使用水作為良性反應介質的銅催化合成4-喹諾酮類的合成
在最近的研究中，高雄醫學大學開發了三組分合成且對環境無害的銅催化方法，對於取代的4-喹諾酮衍生物製備效果很好。研究人員開發了一系列4-喹諾酮類藥物的合成方法，並且成功應用於歐索林酸 (Oxolinic acid)殺菌劑與BQCA藥物的合成。由於以往的合成方法有些缺點，限制了它們的適用性，王志鉦教授的團隊發表以三組分:氨水、3-（2-鹵代苯基）-3-氧代丙烷、醛類在銅催化下，一步合成4-喹諾酮衍生物。這各方法具有應用價值且對環境無害。研究人員也進行了克級反應和藥物合成應用，證明了該方法的實用性。此外，其它取代基例如-CN，-NO2，-SO2Ar，-COAr和雜環化合物與甲醛的反應也可順利進行反應，其廣泛性也獲得證實。
本篇為高雄醫學大學2019年月傑出論文7月份得獎文章，代表作者為醫藥暨應用化學系王志鉦教授。這項工作的主要作者為Babasaheb Sopan Gore (博士生)，李建中 (碩士生)，李芷怡(大學生)與通訊為作者王志鉦（高雄醫學大學醫藥暨應用化學系教授）。
這項工作於2019年4月1日發表在《高級合成與催化》上(Adv. Syn. & Cat. 2019, 361, p3373-3386)。文章的全名是“使用水作為良性反應介質的銅催化合成4-喹諾酮類的合成,可在以下網站在線獲取https://onlinelibrary.wiley.com/doi/epdf/10.1002/adsc.201900286.
聯絡信息：
台灣高雄市三民區十全一路100號
高雄醫學大學醫藥暨應用化學系王志鉦教授
電話：（886）-7-3121101 傳真：（886）-7-3125339，
電子郵件：jjwang@kmu.edu.tw
高雄醫科大學博士後研究員Babasaheb Sopan Gore博士
電話：（886）- 68930195，電子郵件：gorepranav99@gmail.com
Application for the Construction of Oxolinic Acid and BQCA
A copper-catalyzed three-component environmentally benign synthetic method has been developed for the synthesis of substituted 4-quinolone derivatives. In recent study, the researchers at Kaohsiung Medical University have developed a series of 4-quinolones. This method has been successfully applied for the synthesis of available oxolinic acid and BQCA drugs. Traditional synthetic methods limited their applicability due to the requirement of crucial starting precursors, harsh reaction conditions, side product formation and utilization of organic solvents. Thus, considering this facts, the scientist Jeh-Jeng Wang and his colleagues reported water mediated three-component green and sustainable protocol from substituted 3‐(2‐halophenyl)‐3‐oxopropanes, aq. NH3, and aldehydes for the synthesis of valuable N-heterocyclic compounds. In addition, the researchers also demonstrated the synthetic practicality and synthetic application of this strategy; a gram scale reaction and late stage modification of designed product performed. The researchers utilized aq. ammonia as a N1 synthon for the construction of 4-quinolones. Moreover, the researchers extended this reaction with formaldehyde, and other functionalities such as -CN, -NO2, -SO2Ar, -COAr and heterocyclic compounds.
Scheme: Synthesis of 4-Quinolone analogues.
This work was published online in Advanced Synthesis & Catalysis the 1st April 2019. The full name of article entitled “Copper‐Catalyzed Synthesis of Substituted 4‐Quinolones using Water as a Benign Reaction Media: Application for the Construction of Oxolinic Acid and BQCA” is available online through the Adv. Synth. Catal. at: https://onlinelibrary.wiley.com/doi/epdf/10.1002/adsc.201900286.
