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dc.contributor.author李洙瑨-
dc.creator李洙瑨-
dc.date.accessioned2016-08-25T04:08:11Z-
dc.date.available2016-08-25T04:08:11Z-
dc.date.issued1996-
dc.identifier.otherOAK-000000022050-
dc.identifier.urihttp://dspace.ewha.ac.kr/handle/2015.oak/180125-
dc.identifier.urihttp://dcollection.ewha.ac.kr/jsp/common/DcLoOrgPer.jsp?sItemId=000000022050-
dc.description.abstractβ-Lactamase는 β-lactam계 항생제를 불활성화 시키며, 현재 가장 널리 쓰이고 있는 β-lactam계 항생제에 대한 균주 내성의 주 원인이 된다. β-Lactam계 항생제와 함께 사용하여 항생제를 보호할 목적으로 β-lactamase의 mechanism-based-inhibitors로서 6번위치에 다양한 tricycle을 가진 치환기를 도입한 1,1-dioxo-6-(substituted)penicillanic acids를 합성하였다. 즉, β-lactamase와 친화력을 가지면서 β-lactamase의 70번 serine-OH와 acyl-enzyme intermediate를 형성한 후 안정화되어 β-lactamase를 불활성화 시킬 수 있도록 3-thiazolo[3,2,a]benzimidazolyl, 6-methyl-3-thiazolo[3,2,a]-benzimidazolyl, 2-fluorenyl, 9-ethyl-3-carbazolyl, 9-anthracenyl, 10-methyl-9-anthracenyl, 10-chloro-9-anthracenyl, phenanthrenyl기를 도입한 1,1-dioxo-6-bromo-6-(tricyclic)hydroxymethyl penicillanic acids, 1,1-dioxo-6-bromo-6-(tricyclic)acetoxymethyl penicillanic acids, 1,1-dioxo-6-(tricyclic)methylene penicillanic acids 등을 합성하고 이들의 4가지 type의 β-lactamase에 대한 저해 효과와 항생제와 병용시 여러 균주에 대한 상승 효과를 알아보았다. 합성한 화합물들은 tazobactam이나 sulbactam, clavulanic acid와 마찬가지로 모두 assay에 사용할 type Ⅰ enzyme에 대해서는 효과가 없었지만 type Ⅲ와 type Ⅳ enzyme에 대해서는 상당히 효과가 있는 화합물도 있었다. 1,1-Dioxo-6-(tricyclic)methylene penicillanic acids는 type Ⅱ, type Ⅳ enzyme에 대해 비교적 특이적인 저해 효과를 보였는데, 이는 methylene기가 효소의 active site 내의 nucleophile의 공격을 받아 acyl-enzyme intermediate를 안정화 시키기 때문인 것으로 추정하였다. 1,1-Dioxo-6-bromo-6-(tricyclic)hydroxymethyl penicillanic acids는 type Ⅲ, type Ⅳ enzyme에 대해 상당히 좋은 저해 효과를 보였는데, 이는 6-bromo기가 떨어져나가면서 acyl-enzyme intermediate를 안정화 시키고 hydroxymethyl기가 효소와의 친화력을 크게하기 때문인 것으로 추정하였다. 특히 1,1-dioxo-6-(2-fluorenyl) methylene penicillanic acid의 경우 type Ⅱ, type Ⅲ, type Ⅳ enzyme에 대해 모두 양호한 효과가 있었으며 1,1-dioxo-6-bromo-6-(2-fluorenyl)hydroxymethyl penicillanic acid나 1,1-dioxo-6-bromo-6-(2-fluorenyl)acetoxymethyl penicillanic acid의 경우 type Ⅲ, type Ⅳ enzyme에 대해 tazobactam보다 상당히 좋은 효과가 있었는데 이는 fluorenyl기의 크기나 모양 전자밀도 등이 효소와의 친화력을 증가시키는데 적당하였기 때문인 것으로 추정하였다.;The increasing threat of conventional chemotherapy has posed by bacteria which had developed resistance to β-lactam antibiotics via β-lactamase. β-Lactamase inhibitors which have no antibacterial activity can be administered in conjunction with conventional β-lactam