso (DZP-EV) em crianças com crise convulsiva.Método : Estudo randomizado e controlado, envolvendo crianças com crise convulsiva (2 meses a 14 anos) admitidas ao serviço de Emergência do Hospital Universitário de Santa Maria no período de agosto de 2010 a agosto 2011, sendo randomizadas a receber DZP-EV ou MZ-IM como tratamento inicial para convulsões. Os grupos foram comparados em relação ao tempos necessário para iniciar a medicação, para ceder a crise após a administração do fármaco e o tempo total para ceder a crise. Resultados : Não foi obtido acesso venoso aos 4 minutos em 4 pacientes (20%) assinalados ao grupo DZP-EV. Resultaram 32 crianças que completaram o estudo (16 em cada grupo). O DZP-EV apresentou tempo total maior para ceder à crise convulsiva quando comparado ao MZ-IM (10,6 x 7,3 min; p=0,006). Em 2 crianças de cada grupo (12,5%) a crise não cedeu após 10 minutos de tratamento, 3 crianças foram transferidos para a UTI pediátrica, após serem intubadas: 1 (6,25%) do grupo MDZ-IM e 2 (12,5%) do DZP-EV. Não houve diferença quanto a efeitos adversos entre os grupos (p=0,171): uma criança (6,3%) apresentou (hipotensão) após receber MDZ-IM e outras cinco crianças (31%) apresentaram (hiperatividade ou vomito) após receberem DZP-EV. Conclusão : Midazolam intramuscular apresentou menor tempo total para ceder a crise convulsiva que o diazepam endovenoso. Midazolam intramuscular mostrou ser excelente opção no tratamento de crises convulsivas na infância pela eficácia, facilidade e rapidez de aplicação.

Les kallikréines (KLKs) tissulaires humaines sont des protéases à sérine « (chymo)trypsine-like » impliquées dans divers processus physiologiques. Parmi les 15 isoformes connues dans la littérature, la kallikréine 7 (KLK7) est particulièrement impliquée dans les processus de desquamation. La dérégulation de cette enzyme est associée à diverses atteintes dermatologiques, telles que le psoriasis ou la maladie de Netherton. Il est également admis que cette enzyme participe à l'invasion tumorale et à la progression du cancer de la prostate, des ovaires et du pancréas. L'utilisation d'inhibiteurs de la KLK7 pourrait donc constituer une approche prometteuse pour le traitement de certaines atteintes dermatologiques, et pour lutter contre la dissémination métastatique.Depuis deux décennies, plusieurs inhibiteurs synthétiques de cette isoforme ont été développés. Toutefois, la plupart de ces molécules présentent une sélectivité insuffisante et sont dépourvues de propriétés physicochimiques adaptées à une utilisation in vivo. Ce travail de thèse est consacré à la synthèse d'inhibiteurs réversibles et sélectifs de la KLK7. A ce titre, deux séries de composés ont été explorées. La première est issue d'un criblage de molécules pyrido-imidazodiazépinones, qui a permis d'identifier un inhibiteur réversible et sélectif de la KLK7, le JMV4967 (IC50 = 57,0 µM). Ce composé se caractérise par la présence, en position 2 du cycle diazépinique, d'un noyau phényle substitué en ortho par un groupement méthyle. Sur la base de ces résultats, une étude de relations structure-activité (SAR), a été initiée. Les meilleures inhibitions ont été obtenues avec les analogues du JMV4967 possédant en position 2 du cycle diazépinique, un groupement 3,4,5-triméthoxyphényle ou 3,4-diméthoxyphényle. Cette étude a permis l'identification du composé JMV5046 (IC50 = 33,5 µM). Une étude biochimique du JMV5046, a mis en évidence son caractère réversible et compétitif vis-à-vis du substrat dans le site actif de la KLK7, comme le hit initial. La seconde série a été développée à partir d'une quinazoline substituée par un amino-benzimidazole, et une étude de RSA a également