Biosynthesis of Phomactin Platelet Activating Factor Antagonist Requires a Two-Enzyme Cascade

Phomactin diterpenoids possess a unique bicyclo[9.3.1]pentadecane skeleton with multiple oxidative modifications, and are good platelet-activating factor (PAF) antagonists that can inhibit PAF-induced platelet aggregation. In this study, we identified the gene cluster (phm) responsible for the biosynthesis of phomactins from a marine fungus, Phoma sp. ATCC 74077. Despite the complexity of their structures, phomactin biosynthesis only requires two enzymes: a type I diterpene cyclase PhmA and a P450 monooxygenase PhmC. PhmA was found to catalyze the formation of the phomactatriene, while PhmC sequentially catalyzes the oxidation of multiple sites, leading to the generation of structurally diverse phomactins. The rearrangement mechanism of the diterpene scaffold was investigated through isotope labeling experiments. Additionally, we obtained the crystal complex of PhmA with its substrate analogue FGGPP and elucidated the novel metal-ion-binding mode and enzymatic mechanism of PhmA through site-directed mutagenesis. This study provides the first insight into the biosynthesis of phomactins, laying the foundation for the efficient production of phomactin natural products using synthetic biology approaches.     

The Approach to Difluoromethylene Platelet Activating Factor Analogues

Abstract

It is well known that phospholipids have an important role in the metabolic regulation or perturbation of living organisms. For instance, the Bioregdator-Platelet Activating Factor has been shown to initiate platelet aggregation, to produce antihypertensic action, and to take part in allergic responses. These glycerophosphates exhibt selective cytotoxicity against leukemia and sarcoma cells. On the other hand difluoromethylenephosphonates have, and are currently being widely explored as phosphatase stable phosphate mimics for biological systems. From this point of view it was interesting to make structural modi6cations of PAF by replacement of oxygen atom by CF₂ group in phosphoglycerol branch. This modification may lead to novel biological properties and high pharmacological activity of these substances.     

Nonracemic Dimethylphenyl Glycerol Ethers in the Synthesis of Physiologically Active Aminopropanols

Russian Journal of Organic Chemistry - Six regioisomeric nonracemic dimethylphenyl glycerol ethers were synthesized by asymmetric dihydroxylation of the corresponding allyl dimethylphenyl ethers....     

Synthesis of 1-O-Alkyl-2-O-Acetyl-Sn-3-glyceryl-3-phosphoryl Choline the Enantiomer of Platelet Activating Factor (PAF)

A novel stereospecific synthesis of biologically active ether-phospholipids (PAF) is reported, involving chemoenzymatic approach.     

Synthesis of positively charged lipids containing a 1,3-oxathiolane cycle

Positively charged lipids of the 1,3-oxathiolane series were synthesized by interaction of 2-pentadecyl-5-tosyloxymethyl- or -5-iodomethyl-1,3-oxathiolane with 2-(N,N-dimcthyl-amino)ethanol.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 2347–2349, September, 1996.     

胶束电动毛细管色谱分析间接紫外吸收检测人体血小板活化因子

研究了人体血小板活化因子中1-O-十六烷基乙酰甘油磷酰胆碱与1-O-八烷基乙酰甘油磷酰胆碱的胶束电动毛细管色谱分离条件与间接紫外吸收检测条件。首次采用高效毛细管电泳法成功地分析了人体血小板活化因子中两种主要磷酰胆碱的含量。     

Synthesis of a Cyclic Analogue of Galardin

A cyclic analogue 4 of galardin, a known MMP inhibitor, is designed to improve its selectivity. The synthesis of 4 starts from dimethyl (S)‐malate using diaselective alkylation and subsequent cyclization and amide formation as key steps. The compound 4 showed MMP inhibitory activity on all MMPs tested with IC₃₀, ranging from 20.1 μM to 104 μM.     

A Facile Formal Synthesis of Volicitin

A short and concise synthesis of volicitin is presented. The synthesis is based on repeated chemoselective copper salt cross coupling reactions of alkynes and propargylic halides.     

