酰基辅酶A : 胆固醇酰基转移酶抑制剂Beauveriolide I的全合成

报道了酰基辅酶A:胆固醇酰基转移酶抑制剂beauveriolideI的全合成.BeauveriolideI结构中的饱和脂肪酸具有两个相邻的手性中心,是合成的关键中间体,以(4R)-4-苄基-3-丙酰基-2-噁唑烷酮和3-苄氧丙醛为起始原料制备得到.Beauveriolide I的结构经1HNMR,13CNMR,MS和IR谱确定.     

Structure and Synthesis of Simulansamide,a Platelet Aggregation Inhibitor from Zanthoxylum Simulans

Simulansamide, isolated from the root bark of Zanthoxylum simulans, shows strong inhibition of platelet aggregation. The structure of this compound was deduced from spectral data and verified by synthesis.     

新型蛋白酶抑制剂的合成

以(2S,3S)-1,2-环氧基-3-叔丁氧酰胺基-4-苯丁烷为原料,经N-烷基化、对硝基苯磺酰化、脱去氨基保护基,再与3-叠氮基-3-脱氧胸(腺嘧啶核)苷5-单琥珀酸缩合,合成了新型具有芳香磺酰胺基氨基醇骨架的HIV-1蛋白酶抑制剂--N-{3-[3-叠氮基-3-脱氧胸(腺嘧啶核)苷5-单琥珀酰胺基]-2-羟基-4-苯基丁基}-N-异丁基-4-硝基苯磺酰胺,总收率55.2%,其结构经1H NMR和MS确证.     

Chemical Basis of the Action of Glyoxalase I,an Anticancer Target Enzyme

Although glyoxalase I was discovered in 1913 the physiological role of this ubiquitous enzyme is still far from clear. It catalyzes the reaction of α-ketoaldehydes and glutathione to produce S-D-lactoylglutathione, from which D-lactate and glutathione are produced by glyoxalase II. Argument raged for many decades about the nature of the natural substrate. Was it methylglyoxal? Was methylglyoxal ever formed metabolically or was it purely artifactual? Some of these questions have been resolved in that a number of metabolic processes which produce α-ketoaldehydes have now been recognized. Equally unsuccessful have been attempts to ascribe a physiological role to glyoxalase. This is clearly an important question since glyoxalase I occurs in cells at all levels of evolution. Time and time again glyoxalase I has been claimed to be linked to cancer, and a number of research groups worldwide are using it as a model for designing potential anticancer drugs. In this review article the mechanism of action of the enzyme is discussed, knowledge of which enables stronger inhibitors to be synthesized. Until roughly ten years ago when powerful NMR techniques were used to study it for the first time, it was assumed that the key step in the mechanism was a hydride ion transfer. Today, the mechanism is envisaged as a proton transfer.     

Cytotoxic gephyromycins from the Streptomyces sp. SS13I

Two new gephyromycins (1–2), belonging to angucyclinones, were identified from Streptomyces sp. SS13I. Their structures were elucidated by analysis of HRESIMS, 1D and 2D NMR spectroscopic data, and the structure of 1 was further elucidated by X-ray diffraction data. The absolute configurations of compounds 1–2 were evidenced by ECD calculations. To our best knowledge, Compounds 1–2 were the second reported gephyromycin-type angucyclinones. Compound 2 exhibited significant cytotoxicity against PC3 cell lines with IC₅₀ values of 1.38 ± 0.47 μM.     

Synthesis of Tuckolide, a New Cholesterol Biosynthesis Inhibitor

Tuckolide (decarestrictine D), a 10-membered lactone isolated from P. corylophilum and polyporus tuberaster fungi that potently inhibits cholesterol biosynthesis, was synthesized. The key steps include a Sharpless catalytic asymmetric dihydroxylation reaction (AD) of the methoxymethyl (MOM) ether protected diene 2 and a direct Corey-Nicolaou lactonization reaction of seco-acid 1with added silver perchlorate. The selectivity of the dihydroxylation step was found to be highly dependent on the nature of the protecting group adjacent to the diene in 2. The selectivity of the asymmetric dihydroxylation reaction of 2 indicates that both steric and electronic effects can lead to significant amounts of the undesired isomers. This synthesis establishes the absolute stereochemistry of tuckolide showing the C3 hydroxyl bearing carbon with an S-configuration comparable in an absolute sense to that in the lactone portion of the HMG-CoA reductase inhibitor compactin.     

α-葡萄糖苷酶抑制剂Radicamine B的合成

以D-阿拉伯糖为原料,依次合成了中间体(2R,3R,4R)-2,3,5-三-O-苄氧基-4-羟基-O-叔丁基二甲基硅基-戊醛肟(3),(2R,3S,4S)-2,3,5-三-O-苄氧基-4-碘-O-叔丁基二甲基硅基-戊醛肟(4)和(2R,3R,4R)-3,4-二-O-苄氧基-2-(苄氧甲基)-3,4-二氢-2H-吡咯-1-醇(5);5与芳基Grignard试剂进行高立体选择性的加成反应制得(2R,3R,4R,5R)-3,4-二-O-苄氧基-2-[4-(苄氧基)苯基)]-5-吡咯-1-醇(6);6经催化氢化合成Radicamine B,总收率18.5%。3和4为新化合物,其结构经1HNMR,MS和元素分析表征。     