antibiotics to protect β-lactam antibiotics from β-lactamase. In our studies, we synthesized three classes of β-lactamase inhibiors ; 1,1-dioxo-6-(tricyclic)methylene penicillanic acid, 1,1-dioxo-6-bromo-6-(tricyclic)hydroxymethyl penicillanic acid and 1,1-dioxo-6-bromo-6-(tricyclic)acetnxymethyl penicillanic acid with variety of tricyclic substituents and tested β-lactamase inhibitory activity against four types of β-lactamase and synergistic effect with piperacillin against β-lactam antibiotics resistant bacteria. 1,1-Dioxo-6-(tricyclic)methylene penicillanic acid showed specific inhibitory activity against typeⅡ or type Ⅳ enzymes, we believe that acylation of an active site serine by the β-lactam followed by a nucleophilic attack on the methylene C(8) position of the β-lactam by another active site residue. 1,1-Dioxo-6-bromo-6-(tricyclic)hydroxymethyl penicillanic acid and 1,1-dioxo-6-bromo-6-(tricyclic)acetoxymethyl penicillanic acid showed good inhibitory activity against type Ⅲ and type Ⅳ enzymes. we believe that 6-bromo substituent stabilized acyl-enzyme intermediate by acting as a leaving group and hydroxymethyl substituent increased enzyme affinity. In particular, compound 29, 32, which have fluorenyl moiety showed most notable improvement in inhibitory activity against type Ⅲ and type Ⅳ β- lactamases compared to tazobactam and clavulanic acid. We believe that fluorenyl moiety must participate in some favorable interaction within the active site hydrophobic pocket of the β-lactamase.-
dc.description.tableofcontents목차 = Ⅰ 논문개요 = Ⅸ Ⅰ. 서론 = 1 Ⅱ. 실험재료 및 방법 = 14 1. 실험재료 = 14 1) 시약 = 14 2) 기기 = 14 2. 합성방법 = 15 1) 3-Formylthiazolo[3,2,a]benzimidazole의 합성 = 15 ① 3-Chloromethylthiazolo[3,2,a]benzimidazole의 합성 = 15 ② 3-Cholromethy-6-methylthiazolo[3,2,a]benzimidazole의 합성 = 15 ③ Sommlet reaction에 의한 3-formylthiazolo[3,2,a]benzimidazole(화합물 1)의 합성 = 15 ④ 치환반응에 의한 3-hydroxymethylthiazolo[3,2,a]benzimidazole의 합성 = 16 ⑤ 치환반응에 의한 3-hydroxymethy-6-methylthiazolo[3,2,a]benzimidazole의 합성 = 16 ⑥ PCC를 사용한 산화에 의한 3-forrnythiazolo[3,2,a]benzimidazole(화합물 1)의 합성 = 17 ⑦ 3-formyl-6-methylthiazolo[3,,2,a]benzimidazole(화합물 2)의 합성 = 17 ⑧ MnO_(2)를 사용한 산화에 의한 3-formylthiazolo[3,2,a]benzimidazole(화합물 1)의 합성 = 17 2) 1,1-Dioxo-6-(substituted)penicillanic acid의 합성 = 17 a. Methyl Grignard reaction에 의한 1,1-dioxo-6-bromo-6-(tricyclic)hydroxymethyl penicillanic acid esters의 합성 = 17 ① p-Methoxybenzyl 1,1-dioxo-6-bromo-6-(3-thiazolo[3,2,a]benzimidazolyl)-hydroxymethyl