雜環二萜之合成與活性評估

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Title:	雜環二萜之合成與活性評估 Synthesis and biological evaluation of heterocyclic diterpenoids
Authors:	黃柏華 HUANG, BO-HUA
Contributors:	藥學系碩士班林淑娟
Keywords:	雜環二萜;甜菊苷 stevioside;steviol;isosteviol
Date:	2021-01-20
Issue Date:	2021-03-10 11:00:51 (UTC+8)
Abstract:	甜菊苷(stevioside)為甜菊(Stevia rebaudiana (Bertoni) Bertoni)的四環二萜類配糖體成分，文獻指出stevioside具有降血糖、降血壓、抗發炎及抗癌等功效。stevioside利用酸水解可得到甜菊醇(steviol)及異甜菊醇(isosteviol)，而isosteviol經由Beckmann rearrangement可得到具有內醯胺(lactam)結構的4α-isocyanato-13α-amino-13,16-seco-ent-19-norbeyerane衍生物，三個四環二萜結構上的不同主要於D環。過去本實驗室曾以isosteviol及steviol為起始物，針對C-4的羧基(carboxylic group)進行修飾，個別得到異氰酸酯(isocyanate)的基團，經與一級胺化合物反應，得到具ureido結構的衍生物，經抗B型肝炎病毒的活性試驗顯示，兩系列有效化合物的作用機轉不同。為了尋找具新標的及作用機轉的抗B型肝炎病毒的化合物，以及探討不同D環的四環二萜結構與活性的關係，因此本研究利用isosteviol、steviol及isosteviol lactam三種結構進行修飾，得到其isocyanate的衍生物做為中間產物，接著與各種二級胺類化合物反應，得到醯胺(amide)衍生物，這些化合物皆經由核磁共振及高解析質譜鑑定其結構。初步抗B型肝炎病毒的活性試驗發現，這些化合物對抑制B型肝炎病毒複製的能力不甚理想。此外，這些化合物經由MTT assay進行初步MDA-MB-231及MCF-7乳癌細胞株的毒殺(cytotoxicity)試驗結果發現，化合物8、15和20於10 μM時，對於MCF-7細胞株反應與對照組有明顯差異，進一步試驗目前進行中。 Stevioside, a tetracyclic diterpenoid glycoside, which can be isolated in the leaves of Stevia rebaudiana (Bertoni) Bertoni. Stevioside possesses many biological activities, including anti-hyperglycemic, anti-hypertensive, anti-inflammatory and anti-tumor. Acid hydrolysis of stevioside can obtain ent-kaurene of steviol and ent-beyerane of isosteviol. Additionally, isosteviol can undergo the Beckmann rearrangement to produce the lactam derivative, 4α-isocyanato-13α-amino-13,16-seco-ent-19-norbeyerane. In our lab, we used isosteviol and steviol as starting materials to synthesize several C-4 ureido derivatives by transforming C-4 carboxylic group of isosteviol and steviol to isocyanate derivatives and then reacting with different primary amines to give C-4 ureido derivatives. The active compounds of two series of synthesized derivatives showed different action mechanisms. In order to investigative the relationship between anti-HBV activity and D ring of different tetracyclic diterpenoids, several derivatives are prepared by reacting isocyanate derivatives of isosteviol, steviol and isosteviol lactam with secondary amines to form amide derivatives. Structures of derivatives are determined by NMR and HRMS. The preliminary testing for anti-HBV activity of these derivatives are not active. Additionally, these synthesized compounds were also tested for cytotoxicity on MDA-MB-231 and MCF-7 breast cancer cell lines by MTT assay. The results show that compounds 8, 15 and 20 at 10 μM display significant differences in MCF-7 cell line by comparison with the control group. Further testing is still in progress.
Description:	碩士指導教授:林淑娟委員:許秀蘊委員:王莉萱
Data Type:	thesis
Appears in Collections:	[School of Pharmacy] Dissertation/Thesis

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