A Formal Total Synthesis of Aplysin

A formal, total synthesis of aplysin has been described employing intermolecular (2+2) cycloaddition reaction between ketene and an olefin as a key step.     

薯蓣皂苷元-葡萄糖C-苷类似物的合成

采用汇集式合成策略,以葡萄糖为原料,经乙酰化、 溴代、消除、硅炔基化、脱除保护基制得(2R,3R) -6-乙炔基-2-(羟甲基) -3,6-二氢-2H-吡喃-3-醇(5);以薯蓣皂苷元为原料,经磺酰化、叠氮化制得叠氮化薯蓣皂苷元8;以5和8为原料,经Click反应合成薯蓣皂苷元-葡萄糖C-苷类似物(9),收率74%,其结构经¹H NMR, ¹³C NMR以及HR-MS(ESI)表征。      

Synthesis,characterization and crystal structure of the cis-[RhL2Cl2]Cl complex with the bifunctional ligand (L) 2-(2′-pyridyl)quinoxaline. Biological activity towards PAF (Platelet Activating Factor) induced platelet aggregation

The reaction of RhCl₃·3H₂O with the ligand L = 2-(2′-pyridyl)quinoxaline (pqo) in a 1:2 molar ratio formed the mononuclear complex cis-[RhL₂Cl₂]Cl (1), which has been characterized by elemental analysis, FT-IR, FT-Raman, ¹H, ¹³C NMR, electronic absorption spectroscopy and by electrospray mass spectrometry. The molecular structure of 1 (needle like and prismatic polymorphs) in the crystal has been elucidated by single-crystal X-ray diffraction, revealing a bidentate behavior of L, while the geometry around the Rh(III) atom is that of a distorted octahedron.^. Preliminary biological tests revealed that this compound inhibited PAF-induced rabbit platelet aggregation.     

Synthesis of a Fluorescent,Cardioactive Analogue Digoxin

Abstract

In order to develop a better understanding of the mechanism of action of the cardioactive steroid glycoside digoxin, we have synthesized a fluorescent analogue of this drug which retains biological activity. Fluoroscein isothiocyanate has been coupled to digoxin via an ethyl lysine bridge, after mild periodate oxidation of the terminal glycase moiety. The conjugate can displace oubain from the plasma membrane digoxin receptor, Na⁺/K⁺ ATPase and can itself be displaced by native digoxin. The structure of the conjugate based on FAB mass spectroscopy is presented.     

Synthetic Approach to the Synthesis of Physiologically Active Compounds: II. Synthesis of Disubstituted Adamantanes Containing an N-Benzoylphenylisoserine Fragment

A preparation is reported of some previously unknown 1,4-disubstituted adamantane derivatives containing a phenylisoserine fragment.     

一种含硝基的Plakoric酸类似物的合成

Synthesis of a nitro analogue of plakoric acid is presented. The peroxy bond was incorporated into the substrate structure through a boron trifluoride etherate catalyzed methoxy-hydroperoxy group partial exchange reaction in diethyl ether with urea-hydrogen peroxide complex （UHP, a commercially available solid reagent） as the source of the hydrogen peroxide. Under the given conditions, only one of the two methoxyl groups underwent the MeO—— OOH exchange and the resulting hydroperoxy hemiketal proceeded directly to the end product through an intramolecular Michael addition of the hydroperoxyl group to the nitro group activated carbon-carbon double bond.     

全合成海南粗榧新碱类似物的研究

海南粗榧新碱具有一定的抗肿瘤活性，为了提高该类化合物抗肿瘤活性，研究其结构与活性的关系，以３，４－二甲氧基苯乙酸和脯氨醇为起始原料，经７步反应得到消旋的海南粗榧新碱类似物，并经酒石酸拆分得到ｅ．ｅ．值分别为９３％和９５％的一对对映体，经各种光谱及Ｘ－衍射证实其结构。     

A Convenient Method for the Synthesis of Distamycin Analogue

A novel distamycin analogue was synthesized by chloroform reaction and DCC/HOBT coupling reaction without using amino protection and deprotection.