penicillanate(화합물 3)의 합성 = 17 ② p-Methoxybenzyl 1,1-dioxo-6-bromo-6-(6-methyl-3-thiazolo[3,2,a]-benzimidazolyl)hydroxymethyl penicillanate(화합물 4)의 합성 = 18 ③ p-Methoxybenzyl 1,1-dioxo-6-bromo-6-(2-fluorenyl) hydroxymethyl penicillanate(화합물 5)의 합성 = 19 ④ Diphenylmethyl 1,1-dioxo-6-bromo-6-(9-ethyl-3-carbazolyl)hydroxymethyl penicillanate(화합물 6)의 합성 = 19 ⑤ Diphenylmethyl 1,1-dioxo-6-bromo-6-(anthracen-9-yl)hydroxymethyl penicillanate(화합물 7)의 합성 = 19 ⑥ Diphenylmethyl 1,1-dioxo-6-bromo-6-(10-methylanthracen-9-yl)hydroxymethyl penicillanate(화합물 8)의 합성 = 20 ⑦ Diphenylmethyl 1,1-dioxo-6-bromo-6-(10-chloroanthracen-9-yl)hydroxymethyl penicillanate(화합물 9)의 합성 = 20 ⑧ p-Methoxybenzyl 1,1-dioxo-6-bromo-6-(phenanthren-9-yl)hydroxymethyl penicillanate(화합물 10)의 합성 = 20 b. Acetylation에 의한 1,1-dioxo-6-bromo-6-(tricyclic)acetoxymethyl penicillanic acid esters의 합성 = 20 ① p-Methoxybenzyl 1,1-dioxo-6-bromo-6-(3-thiazolo[3,2,a]benzinddazolyl)-acetoxymethyl penicillanate(화합물 11)의 합성 = 20 ② p-Methoxybenzyl 1,1-dioxo-6-bromo-6-(6-methyl-3-thiazolo[3,2,a]benzimidazolyl)-acetoxymethyl penicillanate(화합물 12)의 합성 = 21 ③ p-Methoxybenzyl 1,1-dioxo-6-bromo-6-(2-fluorenyl) acetoxymethyl penicillanate(화합물 13)의 합성 = 21 ④ Diphenylmethyl 1,1-dioxo-6-(9-ethyl-3-carbazolyl)acetoxymethyl penicillanate(화합물 14)의 합성 = 22 ⑤ Diphenylmethyl 1,1-dioxo-6-(anthracen-9-yl)acetaxymethyl penicillanate(화합물 15)의 합성 = 22 ⑥ Diphenylmethyl 1,1-dioxo-6-bromo-6-(10-methylanthracen-9-yl)-acetoxymethyl penicillanate(화합물 16)의 합성 = 23 ⑦ Diphenylmethyl 1,1-dioxo-6-bromo-6-(10-chloroanthracen-9-yl)acetoxymethyl penicillanate(화합물 17)의 합성 = 23 ⑧ p-Methoxybenzyl 1,1-dioxo-6-bromo-6-(phenanthren-9-yl) acetoxymethyl penicillauate(화합물 18)의 합성 = 23 c. Elimination에 의한 1,1-dioxo-6-(tricyclic)methylene penicillanic acid 의 합성 = 23 ① p-Methoxybenzyl 1,1-dioxo-6-(3-thiazolo-[3,2,a]benzimidazolyl) methylene penicillanate(화합물 19)의 합성 = 23 ② p-Methoxybenzyl 1,1-dioxo-6-(6-methyl-3-thiazolo-[3,2,a]benzimidazolyl)methylene penicillanate(화합물 20)의 합성 = 24 ③ p-Methoxybenzyl 1,1-dioxo-6-(2-fluorenyl)methylene penicillanate(화합물 21)의 합성 = 24 ④ Diphenylmethyl 1,1-dioxo-6-(9-ethyl-3-carbazolyl)methylene penicillanate(화합물 22)의 합성 = 25 ⑤ Diphenylmethyl 1,1-dioxo-6-(anthracen-9-yl)methylene penicillanate(화합물 23)의 합성 = 25 ⑥ Diphenylmethyl 1,1-dioxo-6-(10-methylanthracen-9-yl)methylene penicillanate(화합물 24)의 합성 = 25 ⑦ Diphenylmethyl 1,1-dioxo-6-(10-chloroanthracen-9-yl)methylene