été menée. Finalement, une étude de réactivité chimique, a été également entreprise afin d'accéder à deux nouvelles séries de composés diazépiniques fusionnés avec l'imidazo[1,2-a]pyridine ou l'indole. Cette étude a montré que la 2-amino-imidazopyridine pouvait subir une alkylation en position 3 du cycle, dans le cadre de la réaction de nitro-Michael. Les produits d'addition de Michael ainsi formés peuvent ensuite conduire, après réduction du groupement nitro, aux dérivés diazépiniques correspondants. Par ailleurs, nous avons pu montrer que l'acylation du 2-amino-indole, en présence d'un donneur d'acyle de type ester activé d'acide aminé, conduisait aux dérivés N-acylés correspondants. Ces derniers ont été utilisés par la suite, pour la synthèse de dérivés indolodiazépiniques via la réaction de cyclisation de Pictet-Spengler. La synthèse de ces composés, l'étude de leur activité inhibitrice sur la KLK7 sont décrites. Les expériences de modélisation moléculaire par docking in silico, permettant de préciser les bases structurales de l'inhibition de la KLK7 par le JMV5046, sont également présentées
Human tissular kallikreins (KLKs) are members of (chymo)trypsin-like serine proteases, involved in various physiological pathways. Among the 15 known isoforms in the literature, kallikrein 7 (KLK7) plays a significant role in physiological and pathophysiological processes of the skin, like psoriasis and the Netherton syndrome. Several studies report also its implication in multiple processes leading to invasive and metastatic tumor growth, especially in prostatic, ovarian and pancreatic cancers. Strategies focused on KLK7 inhibition are a promising alternative for the treatment of such dermatological diseases, and to avoid metastatic dissemination. In the last two decades, many synthetic inhibitors of this KLK isoform have been developed. However, most of these molecules exhibit low selectivity and unsuitable physicochemical properties for in vivo use. This thesis is devoted to the synthesis of selective and reversible inhibitors of KLK7. Two series of compounds have been explored. The first one, derived from a screening of pyrido-imidazodiazepinones compounds, which led to the discovery of a reversible and selective inhibitor of KLK7, JMV4967 (IC50 = 57.0 µM). This compound is characterized by the presence of an ortho methyl substituted phenyl group, at position 2 of the diazepine ring. Based on these results, a structure-activity relationships (SAR) study was initiated. The best inhibitions were obtained with JMV4967analogs bearing a 3,4,5- trimethoxyphenyl group or 3,4- dimethoxyphenyl group, at position 2 of the diazepine ring. This study led to the discovery of one compound, JMV5046 (IC50 = 33.5 µM). A biochemical study of JMV5046, highlighted its reversible and competitive behavior against the substrate in the KLK7 active site, as previously observed for the initial hit. The second series was developed from an amino-benzimidazole substituted quinazoline, and a SAR study was also carried out. A chemical reactivity study was also initiated to access two new series of imidazo[1,2-a]pyridine-fused or indole-fused diazepine compounds. This study showed that 2-amino-imidazopyridine could undergo alkylation at position 3 of the ring, in the nitro-Michael reaction context. The obtained Michael adducts could then give, after reduction of the nitro group, the corresponding diazepine derivatives. We also showed that, in the presence of an acyl donor (as an activated amino acid ester), 2-amino-indole was N-acylated, unlike the 2-amino-imidazopyridine which leads to an exclusive C-acylation in the same conditions. The N-acylated derivatives were then used for the indolodiazepines synthesis, using Pictet-Spengler cyclization reaction.The synthesis of these compounds and their inhibiting activity against KLK7 are described. Molecular modeling experiments by in silico docking, to determine the structural requirements for KLK7 inhibition by JMV5046, are also presented

