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「如何發展有效策略設計合成藥物」一直是科學家尋思的議題。除了沿循過去的結構藥物設計、結合AI的電腦輔助藥物設計,近年來也有人嘗試以動態組合式化學來設計抗菌藥物。然而要能以動態組合式化學的方法來篩選活性藥物,首要必須找到合適的動態共價系統。所謂「動態共價鍵」:就是一種可以溶劑、溫度、酸鹼等環境變因來調控其生成和斷裂的共價鍵,通常是一個可逆的平衡反應。香粧品系林雅凡副教授與她的研究團隊,包括香粧品學系碩士畢業生邱紀銘、醫化系大四生朱宏豐、香粧品學系105級大學部畢業生張佳汶、與香粧品研究所碩二生陳靚云成功合成新型含雜環縮胺化合物,並探討此系統的物理有機化學性質,以實驗輔助理論計算的方式,確認該系統具備動態共價性質。該縮胺系統能在不同溶劑環境下,以亞胺、縮胺或半縮胺醚的形式存在。舉例來說,含嘧啶雜環縮胺在二甲基亞碸溶劑中以縮胺的型態呈現,然而在乙腈溶劑下,卻有10%的縮胺轉變成亞胺。如果置放於醇類環境,則該縮胺會完全轉變成半縮胺醚。而這些隨著環境變化而產生形態的轉變是可逆的,也因此能透過溶劑來調控分子形態的變化,並透過這樣的調控來增加分子的多樣性。他們的團隊更進一步發現,該系統的動態化學性質取決於溶劑與分子之間的nàπ*作用力。由於雜環官能基往往具有藥物活性,因此他們的研究結果未來亦可能應用於藥物設計上,透過動態共價化學性質增加分子多樣性,用「以一變多」的策略增多候選藥物的可能性,期使找到更有效率的藥物發展方法。

可調控共價鏈的新創應用

本校主要研究者之簡介:

香粧品學系 林雅凡 副教授

台大化學系博士,專長領域為生物無機化學與計算化學。目前實驗室研究興趣為: 結合理論計算與動態共價化學設計有潛力的金屬藥物應用於抗菌劑、抗癌藥物、與環境醫學上。

研究聯繫Email:

yafan@kmu.edu.tw

期刊出處:

RSC Adv., 2020, 10, 40421

研究全文下載:

(原標題: Physical organic studies and dynamic covalent chemistry of picolyl heterocyclic amino aminals)

https://pubs.rsc.org/en/content/articlepdf/2020/ra/d0ra08527h

The theme how to develop effective strategy in designing new drugs is always a hot issue to scientists. Structure-based and computer-aided drug designs are the two conventional ways to discover new drugs. Recently, some research groups have tried to introduce the concept of dynamic combinatorial chemistry (DCL) for developing new antibacterial agents. The primary condition that implementing DCL method to screen drug candidates is to develop a system exhibiting proper dynamic covalent chemistry properties. Dynamic covalent bonds are the covalent bonds that can form or break reversibly. In addition, the formation and the breaking of the covalent bonds can be controlled by the environmental stimuli, such as solvents, temperatures, and acid-base conditions. Dr. Ya-Fan Lin, who is an associate professor in Department of Fragrance and Cosmetic Science, and her team members, including Mr. Ji-Ming Ciou, obtaining his Master degree from Department of Fragrance and Cosmetic Science in the spring of 2020, Mr. Hong-Feng Zhu, a senior student in Department of Medicinal and Applied Chemistry, Miss Chia-Wen Chang, completing her bachelor degree from Department of Fragrance and Cosmetic Science in 2020, and Miss Jing-Yun Chen, currently a second year master’s student in Department of Fragrance and Cosmetic Science, succeeded in the synthesis of a series of novel heterocyclic-based aminals. After investigating the physical organic properties combined with the theoretical calculation study, they confirmed this aminal system displays dynamic covalent properties. The aminals can give different responses and convert to different derivatives in accordance with different solvent environments. For example, the pyrimidyl-based aminal structure can be kept in DMSO, while 10% of them will be transformed to imine form in acetonitrile nitromethane or acetone. Moreover, all of aminals have become hemiaminal ethers if using alcohol as solvents. Noteworthily, the environmental dependent transformations are all reversible, and therefore the molecular species can be switched by solvents. As a result, the dynamic covalent system can generate molecular diversity through solvent effect. The Lin’s group further proved that the existence of the dynamic covalent behaviors in this system is correlated to the nàπ* interaction between the solvent molecule and the aminal. This system is expected to have drug activities since the molecule consists heterocyclic fragments. In the future, the system can be utilized in drug design. Through creating more diversity by dynamic covalent properties, the “from one to more” strategy can generate more candidates in one time and hopefully leads to the buildup of an efficient approach for drug development. 