penicillanate(화합물 25)의 합성 = 26 ⑧ p-Methoxybenzyl 1,1-dioxo-6-(phenanthren-9-yl)methylene penicillanate(화합물 26)의 합성 = 26 d. m-Cresol을 이용한 deprotection에 의한 1,1-dioxo-6-(substituted)penicillanic acid의 합성 = 27 ① 1,1-dioxo-6-bromo-6-(3-thiazolo[3,2,a]benzimidazolyl)hydroxymethyl penicillanic acid(화합물 27)의 합성 = 27 ② 1,1-dioxo-6-bromo-6-(6-methyl-3-thiazolo[3,2,a]benzimidazolyl)-hydroxymethyl penicillanic acid(화합물 28)의 합성 = 27 ③ 1,1-Dioxo-6-bromo-6-(2-fluorenyl)hydroxymethyl penicillanic acid(화합물 29)의 합성 = 27 ④ 1,1-Dioxo-6-bromo-6-(9-ethyl-3-carbazolyl)hydroxymethyl penicillanic acid(화합물 30) 합성 = 28 ⑤ 1,1-Dioxo-6-bromo-6-(phenanthren-9-yl)hydroxymethyl penicillanic acid(화합물 31)의 합성 = 28 ⑥ 1,1-Dioxo-6-bromo-6-(2-fluorenyl) acetoxymethyl penicillanic acid(화합물 32)의 합성 = 28 ⑦ 1,1-Dioxo-6-bromo-6-(9-ethyl-3-carbazolyl)acetoxymethyl penicillanic acid(화합물 33)의 합성 = 28 ⑧ 1,1-Dioxo-6-bromo-6-(phenanthren-9-yl)aceoxymethyl penicillanic acid(화합물 34)의 합성 = 28 ⑨ 1,1-Dioxo-6-(2-fluorenyl)methylen penicillanic acid(화합물 37)의 합성 = 28 ⑩ 1,1-Dioxo-6-(9-ethyl-3-carbazolyl)methylene penicillanic acid(화합물 38)의 합성 = 29 ⑪ 1,1-Dioxo-6-(anthacen-9-yl)methylene penicillanic acid(화합물 39)의합성 = 29 ⑫ 1,1-Dioxo-6-(10-methylanthracen-9-yl)methylen penicillanic acid(화합물 40)의 합성 = 29 ⑬ 1,1-Dioxo-6-(10-chloroanthracen-9-yl)methylen penicillanic acid(화합물 41)의 합성 = 29 ⑭ 1,1-Dioxo-6-(phenanthren-9-yl) methylen penicillanic acid(화합물 42)의 합성 = 29 e. AlCl_(3)를 사용한 deprotection에 의한 sodium 1,1-dioxo-6-(substituted)penicillanate(화합물 35)의 합성 = 29 ① Sodium 1,1-dioxo-6-(3-thiazolo[3,2,a]benzimidazolyl)methylene penicillanate(화합물 35)의 합성 = 29 ② Sodium 1,1-dioxo-6-(6-methyl-3-thiazolo[3,2,a] benzimidazolyl)methylene penicillanate(화합물 36)의 합성 = 30 3. β-Lactamase 저해 효과 검색 = 31 1) In vitro β-lactamase inhibition assay = 31 2) In vitro antimicrobial susceptibility test = 31 Ⅲ. 결과 및 고찰 = 32 1. 합성에 관한 결과 및 고찰 = 32 2. β-Lactamase 저해 효과에 관한 결과 및 고찰 = 43 Ⅳ. 결론 = 51 참고문헌 = 52 ABSTRACT = 57-
dc.formatapplication/pdf-
dc.format.extent2871508 bytes-
dc.languagekor-
dc.publisher이화여자대학교 대학원-
dc.subjectDioxo-
dc.subjectsubstituted-
dc.subjectpenicillanic-
dc.subjectacids-
dc.subject합성-
dc.subjectβ-lactamase저해-
dc.title1,1-Dioxo-6-(substituted)penicillanic acids의 합성 및 β-lactamase저해 효과에 관한 연구-
dc.typeMaster's Thesis-
dc.format.pagex, 57p.-
dc.identifier.thesisdegreeMaster-
dc.identifier.major대학원 약학과-
dc.date.awarded1996. 8-
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