Made available in DSpace on 2015-04-14T13:32:55Z (GMT). No. of bitstreams: 1 436763.pdf: 467410 bytes, checksum: f234f7135286713fce26da90200be9a5 (MD5) Previous issue date: 2011-12-21
Objective : compare the therapeutic efficacy of intramuscular midazolam (IM-MDZ) and intravenous diazepam (IV-DZP) to 529treat seizures in children.Methods : Randomized controlled study enrolling children (2months-14years) presenting seizures admitted to the Pediatric Emergency Department of the Hospital Universit?rio de Santa Maria between August 2010-August 2011; being randomized to receive IV-DZP or IM-MDZ as initial treatment. The groups were compared regarding the length of time to start medication, to interrupt seizures after being medicated and the total length of time to achieve the seizures interruption.Results : Venous access was not obtained in 4 minutes in 4 patients (20%) assigned to the IV-DZP. 32 children completed the study (16 in each group). IV-DZP compared to the IM-MDZ, presented the longest interval to cease seizures (10.6 x 7.3min; p=0.006). Two children of each group (12.5%) the seizures did not stop after 10 minutes, being 3 children transferred to the PICU after tracheal intubation: 1 belonging to the IM-MDZ (6.25%0 and 2 in the IV-DZP group (12.5%). There were not differences regarding adverse effects between the groups (p=0.171): one child in the IM-MDZ presented hypotension (6.3%) and 5 (31%) presented hyperactivity or vomit after receiving IV-DZP.Conclusion : Intramuscular midazolam presented lower interval to cease seizures than IV diazepam. Intrauscular midazolam demonstrate be ans excellent o treat seizures in children as a result of its efficacy, facility and fast administration.
Objetivo : Comparar a efic?cia terap?utica da administra??o de Midazolam Intramuscular (MZ-IM) e do Diazepam Endovenoso (DZP-EV) em crian?as com crise convulsiva.M?todo : Estudo randomizado e controlado, envolvendo crian?as com crise convulsiva (2 meses a 14 anos) admitidas ao servi?o de Emerg?ncia do Hospital Universit?rio de Santa Maria no per?odo de agosto de 2010 a agosto 2011, sendo randomizadas a receber DZP-EV ou MZ-IM como tratamento inicial para convuls?es. Os grupos foram comparados em rela??o ao tempos necess?rio para iniciar a medica??o, para ceder a crise ap?s a administra??o do f?rmaco e o tempo total para ceder a crise.Resultados : N?o foi obtido acesso venoso aos 4 minutos em 4 pacientes (20%) assinalados ao grupo DZP-EV. Resultaram 32 crian?as que completaram o estudo (16 em cada grupo). O DZP-EV apresentou tempo total maior para ceder ? crise convulsiva quando comparado ao MZ-IM (10,6 x 7,3 min; p=0,006). Em 2 crian?as de cada grupo (12,5%) a crise n?o cedeu ap?s 10 minutos de tratamento, 3 crian?as foram transferidos para a UTI pedi?trica, ap?s serem intubadas: 1 (6,25%) do grupo MDZ-IM e 2 (12,5%) do DZP-EV. N?o houve diferen?a quanto a efeitos adversos entre os grupos (p=0,171): uma crian?a (6,3%) apresentou (hipotens?o) ap?s receber MDZ-IM e outras cinco crian?as (31%) apresentaram (hiperatividade ou vomito) ap?s receberem DZP-EV.Conclus?o : Midazolam intramuscular apresentou menor tempo total para ceder a crise convulsiva que o diazepam endovenoso. Midazolam intramuscular mostrou ser excelente op??o no tratamento de crises convulsivas na inf?ncia pela efic?cia, facilidade e rapidez de aplica??o.