The lead author of this work “Copper‐Catalyzed Synthesis of Substituted 4‐Quinolones using Water as a Benign Reaction Media: Application for the Construction of Oxolinic Acid and BQCA” are Dr. Babasaheb Sopan Gore, Chein-Chung Lee, Jessica Lee and corresponding author include Jeh-Jeng Wang. ( Professor, Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Taiwan)
This article-“Copper-Catalyzed Synthesis of Substituted 4-Quinolones using Water as a Benign Reaction Media: Application for the Construction of Oxolinic Acid and BQCA” , written by Rept. Author Jeh-Jeng Wang fom Department of Medicinal and Applied Chemistry, is award for Kaohsiung Medical University 2019 Monthly Excellent Paper Award in July.
The contact Information:
Prof. Dr. Jeh-Jeng Wang, Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, No. 100, Shih-Chuan 1st Rd, Sanmin district, Kaohsiung City, 807 (Taiwan), Tel: (886)-7-3121101 Fax: (886)-7-3125339, E-mail: jjwang@kmu.edu.tw
Dr. Babasaheb Sopan Gore, Postdoctoral Fellow, Kaohsiung Medical University,
Tel: (886)-9-68930195, E-mail: gorepranav99@gmail.com
降血糖藥「鈉-葡萄糖共同輸送器-2抑制劑」減輕高血壓心衰竭鼠之心肌內纖維化並改善心臟生理功能
鈉-葡萄糖共同輸送器-2抑制劑為新一代降血糖藥，作用機轉為抑制腎臟對葡萄糖的吸收，在臨床使用的觀察研究發現，亦可減少心血管死亡率和住院率，且此藥對心臟的保護作用，似乎與血糖獨立無相關，然而詳細機轉未明。
本研究利用具有高血壓的大鼠，餵食32週的高脂飼料後，發展出心室肥大、纖維化與心臟衰竭，為動物實驗模式。隨機分類，施予鈉-葡萄糖共同輸送器-2抑制劑 empagliflozin 藥物，為期共12週。實驗終止結束前，以心電圖、心臟超音波、與心室內心導管檢查，將心臟功能行全盤地評估。結果發現，empagliflozin改善心臟擴大與心臟收縮功能。血液分析發現，empagliflozin組之腎功能有顯著改善，對血糖值卻無顯著影響。高血壓與高脂食物造成之心臟組織中的纖維化程度與膠原蛋白增生，包括心房和心室組織裡，在empagliflozin組都有顯著改善。而分子層面的分析，則發現高血壓心衰竭鼠之心房與心室內具有PPARα、ACADM、natriuretic peptides （NPPA 與 NPPB)、TNF‐α等的上升調控，在empagliflozin組都有顯著改善。
簡言之，empagliflozin在高血壓心衰竭鼠的心房和心室組織中，改善心衰竭相關的分子訊號，減輕心臟組織內纖維化，而顯著改善心臟生理功能。這個研究對於我們進一步了解「鈉-葡萄糖共同輸送器-2抑制劑在改善心衰竭」的機轉上，有重要的幫助，過去醫學認知，心臟組織的纖維化為心肌受損、例如心肌梗塞後或老化過程所發生，一般相信纖維化大多為不可逆，此研究發現，心肌內的纖維化可以改善，而我們所發現的幾個相關分子訊號調控，將能衍伸出更多深入的分子機轉探討，對將來心受損後纖維化相關的心衰竭的治療標的，亦具有重要啟示性的貢獻。
圖說：左上，高血壓心衰竭鼠之動物實驗模式與鈉-葡萄糖共同輸送器-2抑制劑 empagliflozin 治療組之實驗設計；empagliflozin藥物治療效果部分以下說明：左下，心臟超音波檢查顯示左心房擴大的減輕與左心室收縮功能的增進；右上，心導管檢查顯示心臟生理功能改善；右下，組織切片染色顯示心房與心室心肌內纖維化的減輕。
本篇為高雄醫學大學2019年月傑出論文4月份得獎文章，代表作者為高雄醫學大學附設醫院心臟內科李香君主治醫師。
本校主要研究者之簡介:
李香君主治醫師/副教授
高雄醫學大學醫學院國際組組長；高雄醫學大學附設醫院心臟內科主治醫師；高雄醫學大學醫學系內科副教授；中山大學醫學科技研究所合聘副教授；美國心臟病協會國際會士
研究聯繫Email:
hclee@kmu.edu.tw
期刊出處:
Lee et al. Cardiovasc Diabetol (2019) April; 18:45
期刊線上參閱網址:
The sodium–glucose co-transporter 2 inhibitor empagliflozin attenuates cardiac fibrosis and improves ventricular hemodynamics in hypertensive heart failure rats
Sodium glucose co-transporter 2 inhibitor (SGLT2i) is a new class of anti-diabetic drugs, and it acts on inhibiting glucose resorption by kidneys. Empagliflozin, one of SGLT2i in clinical use, has been shown beneficial in reduction of heart failure hospitalization and cardiovascular mortality. The heart protection effect seems independent from the blood glucose control. The protection mechanisms from SGLT2i to the heart remain unclear.
