医学精品课件（71）

Natural Products Chemistry (“Organic“ substances were believed to be obtainable only from organs of living systems and could not be man-made because only living systems have the vital (“life“) force. “Inorganic“ materials were from non living, e.g. mineral, sources.) oIn the 1800s, organic chemistry was exclusively the study of natural products. Introduction to Natural Products Chemistry oExtract the dried and ground plant material with a suitable solvent. oConcentrate the extract. oSeparate and purify each component. oSince the concentrate contains an enormous variety of compounds, early isolations involved selective crystallization of the most dominant component in the mixture. Liquid natural products were distilled. Natural organic acids were isolated by aqueous basic extraction and natural organic bases (alkaloids) were isolated by aqueous acidic extraction. Introduction to Natural Products Chemistry oModern chromatographic methods have been greatly developed to isolate and purify a large number of different compounds in very small quantities: column, GC, TLC, HPLC, paper, electrophoresis, ion exchange, etc. oNatural products are usually given names that are derived from the species name of the plant or animal, or from the biological action, or property, of the compound. Introduction to Natural Products Chemistry oIn the late 1800s, natural products were identified and analyzed by mp, bp, a (optical rotation), hoping to find correlations between data and structure. This initiative was not successful in predicting structure, but useful data on natural products were obtained. Introduction to Natural Products Chemistry oClassical structural elucidation is done by: n Determination of functional groups n Determination of the carbon skeleton and the location of the functional groups n Degradation to smaller fragments (A-B-C - A + B + C) n Elemental analysis n Reactivity (leading to new reactions) n Stereochemistry n Synthesis of the smaller fragments (A, B, C) and the entire molecule (A-B-C) n Classification of the compound into a biogenetic family of compounds Introduction to Natural Products Chemistry o More modern structural elucidation and characterization by spectroscopy: n 1930s UV (ultraviolet) light (cf. Woodwards Rules, 1941) n 1940s IR (infrared) spectroscopy (note: penicillin structure problem in W.W.II) n 1950s NMR (nuclear magnetic resonance) spectroscopy n 1960s MS (mass spectrometry) n ESR (electron spin resonance) spectroscopy oand by other methods: n ORD (optical rotatory dispersion) n CD (circular dichroism) n acidity and basicity measurements (pK) n advanced synthetic and biosynthetic technology n X-ray crystallography Introduction to Natural Products Chemistry oModern methods reduces the necessity of chemical degradation methods, so much less material is required. oWhy synthesize natural products? nStructure determination nChallenge oDevelop new synthetic methods oPractical and commercial interests Introduction to Natural Products Chemistry General isolation strategy of natural products: Topical anti-inflammatory activity of Salvia officinalis L. leaves o Plant material o Extraction of plant material o Fractionation of the chloroform extract o High performance thin-layer chromatography (HPTLC) o High performance liquid chromatography (HPLC)-UV-Mass spectrometry (MS) o Topical anti-inflammatory activity Journal of Ethnopharmacology 75 (2001) 125132 Topical anti-inflammatory activity of Salvia officinalis L leaves the relevance of ursolic acid SOLVENT-SOLVENT EXTRACTION oSolvent-solvent extraction is a technique used to separate components of a mixture that have very different solubilities in each of two solvents which are immiscible. oOne solvent is usually water, the other a volatile organic solvent of low or moderate polarity (e.g., ethyl acetate or diethyl ether). oThe efficiency of the separation (partitioning) depends on the relative solubilities of the components to be separated in the two immiscible solvents. ANALGESICS IN GOODYS POWDERS 500 mg/powder 325 mg/powder Strength Headache Powder ACIDBASE EXTRACTION OF ASPIRIN AND ACETAMINOPHEN SEPARATORY FUNNEL TECHNIQUE oAdd the two solvents and the substance to be extracted. Do not fill the separatory funnel more than 3/4 full so as to allow room for agitation. oStopper the funnel. SEPARATORY FUNNEL TECHNIQUE oCradle the funnel with your fingertips of