博士
國立交通大學
應用化學系碩博士班
106
This dissertation describes the development of new synthetic organic transformations by using metal free catalyst and with metal catalyst. Transition metal free catalyst transformations such as Pictet-Spengler reaction and with transition metal-catalyst transformation such as [5+2] annulation are described in this dissertation. For sake of convenience and better understanding, the thesis is divided into four chapters. The first chapter deals with the synthesis of structurally diverse indole-fused diazocine and diazepine derivatives. A substrate-based diversification approach of methyl-3- aminoindole/ indoline benzoates coupled with the Pictet−Spengler reaction and three different reaction cascades furnished indolodiazepine and indoloquinoxalines. The formation of indolodiazocines proceeds through an initial condensation followed by intramolecular alkylation. In the second chapter describes an efficient and regioselective Pd(II)-catalyzed [5+2] annulation of unprotected o-indolo anilines with internal alkynes under microwave irradiation. The diverse imine-containing 1,2-fused indole [1,7-a] diazepines are constructed in moderate to excellent yields. The mechanistic pathway shows pivalic acid and molecular oxygen to play crucial roles for the regeneration of highly active electrophilic Pd-species in the catalytic cycle. The third chapter emphasized the efficient and regioselective synthesis of novel 1,2,3- triazole-fused-1,5-benzoxazocinones through intramolecular cyclization of substituted ethynyl triazoyl benzoic acids. A crucial precursor 5-iodo-1,2,3-triazole benzoate was obtained from substituted 2-azido benzoic acid esters in a single step through a Copper- Catalyzed Azide−Alkyne Cycloaddition (CuAAC) reaction using a CuI/NBS catalytic system. A carbon−carbon triple bond was installed through a Sonogashira coupling reaction by various terminal alkynes. Finally, the 1,4,5-substituted ethynyl triazoyl benzoic acids were cyclized by a AgOTf mediated intramolecular cyclization to afford 8-endo-dig 1,2,3-triazolefused- 1,5-benzoxazocinones exclusively. The fourth chapter deals with a facile and efficient synthesis of novel oxo, thio and selenohydantoin fused tetrahydroazepino [4, 5-b]indoles. Naturally occurring iboga class alkaloid inspired seven-member azepino[4,5-b]indole ring was synthesized as a new scaffold through Pictet-Spengler reaction followed by skeletal rearrangement of aziridine ring. To improve the efficiency of the synthetic route, the double bond of the rearranged olefinic product was reduced and privileged hydantoin moiety was constructed on the core system through urea formation using variety of isocyanates, isothiocyanates and isoselenocyanates followed by intramolecular cyclization to incorporate elements of diversity. The regeneration of the double bond afforded hydantoin-fused tetrahydroazepino [4, 5-b]indoles.

A previous study in chickens revealed that myosin light chain kinase (MLCK), f actin, and myosin are found on the crystalline lens. Their polygonal arrangement at the posterior surface resembles a muscle tissue, which suggests that these proteins may have a contractile role in accommodation. The ciliary muscle in chickens is skeletal in nature and, therefore, chickens were used to test the hypothesis that contractile microfilaments play a role in accommodation. Ciliary nerve-induced accommodation was measured in the presence of an MLCK inhibitor 1-(5-Iodonaphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazepine hydrochloride (ML-7). Eyes of 6-day old white Leghorn chickens (gallus gallus domesticus) were enucleated in Tyrode’s saline solution while keeping the ciliary nerve intact. One eye was treated with ML-7 and the other eye was treated with vehicle only. Three concentrations of ML-7 were used: 1 µM, 10 µM, and 100 µM. Two experiments were carried out, one including a (3×10 min) wash and one without. Focal lengths of the vehicle- and ML-7-treated eyes were measured before, during and after accommodation. Immunoblots were used to detect the amount of phosphorylated myosin with and without the inhibitor. Focal lengths for accommodation were shorter than those at rest (p<0.001). In the wash experiment, vehicle-treated eyes had higher accommodative amplitudes compared to ML-7-treated eyes for all three dosage groups. In the no-wash experiment, only the 1 µM group demonstrated the same trend as the wash experiment. For the 10 µM and 100 µM groups, ML-7-treated eyes had higher accommodative amplitudes compared to vehicle-treated eyes. Immunoblots revealed varying amounts of inhibition within pairs of eyes as well as between birds for both experiments. Results from this experiment indicate that ML-7 was not effective at determining whether contractile microfilaments found on the lens contribute to accommodation.

