초록 ▼

6-Aminopenicilanic acid를 출발물질로 하여 bromination, debromination, sulfoxidation, cyclization, Swern oxidation 등의 여러 단계를 거쳐서 주요 중간 물질인 2β-formyl penam을 합성한 다음 이 aldehyde에 여러종류의 치환기 및 이중결합을 가진 wittig reagentdhk 반응시켜 이중결합을 도입하여 2β-conjugated alkenyl penam sulfone 유도체를 약 30종 합성하였다.
Quinone 계열 물질은 항진균, 항

6-Aminopenicilanic acid를 출발물질로 하여 bromination, debromination, sulfoxidation, cyclization, Swern oxidation 등의 여러 단계를 거쳐서 주요 중간 물질인 2β-formyl penam을 합성한 다음 이 aldehyde에 여러종류의 치환기 및 이중결합을 가진 wittig reagentdhk 반응시켜 이중결합을 도입하여 2β-conjugated alkenyl penam sulfone 유도체를 약 30종 합성하였다.
Quinone 계열 물질은 항진균, 항균, 항암, 항말라리아 작용등 다양한 약리작용을 가지고 있다. Quinone 유도체 중 우수한 항진균 작용과 암세포주에 대한 세포 독성이 우수하다고 알려진 5,8-quinolinedione 모핵의 biosostere인 5,8-quinazoline-dione 유도체를 합성하여 항진균 작용을 검색하였다. 5,8-Dimethoxyquinazoline(3)을 60% 이상의 높은 수율로 합성하여 AlCl₃로 산화하여 5,8-dihydroxyquinazoline (5)과 5,8-quinazolinedione(6)을 얻은 후 다양한 arylamino-5,8-quinazolinedione(8) 유도체를 합성하였다. 또한 5,8-dimethoxyquinazoline을 HCl과 HNO₃로 직접 산화하여 6,7-dichloro-5,8-quinazolinedione을 합성한후 동일한 방법으로 arylamine과 반응시켜 6-arylamino-7-chloro-5,8-quinazolinedione (8) 유도체를 합성하였다. 위에서 얻은 유도체들의 항진균 작용을 알아보기 위하여 병원성 진균의 대표적인 지표가 되는 Candida albicans, C. krusei, C. tropicalis와 Aspergillus niger에 대해 시험하였다.
당의 2번위치가 불소로 치환된 4'-thionucleosides를 합성하기 위해 먼저 중요중간체인 4-thiosugar acetate를 합성하고 이 acetate를 여러 pyrimidine 및 purine염기와 축합하여 목적하는 최종물질을 합성하였다. 구체적인 실험방법을 보면 D-xylose로부터 시작하여 환개열반응 및 폐환반응을 거쳐 중간체인 L-4'-thioarabitol을 합성한 후 여기에 DAST반응을 시켜 불소를 도입한 acetate를 합성하였다. 이때 불소반응시 4-thiosugar의 유황원자가 참여하여 4원환이 생성되거나 치환체가 재배열되는 현상을 발견하였다. 이 4-thiosugar acetate를 uracil, thymine, 5-fluorouracil, 5-iodouracil과 축합하여 α체와 β체의 6-chlropurine유도체를 합성하였고 이 유도체들은 각각 adenine과 N-methyladenine유도체로 전환되었다. 합성된 최종 물질들은 HIV, HBV, HSV, HCMV 등 각종 바이러스에 대해 활성이 검색되었다.

Abstract ▼

As a search for new broad-spectrum β-lactamase inhibitors, 2β-conjugated alkenyl penam sulfones which had no heteroatom functional group on side chain at 2-position were prepared and their β-lactamase inhibitory activities were evaluated in vitro. Most of conjugated alkenyl compounds synthesized sho

As a search for new broad-spectrum β-lactamase inhibitors, 2β-conjugated alkenyl penam sulfones which had no heteroatom functional group on side chain at 2-position were prepared and their β-lactamase inhibitory activities were evaluated in vitro. Most of conjugated alkenyl compounds synthesized showed inhibitory activity against type IV and only 4f against TEM b-lactamase. For type III b-lactamase, 4-alkyl(4e, 4f, 4g, 4h, 4i, 4j) showed differenr activity depending the type of alkyl group (methl=dimethylHowever only one isomer was active in inhibitory effects against type IV or TEM β-lactamase. Most of synthestized compounds showed good synergistic effect in vitro in combination with ceftriaxone against clinically important E. coli strains. The most active compound of the series, 4f showed good synergic effect against E. coli ML 1410 RGN14 (type Ia, TEM1) and RGN 823 (type Ib, TEM2). Compouds with 30methyl (4k, 41) showed good activity against S. marcescens, P. vulgaris and E. coli. But the potency was similar to that could be obtained with tazobactam. A little difference in antagonistic effects between E and Z isomers was observed. In conclusion some 2β-conjugated alkenyl penam sulfones without polar functional group have β-lactamase inhibitory properties. Optimization of 3-methyl-conjugatedalkenyl penam sulfones could lead to potent β-lactamase inhibitors.
6-Arylamino-7-chloro-5,8-quinazolinediones were prepared by substitution of 6,7-dichloro-5,8-quinazolinedione with arylamines in ethanol. These derivaties were evaluated for antifungal activities in vitro MIC test using the two fold agar streak dilution method against Candida albicans, C. tropicalis, C. krusei and Aspergillus niger. 6-Arylamino-7-chloro-5,8-quinazolinediones and 6-arylamino-5,8-quinazolinediones showed more potent antifungal activities than reference compound, fluconazole, QZ1, 2, 3 and 4 showed very potent antifungal activities.
For the development of new antiviral agents, L-2'-Deoxy-2'-fluoro-arabinofuranosyl-4'-thiopyrimidine and purine nucleosides have been synthesized from the condesatin of 2-deoxy-2-fluoro-4-thiosugar acetate with silylated pyrimidines (uracil, thymine, cytosine, 5-iodouracil, and 6-chloropurine) followed by deprotection of the protecting groups, 5-Iodouracil derivative was converted to the 5-iodocytosine derivative. 6-Choropurineanalogue was converted to the adenine and N-methyladenine derivatives by treating with methanoic ammonia and N-methylamine in methanol, respectively. The synthesized final nucleosides were evaluated for antiviral activities against HIV-1, HSV-1, HBV, and HCMV, among which thymine derivative was found to be active against HSV-1 and HSV-2 and adenie derivative exhibited significant anti-HCMV activity.

목차 Contents

• 제 1 장 서론...9
• 제 2 장 국내외 기술개발 현황...10
• 제 3 장 연구개발수행 내용 및 결과...15
• 제 4 장 연구개발목표 달성도 및 대외기여도...34
• 제 5 장 연구개발결과의 활용계획...35
• 제 6 장 참고문헌...36