one hand and invert the funnel gently, then open the stopcock to release the pressure. (Make sure the tip is pointed into the hood before you vent.) oClose the stopcock, rock the funnel gently a few times, invert it and vent the pressure as before. oAgitate more vigorously, venting the pressure several times. SEPARATORY FUNNEL TECHNIQUE oPlace the separatory funnel in the cushioned iron ring attached to a ring stand and let the two layers (phases) separate. oRemove the stopper, and drain the lower layer through the stopcock. oPour off the top layer out the top of the separatory funnel. oBe sure to label each phase that you remove from the separatory funnel. o(It is best to keep all phases until you are sure that you have the desired product. Then the others may be discarded as directed.) ACIDBASE EXTRACTION OF ASPIRIN AND ACETAMINOPHEN DRYING ORGANIC SOLVENTS oOrganic solvents which have come in contact with water will have some water dissolved in them, even though they are immiscible with water. (Organic layers containing water appear cloudy.) oThe solubility of water in organic solvents is dependent upon intermolecular forces: Hexane 0.01 g / 100 g Diethyl ether 1.26 g / 100 g Ethyl Acetate 3.3 g / 100 g. oWater can be removed from organic compounds when the compound is in solution by using a drying agent. oDrying agents are anhydrous salts which readily form hydrates, which can then be removed by filtration or by decanting. DRYING ORGANIC SOLVENTS oCommonly used drying agents include: MgSO4, CaCl2, CaSO4, and Na2SO4 oThe amount of drying agent is rarely measured; it is added in sufficient amount so that excess drying agent swirls freely (vs. clumping as it is complexes with water) oMost drying agents are fast acting; 5-10 minutes is usually sufficient. oThe drying agent is removed by decanting or by filtration. High performance thin-layer chromatography High performance liquid chromatography Introduction to Natural Products Chemistry o morphine (narcotic analgesic) 1817 o Named after the Roman god of dreams, Morpheus o Numbs pain, alters mood and induces sleep. o Less popular and less mentioned effects include nausea, vomiting and decreased gastrointestinal motility Morphine, C17H19NO3, is the most abundant of opium of 24 alkaloids Introduction to Natural Products Chemistry o strychnine(poison) 1818 o 含劇毒的植物鹼，味苦，少 量注射可對蛇毒免疫，十五 份之一克便可致命。 o 劇烈的肌肉痙攣，下巴麻痺 而失語，嘴唇內收而露出古 怪的笑容，最終死于呼吸系 統衰竭。 o 散血熱，消腫，止痛。治咽 喉痺痛，癰疽腫毒，風痺疼 痛，骨折。並治面神經麻痺 ，重症肌無力。 追殺異見人士毒藥派上用場 馬錢子 番木鱉鹼 Introduction to Natural Products Chemistry ococaine (narcotic stimulant) 1859 onicotine (toxic) 1828 A Birth of a Medicinal Chemist Paul Ehrlich oAs a medical student in the laboratory of the anatomist Wilhelm Waldeyer, between 1872 -74 at the Univ. of Strasbourg A Birth of a Medicinal Chemist Paul Ehrlich o 保羅奧利克（ Dr.Paul Ehrlich）時代（西元 1892 1950年） 是 德國免疫學家、血液學家，亦是化學療法的奠基人之一。因對免疫學的 貢獻，於 1908年與梅契尼科夫共獲諾貝爾生理學或醫學獎。 o 1907年他認為藥物既能與病原體細胞上的化學受體結合，又能與機體 細胞上的化學受體結合，所以一個藥物既對病原體有殺滅作用，同時也 損傷機體。 o 所以他的目希望能 找到一化學物質其對病原生物表現特別的親和性 ，它 們之間的關係就如同抗毒素作用於特定的毒素一般，會作用於這些病原 生物，而對成為目標的病原生物，就像魔術的子彈 (Magic bullets) 般直接產生作用。 o 於是他以德國發達的化學工業與染料工業為基礎 ,致力於探尋低毒高效的 化學藥物。在秦佐八郎的協助下，他們曾 以砷苯化合物為基礎 ,通過改變 化學結構，合成千餘種衍生物，逐一篩選 。 o 1910年發現的第 606號化合物，即二氨基二氧偶砷苯 (商品名砷凡納明 或 606)不僅對錐蟲病有較好療效，而且能成功地治療梅毒。他被譽為化 學療法的先驅。 A Father of Modern Medicinal Chemistry oPh.D. earned at the University of Wisconsin (1952) oProfessor and chairman of medicinal chemistry at the University of Kansas (1960) oFather of rigid analog design oTrained over 70 Ph.D. students and 20 post-docs Edward E. Smissman A Father of Modern Medicinal Chemistry oreceived numerous honors including nChaired the long range planning committee of the Division of Medicinal Chemistry nChaired the international educational committee of the section of Medicinal Chemistry nCo-authored over 100 scientific papers nSmissman Award of the ACS Division of Medicinal Chemistry named in his honor Edward E. Smissman Alfred Burger University of Virginia obegan with his education in his native Austria oPh.D. work at the University of Vienna and postdoctoral research in Switzerland oin 1929 Research Associate in a newly created Drug Addiction Laboratory at the University of Virginia omany years as Professor of Chemistry and a term as Department chairman (official retirement in 1970) Known as one of the fathers of Medicinal Chemistry Alfred Burger University of Virginia oreceived numerous honors in