Bei der Suche nach den Ursachen und der Natur von „Aromatizität“ erwiesen sich zahlreiche nicht-benzoide, carbocyclisch und heterocyclisch konjugierte pi-Elektronensysteme als wertvolle Prüfsteine für quantenchemische Berechnungen. Im Zusammenhang damit war ein Ziel dieser Arbeit, einen Syntheseweg für die bislang unbekannten 4,5-Diazaazulene und 5,6-Diazaazulene zu entwickeln. Durch Reaktionen von semicyclischen 1,5-Diketonen mit verschiedenen Hydrazinen gelang die Darstellung von teilgesättigten literaturunbekannten Cyclopenta[c]1,2-diazepinen, Cyclopenta[d]1,2-diazepinen, Tetraaza[14]annulenen, [1]Pyrindinen und propanoverbrückten alpha-Carbolinen. Verschiedene Methoden zur Dehydrierung der Cyclopenta-1,2-diazepine wurden angewendet, doch führten alle Versuche nicht zu den erwarteten Diazaazulen. Andererseits wäre eine direkte Synthese durch [6+4]-Cycloaddition von 1,2,4,5-Tetrazinen mit Fulvenen denkbar. Doch führten alle Umsetzungen von 2-Cyclopentadienyliden-1,3-dioxolan mit verschieden 1,2,4,5-Tetrazinen unter [4+2]-Cycloaddition zu den entsprechenden Cyclopenta[d]pyridazinen. Neben den schon erwähnten alpha-Carbolinen konnten erstmals auch tricyclische Cyclopenta[d]1,2-diazepine dargestellt werden. Dies ist insbesondere für die Suche nach neuen Leitstrukturen bei der Entwicklung von pharmakologischen Wirkstoffen von Interesse. Alle in der Literatur bisher nicht bekannten Verbindungen wurden mit Hilfe der Massenspektrometrie, Infrarot- und NMR-Spektroskopie sowie Elementaranalysen vollständig charakterisiert. Die Bestimmung der räumlichen Struktur dieser Verbindungen stützt sich dabei im Wesentlichen auf die Ergebnisse zweidimensionaler korrelierter NMR-Experimente und in einigen Fällen auch auf Röntgenstrukturanalysen.

碩士
國立交通大學
應用化學系碩博士班
107
The first part: Compounds containing heteroatoms are the most prominent entities in commercially available drugs that are sold in large quantities.Among all heteroatom molecules, benzimidazole,benzoselenazole, guanidine and pyrrole are considered to be the privileged core of drug and drug discovery.In particular, these biologically important heterocyclic fused/linked heterocyclic molecules are considered to be well known scaffolds in medical and drug discovery research. Therefore, the synthesis of fused and linked heterocyclic molecules must be taken care of this paper deals with the design and synthesis of biologically interesting fused and linked heterocycles.A catalyst-controlled chemical reaction cyclization strategy was reported to obtain diazepam [1,7-a] fluorene and hydrazine from the reaction of the readily available ortho-anisidine and diazonium ester as coupling partners.And [1,2-a] quinoxaline.Under Rh(III) catalyst, the reaction is carried out by amine-assisted C2-H activation followed by amidation to obtain diazepam [1,7-a]pyrene in a highly selective manner.Under the Ru(II) catalyst, the reaction involves the formation of a Ru-carbene complex, followed by a metal-olefin reaction and a β-hydrogen removal reaction, and finally the insertion of the -NH2 group and the cascade cyclization to obtain a ruthenium. Indole [1,2-a] quinoxaline.This newly developed catalyst control strategy is broadly applicable to the construction of a series of very high yields of ruthenium diazide/quinoxaline and pyrrole fused diazapest/quinoxaline scaffolds.We believe this approach opens up new avenues in the fields of catalysis and organic synthesis. The second part: We have successfully developed a regioselective method for the synthesis of isoquinoline [1,2-a]isoquinolines.First of all, the tetrahydroisoquinoline skeleton is synthesized by a Pictet-Spengler reaction, and then reacted with allyl bromide to carry out cyclization and rearrangement of a six-membered ring in the presence of a monovalent gold catalyst.The process of this cascade involves a metal catalyzed cyclization reaction and a process in which the allyl group migrates from the nitrogen atom to ethylene. The third part: In order to obtain the biologically active 2-thiohydantoin ring (B), we perform the Pictet-Spengler reaction by radical to form a tetrahydroisoquinoline skeleton compound having antibacterial and antitumor activity, and then it will react with isothiocyanate, a biologically active heterocyclic small molecule structure is obtained.

