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Synthesis and Characterization of Antifungal Kinase Inhibitors and β-Lactam Antibiotics.
Synthesis and Characterization of Antifungal Kinase Inhibitors and β-Lactam Antibiotics.
상세정보
- 자료유형
- 학위논문(국외)
- 기본표목-개인명
- 표제와 책임표시사항
- Synthesis and Characterization of Antifungal Kinase Inhibitors and β-Lactam Antibiotics.
- 발행, 배포, 간사 사항
- 발행, 배포, 간사 사항
- 형태사항
- 220 p.
- 일반주기
- Source: Dissertations Abstracts International, Volume: 87-02, Section: B.
- 일반주기
- Advisor: Willson, Timothy M.
- 학위논문주기
- Thesis (Ph.D.)--The University of North Carolina at Chapel Hill, 2025.
- 요약 등 주기
- 요약With the most recent COVID-19 pandemic having a global impact on the population and healthcare system, there is a need to focus efforts on development of anti-infective agents. Antimicrobial resistance is increasing among bacteria and fungi, leading to a growing number of mortalities related to pathogen infection. Our work focused on developing newly characterized antifungal kinase inhibitors and modernizing the synthesis of penicillin.Kinase inhibitors have been extensively studied for use in humans but scarcely applied as anti-infective agents. The UNC-Structural Genomic Consortium previously discovered a kinase inhibitor from the Published Kinase Inhibitor Set that acts as an antifungal against pathogenic Candida albicans via inhibition of yeast casein kinase 2 (Yck2). We sought to characterize the C. albicans kinome via chemoproteomics to define the selectivity of current Yck2 inhibitors. Using multiplexed inhibitor beads (MIBS) alongside tandem mass spectrometry analysis, we successfully captured 89% of the fungal kinome and were able to profile the selectivity of lead antifungal kinase inhibitors YK and MN across the fungal and human kinome. Using our knowledge of human kinase inhibitors, we selected thirteen human casein kinase 1 (CK1) inhibitors from literature to repurpose for antifungal activity. Hit compound LY was determined via MIBS experiments and cell-based target engagement. Medicinal chemistry efforts were employed to improve LY's Yck2 potency and selectivity. Our results from cell-based assays and crystal structures establish early SAR en route to a potent, selective antifungal kinase inhibitor.Electrochemistry has garnered attention for its ability to implement "green chemistry" for performing chemoselective C-H functionalization that was previously unobtainable across many scaffolds. We sought to implement electrochemistry to access penicillin by means of modern chemistry for expeditious derivatization of the penam scaffold. Model molecules and penicillin intermediates showed the ability to undergo chemoselective Shono-oxidation in good yields. Attempts to perform intramolecular cyclization failed. Penicillin intermediates displayed an ability to undergo nucleophilic displacement of methoxy-thioaminals by carbon-based nucleophiles to afford interesting scaffolds. Shono-oxidation in HFIP was found to take place with isolatable intermediates, however current displacement conditions failed to work. These proof-of-concept experiments showed the ability to electrochemically oxidize thiazolines chemoselectively for different transformations.
- 주제명부출표목-일반주제명
- 주제명부출표목-일반주제명
- 주제명부출표목-일반주제명
- 주제명부출표목-일반주제명
- 비통제 색인어
- 비통제 색인어
- 비통제 색인어
- 비통제 색인어
- 비통제 색인어
- 비통제 색인어
- 부출표목-단체명
- 기본자료저록
- Dissertations Abstracts International. 87-02B.
- 전자적 위치 및 접속
- 원문정보보기
MARC
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■1001 ▼aShirley, David J.
■24510▼aSynthesis and Characterization of Antifungal Kinase Inhibitors and β-Lactam Antibiotics.
■260 ▼a[S.l.]▼bThe University of North Carolina at Chapel Hill. ▼c2025
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a220 p.
■500 ▼aSource: Dissertations Abstracts International, Volume: 87-02, Section: B.
■500 ▼aAdvisor: Willson, Timothy M.
■5021 ▼aThesis (Ph.D.)--The University of North Carolina at Chapel Hill, 2025.
■520 ▼aWith the most recent COVID-19 pandemic having a global impact on the population and healthcare system, there is a need to focus efforts on development of anti-infective agents. Antimicrobial resistance is increasing among bacteria and fungi, leading to a growing number of mortalities related to pathogen infection. Our work focused on developing newly characterized antifungal kinase inhibitors and modernizing the synthesis of penicillin.Kinase inhibitors have been extensively studied for use in humans but scarcely applied as anti-infective agents. The UNC-Structural Genomic Consortium previously discovered a kinase inhibitor from the Published Kinase Inhibitor Set that acts as an antifungal against pathogenic Candida albicans via inhibition of yeast casein kinase 2 (Yck2). We sought to characterize the C. albicans kinome via chemoproteomics to define the selectivity of current Yck2 inhibitors. Using multiplexed inhibitor beads (MIBS) alongside tandem mass spectrometry analysis, we successfully captured 89% of the fungal kinome and were able to profile the selectivity of lead antifungal kinase inhibitors YK and MN across the fungal and human kinome. Using our knowledge of human kinase inhibitors, we selected thirteen human casein kinase 1 (CK1) inhibitors from literature to repurpose for antifungal activity. Hit compound LY was determined via MIBS experiments and cell-based target engagement. Medicinal chemistry efforts were employed to improve LY's Yck2 potency and selectivity. Our results from cell-based assays and crystal structures establish early SAR en route to a potent, selective antifungal kinase inhibitor.Electrochemistry has garnered attention for its ability to implement "green chemistry" for performing chemoselective C-H functionalization that was previously unobtainable across many scaffolds. We sought to implement electrochemistry to access penicillin by means of modern chemistry for expeditious derivatization of the penam scaffold. Model molecules and penicillin intermediates showed the ability to undergo chemoselective Shono-oxidation in good yields. Attempts to perform intramolecular cyclization failed. Penicillin intermediates displayed an ability to undergo nucleophilic displacement of methoxy-thioaminals by carbon-based nucleophiles to afford interesting scaffolds. Shono-oxidation in HFIP was found to take place with isolatable intermediates, however current displacement conditions failed to work. These proof-of-concept experiments showed the ability to electrochemically oxidize thiazolines chemoselectively for different transformations.
■590 ▼aSchool code: 0153.
■650 4▼aPharmaceutical sciences.
■650 4▼aChemistry.
■650 4▼aMicrobiology.
■650 4▼aBiochemistry.
■653 ▼aAntifungals
■653 ▼aChemoproteomics
■653 ▼aKinase inhibitors
■653 ▼aMultiplexed inhibitor beads
■653 ▼aCandida albicans
■653 ▼aGreen chemistry
■690 ▼a0572
■690 ▼a0485
■690 ▼a0410
■690 ▼a0487
■71020▼aThe University of North Carolina at Chapel Hill▼bPharmaceutical Sciences.
■7730 ▼tDissertations Abstracts International▼g87-02B.
■790 ▼a0153
■791 ▼aPh.D.
■792 ▼a2025
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17357115▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
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