This study used a hypertensive heart failure animal model that was created by feeding spontaneous hypertensive rats (SHR) with high fat diet for 32 weeks. The elevated blood pressure and lipotoxicity caused atrial dilatation, left ventricular hypertrophy, intra-cardiac fibrosis and impairment of heart function. Half SHRs were randomized to be administered with SGLT2i, empagliflozin at 20 mg/kg/day for 12 weeks. Before the end of experiments, evaluation of electrocardiography and echocardiography, and invasive hemodynamic study were performed and followed by blood and tissue samples collection. The results showing benefits from empagliflozin in this hypertensive heart failure model are as following: (1) improved cardiac remodeling (improvement in atrial size and ventricular hypertrophy) ; (2) renal function improvement, while plasma glucose level unaffected; (3) normalization of both end-systolic and end-diastolic volume in SHR, in parallel with echocardiographic parameters improvement; (4) normalization of systolic dysfunction; (5) empagliflozin significantly attenuated cardiac fibrosis in both atrial and ventricular tissues; and (6) upregulation of atrial and ventricular expression of PPARα, ACADM, natriuretic peptides (NPPA and NPPB), and TNF-α in SHR, was all recovered by treatment of empagliflozin.
In short, empagliflozin improved atrial and ventricular remodeling, signaling pathways in heart failure, attenuated intra-cardiac fibrosis, improved hemodynamics in our hypertensive heart failure rat model. Our results contribute further understanding of the pleiotropic effects of empagliflozin regarding heart protection. The improvement of intra-cardiac fibrosis and the discovered modulated signaling pathway by empagliflozin will inspire more molecular biological studies, in order to find out more therapeutic targets for heart failure that is related to cardiac fibrosis.
Figure caption. Left upper. The experimental design for testing effects of empagliflozin on hypertensive heart failure model. The therapeutic effects are summarized as following: Left lower. Improvement of atrial and ventricular remodeling, and ventricular systolic function shown in echocardiography; Right upper. Improvement of cardiac hemodynamics in the empagliflozin group; Right lower: attenuation of intra-cardiac fibrosis in atrial and ventricular tissue histology.
Main researcher Intro.