博士
中國醫藥大學
藥物化學研究所博士班
97
Part I. As part of our continuing investigation of azo-flavonoid derivatives as potential anticancer drug candidates, a series of 2-aryl-6,7-methylenedioxyquinolin-4-one analogs was designed and synthesized. The design combined structural features of 2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one (CHM-2133), a previously discovered compound with potent in vivo antitumor activity, and 2-arylquinolin-4-ones identified by CoMFA models. The newly synthesized analogs were evaluated for cytotoxicity against several human cancer cell lines, and structure-activity relationship (SAR) correlations were established. Analogs 1, 37, and 39 showed potent cytotoxicity against different cancer cell lines. Compound 1 demonstrated selective cytotoxicity against Hep 3B (hepatoma) cells. Compound 37 was cytotoxic against HL-60 (leukemia), HCT-116 (colon cancer), Hep 3B (hepatoma), and SK-MEL-5 (melanoma) cells. Compound 39 exhibited broad cytotoxicity against all seven cancer cell lines, with IC50 values between 0.07−0.19 μM. Results from mechanism of action studies revealed that these new quinolone derivatives function as anti-tubulin agents. Continuing with the screening result, CWC-8 (compound 39) was chosen to detect the mechanism of anticancer activity in the experiment. We have defined the viability inhibition and apoptotic mechanisms of CWC-8 on human osteogenic sarcoma U-2 OS cells. According to the MTT assay, the cell viability was inhibited by CWC-8 in a dose- and time-dependent manner, with an IC50 of 4.97±0.24 μM. CWC-8 treatment induced G2/M arrest and apoptosis in U-2 OS cells by cell cycle and flow cytometry analysis. Western blotting and CDK1 kinase assay showed that CWC-8 treatment caused a time-dependent increase of Cyclin B and CDK1 protein levels and activity during G2/M arrest. CWC-8 treatment also caused a time-dependent increase in Fas/CD95, FADD, cytosolic cytochrome c, caspase-8/-9/-3 active form, Apaf-1, AIF, Bax protein levels, and decrease in Bcl-2 protein level. CWC-8 also promoted caspase-8/-9 and -3 activities; however, pretreatment of cells with pan-caspase, caspase-8/-9 and -3 inhibitors led to reduced cell growth inhibition action. Taken together, these findings show CWC-8 could be a potential candidate for cancer therapy. Part II. The intrinsic mobility of proteins has often been ignored in drug design field. Conformational induction is the energy balance process in which ligand converts protein into a conformation that would not spontaneously adopt in its unligated state. This flexible property of protein limits the development of rational drug design model nowadays. Therefore, we proposed a concept that describes raise of ligand flexibility is the strategy to accommodate protein mobility. In this study, we synthesized a series of 4-phenyl-1H-benzo[b][1,4]diazepin-2(3H)-one derivatives which are more flexible than our previous antitumor compound− 2-phenyl-4-quinolones. Unexpectedly, the cytotoxicity screening result shows little activity of these derivatives. Only 7-4, 7-5, 7-9, 7-15, 7-16, 7-20 and 7-27 compounds exhibt the potency to inhibt HL-60 cell line. Despite the unideal outcome in anti-cancer test, we acquired the anti-inflammation activity of compound 7-4 via random screening insteadly. It inhibited fMLP-induced superoxide anion production through a PKA-dependent pathway and increased cAMP by activating protein phosphatase 2A, which subsequently inhibited phosphodiesterase 4.