可調控共價鏈的新創應用

Main researcher Intro.

Dr. Ya-Fan Lin, Associate Professor in Department of Fragrance and Cosmetic Science

Ya-Fan Lin obtained her PhD degree in Department of Chemistry, National Taiwan University. Her main research interests are in bioinorganic and computational chemistry. Her current research emphasizes a combination of computational and dynamic covelent chemistry strategies to design potential metallodrugs for application in antimicrobial, anticancer, and environmental medicine.

Author Email

yafan@kmu.edu.tw

Paper cited from:

RSC Adv., 2020, 10, 40421

Research Paper available online on website

(Title: Physical organic studies and dynamic covalent chemistry of picolyl heterocyclic amino aminals)

https://pubs.rsc.org/en/content/articlepdf/2020/ra/d0ra08527h

慢性B型與C型肝炎雙重感染病患接受口服抗病毒藥物成功治療C型肝炎後,可能引發B型肝炎嚴重發作及死亡

慢性B型與C型肝炎雙重感染常會加重C型肝炎之嚴重度並加速病程惡化。新型C型肝炎口服抗病毒藥物(DAA)上市後,可以有效清除95%以上之C型肝炎病毒,然而其對合併之B型肝炎感染之長期預後仍不得而知。高醫肝炎團隊針對台灣慢性B型與C型肝炎雙重感染病患接受C型肝炎口服抗病毒藥物治療後對B型肝炎相關預後及機轉進行研究,研究顯示有高達38%慢性B型與C型肝炎雙重感染病患接受DAA治療後,發生B型肝炎病毒發作,其中五分之一出現臨床肝炎發作,當中又有三分之一導致死亡。然而,也有10%病患在接受DAA治療後B型肝炎表面抗原消失,代表病患由B型肝炎帶原者轉變成非帶原者。我們進一步發現, 使用B型肝炎表面抗原濃度(HBsAg),以10 IU/ml分水嶺,可以成功預測病人未來會發生B型肝炎病毒發作(>10 IU/ml, (hazard ratio [HR] 2.88; 95% CI 1.057–7.844)或者是B型肝炎表面抗原消失(。這些發現顯示,治療前B型肝炎表面抗原濃度可以作為預測這類病患接受DAA治療是否能產生B型肝炎表面抗原消失及發生B型肝炎病毒發作的標記,近一步幫助指引臨床醫師治療此類病患前是否給予預防性B型肝炎抗病毒藥。我們的研究報告中另一重要發現是這些接受DAA治療後發生B型肝炎發作導致死亡的病患都是肝硬化同時沒有接受預防性抗B型肝炎藥物之病患,因此未來應考慮對肝硬化病患同時給予預防性B型肝炎抗病毒藥以減少風險。

除此之外,本研究也進行一系列細胞激素與微核醣核酸檢測來探討兩種病毒間免疫反應。 我們發現,治療前血清miR-122miR-125b濃度較低、或治療過程當中血清IP-10濃度沒有降低的病人,B型肝炎表面抗原消失的機會明顯較高;相對的,B型肝炎病毒發作的病人,其治療過程當中血清miR-122miR-125b濃度有持續降低的現象。

本研究結果可作為臨床醫師在診療此類病患之參考,幫助指引臨床醫師治療此類病患前是否給予預防性B型肝炎抗病毒藥以避免治療過程中可能發生的B型肝炎嚴重發作及死亡。同時減少無或微風險病患可能接受預防性B型肝炎抗病毒藥物之副作用風險與醫療花費。

01 余明隆 慢性B型與C型肝炎 CH 

本校主要研究者之簡介:

葉明倫副教授和余明隆講座教授為高雄醫學大學醫學院肝炎研究中心成員,也是高雄醫學大學附屬機構肝膽胰內科的主治醫師,致力於肝臟疾病之病因、致病機轉、治療及預防的研究及服務。

研究聯繫Email:

fish6069@gmail.com; fishya@ms14.hinet.net

期刊出處:

Yeh ML, Huang CF, Huang CI, Holmes JA, Hsieh MH, Tsai YS, Liang PC, Tsai PC, Hsieh MY, Lin ZY, Chen SC, Huang JF, Dai CY, Chuang WL, Chung RT, Yu ML*. Hepatitis B-related outcomes following direct-acting antiviral therapy in Taiwanese patients with chronic HBV/HCV co-infection. J Hepatol. 2020 Jul;73(1):62-71.