Discovery,Synthesis and Evaluation of a Ketol-Acid Reductoisomerase Inhibitor

Ketol-acid reductoisomerase (KARI), the second enzyme in the branched-chain amino acid biosynthesis pathway, is a potential drug target for bacterial infections including Mycobacterium tuberculosis. Here, we have screened the Medicines for Malaria Venture Pathogen Box against purified M. tuberculosis (Mt) KARI and identified two compounds that have K_i values below 200 nm . In Mt cell susceptibility assays one of these compounds exhibited an IC₅₀ value of 0.8 μm . Co-crystallization of this compound, 3-((methylsulfonyl)methyl)-2H-benzo[b][1,4]oxazin-2-one (MMV553002), in complex with Staphylococcus aureus KARI, which has 56 % identity with Mt KARI, NADPH and Mg²⁺ yielded a structure to 1.72 Å resolution. However, only a hydrolyzed product of the inhibitor (i.e. 3-(methylsulfonyl)-2-oxopropanic acid, missing the 2-aminophenol attachment) is observed in the active site. Surprisingly, Mt cell susceptibility assays showed that the 2-aminophenol product is largely responsible for the anti-TB activity of the parent compound. Thus, 3-(methylsulfonyl)-2-oxopropanic acid was identified as a potent KARI inhibitor that could be further explored as a potential biocidal agent and we have shown 2-aminophenol, as an anti-TB drug lead, especially given it has low toxicity against human cells. The study highlights that careful analysis of broad screening assays is required to correctly interpret cell-based activity data.     

2型环氧酶抑制剂赛来昔布的合成

以对甲苯乙酮和三氟醋酸乙酯为原料，经缩合、环合两步反应得到2型环氧酶抑制剂赛来昔布，总收率为67％。     

Interactions of a Low Molecular Weight Inhibitor from Streptomyces sp. MBR04 with Human Cathepsin D: Implications in Mechanism of Inactivation

Cathepsin D, a lysosomal aspartic protease, is of potential interest as a target for drug design due to its implication in breast and ovarian cancer. The article reports a low molecular weight cathepsin D inhibitor from Streptomyces sp. MBR04. The M_r of the inhibitor was 1,078 Da as determined by MALDI-TOF, and the amino acid analysis showed the presence of Asp, Asp, Gly, Ala, Lys, Leu, Tyr, Trp residues. The steady-state kinetic interactions revealed reversible, competitive, slow-tight-binding nature of the inhibitor with an IC₅₀ and K _i values of 3.2 and 2.5 nM, respectively. The binding of the inhibitor with the enzyme and the subsequent conformational changes were monitored by exploiting the intrinsic fluorescence of the surface exposed Trp-54 residue. Based on the fluorescence and circular dichroism studies, we demonstrate that the inhibitor binds to the active site of cathepsin D and causes inactivation. All these kinetic, thermodynamic, and quenching studies suggest that the newly isolated peptidic inhibitor could be a potential scaffold to study and can be used to develop new potent therapeutic lead molecule for the development of drugs. The inhibitor will be significant as a potential lead molecule to target cathepsin D.     

Design and Synthesis of a Novel Peptidomimetic Inhibitor of Caspase-3

Introduction Thecaspase(cysteinyl aspartateprotease)family representsaclassofintracellularproteases,playinga criticalroleinapoptoticcelldeathpathwaysandactiva tionofpro inflammatorycytokines[1].Theirenzymatic propertiesaregovernedbyanearlyabsolutespecific…     

Synthesis and stereochemistry of musacins isolated from Streptomyces griseoviridis(FH-S 1832)

Musacins E (1a), B(1)(2a) and B(2)(3a) have been synthesized starting from D-erythronolactone, L-tartaric acid and (S)-malic acid. The absolute stereochemistry of musacins was unambiguously established by this synthesis.     

SGLT2抑制剂Dapagliflozin的全合成

以5-溴-2-氯苯甲酸和D-葡萄糖酸內酯为起始原料,完成了SGLT2抑制剂Dapagliflozin的全合成,总收率34.5%,其结构经NMR表征。     

Facile Synthesis of the Neuraminidase Inhibitor Peramivir

An improved and convenient synthetic route for the synthesis of peramivir has been developed with a total 34% yield. The process was improved from previous methods in three key reaction steps including 1,3-dipolar cycloaddition, reductive ring cleavage of the isoxazoline, and incorporation of the peripheral guanidino group. First, an activated sodium hypochlorite (Cl% = 10%) was employed for the catalytic 1,3-dipolar cycloaddition, and 61–68% yields were obtained. Second, the NaBH₄-NiCl₂ was used as a new reducing reagent instead of the expensive catalyst PtO₂. Most important, an innovative and environmentally friendly method of guanylation in the final step was developed using chloroformamidine hydrochloride as the amidino reagent, which avoided the use of the highlytoxic reagent of HgCl₂ and made the process greener.

Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.     

Synthesis of Berberine-Efflux Pump Inhibitor Hybrid Antibacterials

This paper reports the compact synthesis of two isomeric dual-action hybrid antimicrobials where the 13-position of the antibacterial berberine has been linked via 3'- and 4'-methylene bridges to INF55 (5-nitro-2-phenylindole), an inhibitor of the bacterial NorA multidrug-resistance pump.     

Short Synthesis of COX-2 Inhibitor Inotilone

An efficient three-step synthesis of COX-2 inhibitor inotilone from acetaldoxime is described. The structure of inotilone was elucidated via an aldol reaction between 5-methyl-3(2H)-furanone and 3,4-dihydroxybenzaldehyde. This approach describes a convenient pathway to 5-alkyl-3-furanones through isoxazole chemistry.