Researcher:
Hsiang-Chun Lee, MD, MSc, PhD, FAHA
Director of Global Affairs, College of Medicine, Kaohsiung Medical University;
Cardiologist, Kaohsiung Medical University Hospital;
Associate Professor, Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University
Author Email
Paper cited from:
Lee et al. Cardiovasc Diabetol (2019) April; 18:45
Paper online website
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找到子宮內膜異位症早期發展的關鍵細胞激素–IL-10的雙重角色
[簡介]
子宮內膜異位症是惱人的婦科疾病，生育年齡的婦女約有6–10%的人患有此病，主要症狀是經痛、性交疼痛與不孕，治療後又很容易復發，是很不容易治癒的婦科疾病◦
[迷路的內膜組織]
這種百年無法解決的婦女疾病，成因到底為何呢?目前最被接受的說法是「經血逆流」理論，婦女每月剝落的子宮內膜組織，有部分可能會逆流回腹腔，此時體內免疫系統的白血球細胞會吞噬清除這些異位組織，這個清除過程會發生短暫且微弱的發炎反應，若這發炎反應能夠調控得當的話，就能順利清除逆流組織而又不產生副作用(強烈發炎)，這樣這些異位組織就不會累積、黏附、與生長於腹腔中，變成子宮內膜異位的良性腫瘤，每個月報到的「好朋友」也就不會造成女性的生理與心理負擔。
[失調的發炎反應]
那什麼原因會使清除異位組織的發炎反應失調呢?高醫大孫昭玲副教授研究團隊發現「抗發炎因子IL-10」的濃度過高，可能是重要的原因之一；IL-10是各種發炎反應都會伴隨產生的細胞激素(蛋白質)，當腹腔中的白血球在清除迷路的內膜組織時，也會產生適量的IL-10，功能是讓發炎不至於太強烈而傷害自己組織，但是如果IL-10量太高，反而會抑制白血球的吞噬功能而阻礙異位組織的清除，而高醫研究團隊利用小鼠模式與斑馬魚模式，發現IL-10居然還能促進血管的新生成，新生血管會讓幸運躲過攻擊的內膜組織生長於腹腔中，四處流竄與沾黏，最終變成子宮內膜異位瘤，成為婦女生活中的夢靨◦
[IL-10的雙重角色]
異位內膜組織中IL-10量太高，不僅阻礙了異位細胞清除，又促進血管新生成支持異位組織生長，那甚麼白血球會產生IL-10呢? 高醫研究團隊利用小鼠動物模式發現可能類漿性樹突細胞(plasmacytoid dendritic cell)在早期子宮內膜異位瘤生長時，就會產生IL-10支持子宮內膜異位瘤的生長與血管新生，而且在病人第四期子宮內膜異位瘤的病理組織中，也確實發現分泌IL-10的類漿性樹突細胞的蹤跡。
[結語]
我們正進行深入研究釐清類漿性樹突細胞在這疾病早期發展時的角色，還有哪些環境汙染物會影響免疫細胞產生IL-10的能力，希望將來能針對這複雜疾病提供預防與新的治療方法。
圖形摘要
圖說：月經週期時部分子宮內膜組織會逆流回腹腔，內膜組織內的免疫細胞–類漿性樹突細胞(pDC)可能在清除異位細胞時產生IL-10，若IL-10產量太高，會促進子宮內膜細胞遷移與血管新生，這可能奠定了早期異位瘤的發展，異位瘤長大後就有多種免疫細胞也會產生IL-10，而過多的IL-10使得疾病惡化快速，進入後期的發展，病人多在此時出現症狀並就醫治療。(本圖修改自Suen et al. J Pathol. 2019 Dec;249(4):485-497.)
本校主要研究者之簡介:
1. 高醫大醫研所孫昭玲副教授為本研究第一作者，研究領域為先天免疫細胞在過敏性氣喘的調控角色，近年也探究慢性發炎促進子宮內膜異位瘤癌化的免疫機制◦
2. 高醫大醫研所蔡英美教授為本研究責任作者，不只為高醫婦產科主治醫師，專長生殖醫學，也長期從事內膜異位症機制研究。
3. 高醫大生化學科侯自銓教授為本研究共同責任作者，專攻泌尿腫瘤與血管新生機制研究。
研究聯繫Email：jlsuen@kmu.edu.tw
期刊出處: J Pathol. 2019 Dec;249(4):485-497. doi: 10.1002/path.5339.
Popular Science Format in Academic and Research Column
[Introduction]
Endometriosis is a chronic inflammation-associated and common benign gynecological disorder. It affects 6–10% of women of reproductive age with syndromes, including dysmenorrhea, dyspareunia, and infertility. Because endometriosis recurrence following conservative surgery is relatively high, it substantially affects patients’ daily activities.