研究全文下載:

https://doi.org/10.1016/j.jhep.2020.01.027

Taiwanese patients with HBV and HCV co-infection are likely to experience HBV functional cure, but also HBV reactivation following direct-acting antiviral treatment for HCV

This study shows the outcomes after the direct acting antiviral (DAA) treatment in patients with chronic hepatitis B (HBV)/ hepatitis C (HCV) dual-infection, that including 10% of hepatitis B surface antigen (HBsAg) loss and 38% of HBV reactivation. Our findings published in the Journal of Hepatology provide new insights into understanding the viral interaction between HBV and HCV.

The research group led by Chair Professor Ming-Lung Yu from Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan, in collaboration with Professor Raymond T Chung from Massachusetts General Hospital, Boston; Department of Medicine, Harvard Medical School, reported a new insight into the viral interaction between HBV and HCV following DAA treatment and found it might be a blessing (HBsAg loss) in disguise (HBV reactivation) for patients. They also suggested the high risked cirrhotic patients to undergo HBV prophylaxis simultaneously.   

The new all-oral DAA regimens for HCV have greatly improved treatment efficacy with sustained virological response rates of > 95% for HCV monoinfected patients. Unfortunately, HBV reactivation and HBV-related clinical reactivation during or after DAA therapy were not infrequent, and might lead to mortality in HBV/HCV-coinfected patients, especially among those with cirrhosis.

This study enrolled 79 HBV/HCV-coinfected patients receiving DAA therapy to investigate their HBV-related outcomes. One exciting finding was that during one year post-DAA follow up, 8 (10.1%) patients experienced HBsAg loss (an ideal outcome of “HBV functional cure”) with a 12-month cumulative probability of 10.3%. Another new finding was the specific decline of HBsAg level during therapy, and rebound after stopping DAA.

Alternatively, up to 30 (38%) patients were found developing a HBV reactivation (means a rebound of HBV replication). Of them, 6 (20%) patients even experienced a HBV related clinical reactivation (means a clinical hepatitis) and 3 patients further developed hepatic failure with 2 died despite the immediate anti-HBV therapy. All these 2 patients had liver cirrhosis and were without an HBV prophylaxis before DAA. Thus prophylactic anti-HBV therapy is mandatory for cirrhotic patients, irrespective of baseline HBV DNA levels.

Pre-treatment HBsAg titer can be a surrogated marker to guide decision making. This study further found that using the pre-treatment HBsAg titer of less than 10 IU/mL could predict the higher chance of HBsAg loss and lower risk of HBV reactivation.

Researchers from Kaohsiung Medical University and Harvard Medical School also demonstrates a complex interaction among the host and the two viruses in determining HBV outcomes following the results from cytokines and micro RNAs experiments. 

Getting together, this study provides a new insight into the management of HBV/HCV-coinfected patients being treated with DAA.

 01 余明隆 慢性B型與C型肝炎 EN

Main researcher Intro.

Associate Professor Ming-Lun Yeh and Chair Professor Ming-Lung Yu are members of Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital and Hepatitis Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. They dedicate in the research and service of Liver diseases, including etiologies, epidemiology, pathogenesis, therapeutic modalities and prevention of hepatitis B, hepatitis C, steatohepatitis and liver cancers.

Author Email

fish6069@gmail.com; fishya@ms14.hinet.net

Paper cited from:

Yeh ML, Huang CF, Huang CI, Holmes JA, Hsieh MH, Tsai YS, Liang PC, Tsai PC, Hsieh MY, Lin ZY, Chen SC, Huang JF, Dai CY, Chuang WL, Chung RT, Yu ML*. Hepatitis B-related outcomes following direct-acting antiviral therapy in Taiwanese patients with chronic HBV/HCV co-infection. J Hepatol. 2020 Jul;73(1):62-71.