[Lost way of endometrial tissue]
What is the pathogenesis of endometriosis? The wildly accepted hypothesis nowadays is the “retrograde menstruation/transplantation theory. The endometrial tissue shed during the menstrual cycle flow from the uterus into the peritoneal cavity. The retrograded cells or tissue are cleared by white blood cells. During this process, it would locally happen mild and transient inflammation in peritoneal cavity. If the process between clearance and inflammation keeps balance, the ectopic endometrial tissue can be effectively cleared and the inflammation would not damage the tissue in peritoneal cavity. Therefore, the lost-way endometrial tissue would not become endometriotic tumor and disturb daily activity in women of reproductive age.
[Dysregulated inflammation]
What might disturb the balance between clearance and inflammation when retrograde tissue loses its way into peritoneal cavity? The research team led by Dr. Jau-Ling Suen at Kaohsiung Medical University discovered that the high local activity of anti-inflammatory cytokine IL-10 may promote the growth of the endometriotic tissue. It has been demonstrated that IL-10 can control unwanted inflammation to avoid tissue damage; however, high activity or level of IL-10 may inhibit the functions of white blood cells and diminish the clearance of ectopic tissue. In addition, Dr. Suen and her colleges discovered that IL-10 can promote angiogenesis through IL-10R signaling in vitro and in vivo, including a murine model as well as a zebra fish model. Thus, the IL-10-mediated angiogenesis may promote the growth of endometriotic lesions through enhancing angiogenesis during the early stage of endometriosis.
[The dual activity of IL-10]
These findings discovered by Dr. Suen’s team suggest that the dual functions of IL-10 with respect to suppressing immunity against unwanted cells and promoting angiogenesis in the microenvironment may substantially contribute to the development of endometriosis. The next question is which immune cell type can secrete IL-10 in the microenvironment, particularly during the early stage of disease? Using a surgery-induced endometriosis murine model, Dr. Suen’s team demonstrated that local plasmacytoid dendritic cell (pDC), a key innate cell type in viral immunity, can secrete IL-10 to enhance angiogenesis in and promote growth of endometriotic lesions. In addition, IL-10–secreting pDCs have been found in the human endometrioma tissues, in which higher percentages of cells express IL-10 receptor and angiogenic marker CD31 compared with the corresponding normal counterparts.
[Conclusion]
We continue to put effort in elucidating the pathogenic role of IL-10–secreting pDCs and developing strategy targeting the IL-10–IL-10 receptor pathway in the endometriotic milieu.
Graphical Abstract
Figure. The cartoon shows the effect and immune cell sources of IL-10 during the early and late stages of endometriosis. During the menstrual cycle and the early stage of endometriosis, retrograded endometrial cells or tissue enter peritoneal cavity. Lesion plasmacytoid dendritic cells (pDCs) may produce IL-10 in response to unwanted cells. Local IL-10 further promotes lesion growth by either suppressing anti-ectopic fragment immunity or stimulating angiogenesis. During the late stage of disease, the complex interaction among genetic factors, endogenous hormones, environmental endocrine disruptors (EEDs), and impaired immune surveillance leads to chronic inflammation. In the context of chronic inflammation in the peritoneal cavity, other immune cells can secrete IL-10 and other mediators to further promote the growth and maintenance of ectopic implants. [The figure is cited from Suen et al. 2019. (J Pathol. 2019 Dec;249(4):485-497)]
Main researcher Intro.
1. Dr. Jau-Ling Suen, the first author, at Kaohsiung Medical University study the role of innate immune cells in the pathogenesis of allergic asthma and endometriosis.
2. Dr. Eing-Mei Tsai, the corresponding author, a gynecologist and reproductive endocrinologist, at Kaohsiung Medical University Hospital. She has devoted in the mechanistic study in endometriosis.
3. Dr. Tzyh-Chyuan Hour, the equally contributed corresponding author, at Kaohsiung Medical University focus on the mechanistic study in prostate cancer and angiogenesis.
Author Email
Paper cited from: J Pathol. 2019 Dec;249(4):485-497. doi: 10.1002/path.5339.
Paper online website: https://pubmed.ncbi.nlm.nih.gov/31418859/
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