Research Paper available online on website

https://doi.org/10.1016/j.jhep.2020.01.027

阿茲海默症是目前最常見的失智症且是一種很複雜的中樞神經系統疾病,成因至今尚不明確。慢性神經發炎被認為是造成阿茲海默症的一項重要致病因子而人類白細胞抗原(HLA)基因則是與慢性神經發炎相關的重要基因。但目前對HLA基因型的深入研究仍然缺乏,可能的原因是HLA基因組區域中的高度多態性和複雜結構使得研究困難。以前,中樞神經系統被認為是一個可以豁免免疫影響的部位,但最新的研究顯示淋巴和膠淋巴系統能夠排出中樞神經系統衍生的抗原並引發相關的免疫反應。這些自體抗原可以排出到中樞神經系統外的淋巴結,並透過抗原呈現細胞呈現給T細胞。因此,HLA基因分型結合自體抗原呈現有潛力可以當作阿茲海默症的生物標記。然而,之前由於HLA區域中非常複雜的基因組變異,難以對HLA做非常精細的基因分型和研究以HLA基因分型為基礎的自體抗原呈現。現在我們已可以使用次世代定序儀(Next Generation Sequencing- NGS)來建立HLA精細的基因分型並利用全外顯子定序的技術來獲取以HLA基因分型為基礎的自體抗原呈現數據。我們的研究團隊利用以上的分析技術發現,阿茲海默症病人HLA自體抗原的呈現量,跟阿茲海默症發病的早晚顯著相關,早發型阿茲海默症的自體抗原呈現量明顯高於晚發型阿茲海默症。這樣的結果不但支持自體抗原的呈現在阿茲海默症等神經退化性疾病中有著重要角色這樣的假設,也證實了HLA自體抗原呈現量的確具有潛力作為阿茲海默症發病早晚的生物標記。我們的研究成果可替從事相關研究的學者提供研究阿茲海默症治療目標或致病機轉的參考,並有助於精準醫學的發展,對開發用於阿茲海默症風險篩檢,預防,預後評估之生物標記,以及免疫治療藥物的醫療相關技術有所貢獻。  

04 黃柏穎 Figure自體抗原在慢性神經退化中的角色    

A.  自體抗原經由抗原呈現細胞活化T細胞   

B.   具中樞神經系統抗原特異性的T細胞經由脈管系統進入大腦

C.    T細胞引發免疫神經發炎反應造成神經元受損


本校主要研究者之簡介:

黃柏穎主治醫師/助理教授

研究聯繫Email:u99802003@gmail.com

期刊出處: Transl Psychiatry. 2020;10(1):146.

研究全文下載: https://www.nature.com/articles/s41398-020-0826-6

Alzheimer's disease is the most common dementia and a very complicated central nervous system (CNS) disease. The etiology is still unclear. Chronic neuroinflammation is considered to be an important pathogenic factor for Alzheimer's disease, and human leukocyte antigen (HLA) genes are important genes associated with chronic neuroinflammation. However, there is still a lack of advanced research on HLA genotypes. The possible reason is that the high polymorphism and complex structure in the HLA genome region make research difficult. Previously, the central nervous system was considered to be a site that can be exempted from immune influence, but the latest research shows that the lymphatic and glial lymphatic system can excrete central nervous system-derived antigens and trigger related immune responses. These self-antigens can be excreted to lymph nodes outside the central nervous system and presented to T cells through antigen presenting cells. Therefore, HLA genotyping combined with self-antigen load has the potential to be used as a biomarker for Alzheimer's disease. Previously, due to the very complex genomic variation in the HLA region, it was difficult to perform very precise genotyping of HLA and study the presentation of self-antigens based on HLA genotyping. Now we can use Next Generation Sequencing (NGS) with whole exome sequencing technique to establish HLA fine genotyping and obtain self-antigen load data. We used the above techniques and found that self-antigen load is associated with the onset of Alzheimer's disease and self-antigen load of early-onset Alzheimer's disease is significantly higher than that of late-onset Alzheimer's disease. Such results not only support the hypothesis that the presentation of self-antigen plays an important role in Alzheimer’s disease, but also confirm that the presentation of self-antigen does have the potential as a biomarker for the onset of Alzheimer’s disease. Our results can also provide useful information regarding target therapy or pathogenic mechanisms research of Alzheimer’s disease, and contribute to the development of precision medicine.

04 黃柏穎 Figure Figure Eng

The role of self-antigens in chronic neurodegeneration

A.   Self-antigens activated T-cells through antigen-presenting cells

B.   CNS-antigen-specific T-cells enter the brain through the vasculature system

C.  T-cells induce neuroinflammation which further damages the neuron


Main researcher Intro.

Poyin Huang

Neurologist /Assistant Professor

 

Author Email

u99802003@gmail.com

Paper cited from:

Transl Psychiatry. 2020;10(1):146.

Research Paper available online on website

https://www.nature.com/articles/s41398-020-0826-6

啶為重要的雜環芳香族化合物,具有多種生物活性,例如抗瘧疾,抗癌和抗白血病,因此,許多研究人員正在努力為啶衍生物尋找新的合成途徑。在此研究中,高雄醫學大學的研究人員開發了以酸促進分子內脫酮基偶合反應來合成啶。

  以往脫酮基反應需在鹼性金屬錯合物、或酶、過氧化物和碘等條件下進行。這些方法大部分都是條件嚴苛或無選擇性,為了改善這個缺點,王志鉦教授團隊發現在無金屬條件下以酸促進酮分子內脫羰反應合成啶衍生物。

  這個方法條件溫和,對環境友善,不需過渡金屬催化,並可以使用易取得且低成本的酸在反應中取代貴金屬。重要的是,透過甲氧基苯丙胺氯化鈀來證實一氧化碳氣體的產生。此外,這個合成方法也可應用到簡單的芳香族內炔以產生二芳香基酮。

本篇為高雄醫學大學20203月份傑出論文得獎文章,代表作者為高雄醫學大學醫藥暨應用化學系教授王志鉦博士

這項研究於2020219日發表在《有機化學通訊》上,名為吖啶衍生物的新合成方法的研究通訊,可在以下網站在線獲取:https://pubs.acs.org/doi/pdf/10.1021/acs.orglett.0c00304  題為“吖啶衍生物的新合成方法”主要作者Ganesh Kumar Dhandabani,通訊作者包括王志鉦博士(高雄醫學大學醫藥暨應用化學系教授)。王志鉦 吖啶衍生物的新合成方法 CH

媒體聯繫人:

高雄醫學大學醫藥暨應用化學系教授王志鉦博士

電話:+ 886-7-3121101(轉2275),電子郵件:jjwang@kmu.edu.tw

高雄醫學大學醫藥暨應用化學系博士後研究員 Ganesh Kumar Dhandabani

電話:+886-7-3121101(轉2275),電子郵件:ganechem@gmail.com

In this study, the researcher at Kaohsiung Medical University developed synthesis of acridines and diaryl ketones under acid promoted intramolecular decarbonylative coupling of unstrained ketone. Acridines are an important class of heteroaromatic compounds that have versatile biological properties, such as antimalarial, anticancer and antileukaemia. Therefore, several researchers are pursuing efforts to create new synthetic routes for acridine derivatives.  

     The success of intermolecular decarbonylation reactions of aldehyde, thioesters, amides, and anhydrides, intramolecular carbonyl group cleavage of ketone molecules remains challenging. This difficulty is likely due to the substantially inert nature of the C(Aryl)C(O) bond and its hindered structure, making these motifs unsusceptible to the installation of a directing group. To develop a sustainable CC bond activation method, basic metal complexes, enzymes, peroxides, and iodine source have been recently employed. The reported methods don’t have selective cleavage/activation of carbon bonds that accompanies transition metal-free CC bond activation, especially for unstrained CC bond cleavage. To overcome this drawback, in this study, the scientist Prof. Jeh-Jeng Wang and co-workers found that metal free acid promoted intramolecular decarbonylative of unstrained ketones for the synthesis of acridine derivatives.

    The developed protocol is mild condition, environmentally friendly, transition-metal and directing group free, and can replace benchmark expensive noble metals in unstrained CC bond activation reactions using abundant and low-cost acids. Importantly the liberation of CO gas confirmed by performing experiment with PMA-PdCl2.

This study was published online in Organic Letters on 19th February 2020 as a research communication entitled “Acid-Promoted Intramolecular Decarbonylative Coupling Reactions of Unstrained Ketones: A Modular Approach to Synthesis of Acridines and Diaryl Ketones” and is available online at https://pubs.acs.org/doi/pdf/10.1021/acs.orglett.0c00304.

The lead author of entitled “Acid-Promoted Intramolecular Decarbonylative Coupling Reactions of Unstrained Ketones: A Modular Approach to Synthesis of Acridines and Diaryl Ketones” Ganesh Kumar Dhandabani, Chia-Ling Shih, and corresponding author include Dr. Jeh-Jeng Wang (Professor, Kaohsiung Medical University, Department of Medicinal and Applied Chemistry). This article is award for Kaohsiung Medical University 2020 Monthly Excellent Paper Award in March.

王志鉦 吖啶衍生物的新合成方法 EN

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Dr. Jeh-Jeng Wang, Research fellow, Kaohsiung Medical University, Department of Medicinal and Applied Chemistry Tel: +886-7-3121101(Ext: 2275), E-mail: jjwang@kmu.edu.tw

Dr. Ganesh Kumar Dhandabani, Postdoctoral fellow, Kaohsiung Medical University, Department of Medicinal and Applied Chemistry Tel: +886-7-3121101(Ext: 2275), E-mail: ganechem@gmail.com

Chia-Ling Shih, Undergraduate student, Kaohsiung Medical University, Department of Medicinal and Applied Chemistry Tel: +886-7-3121101(Ext: 2275), E-mail: ymtc9801@gmail.com

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