Two versatile routes towards Cerpegin and analogues: applications of a one pot reaction to new analogues of Cerpegin

Simple and efficient routes to the natural alkaloid Cerpegin and new analogues are described herein. In a first approach, we extend the scope of a one pot three steps reaction, which permits the synthesis of new analogues of Cerpegin, substituted in different ways. In a second line of approach, we present an unprecedented synthesis of Cerpegin and analogues where methylfuranones are condensed with dimethylformamide diethylacetal (DMFDEA) to yield enaminolactone esters, which react easily with various primary amines affording Cerpegin and new analogues. We applied this second approach to the synthesis of new bis-Cerpegins and N-amino-Cerpegins. Most of the syntheses are performed under environmental friendly conditions.     

Synthesis of alpha-galactosyl ceramide (KRN7000) and analogues thereof via a common precursor and their preliminary biological assessment

A new practical synthesis of alpha-GalCer and of its analogues is presented, opening the chance to easily modify the sphingosine chain. The common precursor is a disaccharide, obtained by coupling tetra-O-benzyl-D-galactose with allyl 2,3-O-isopropylidene-D-lyxofuranoside. Introduction of alkyl chains via Wittig reaction (for alpha-GalCer and OCH) or via Williamson reaction (for oxa analogues) followed by standard synthetic steps allows one to efficiently obtain such compounds. The analogues are able to activate iNKT cells when presented by CD1d expressing cells.     

Efficient synthetic access to a new family of highly potent bryostatin analogues via a Prins-driven macrocyclization strategy

The step-economical synthesis of a new class of bryostatin analogues that contain the complete oxycarbocyclic core ring system of the bryostatin natural products is reported. These agents are convergently assembled via a highly efficient, functional-group-tolerant, and stereoselective Prins-driven macrocyclization. These tetrahydropyranyl B-ring analogues are among our most potent and efficacious analogues to date, exhibiting nanomolar and picomolar activities in protein kinase C affinity assays as well as in cellular antiproliferation assays.     

Synthesis and Anticholinesterase Activity of (-)-Physostigmine Analogues with Modifications at C3a and C5

A new series of physostigmine analogues 3a―3j with modifications at the C3a and C5 positions was designed and synthesized. Bioassay of the synthetic analogues 3a―3j, along with the previous synthesized C3a-ethyl-C5-triazole physostigmine analogues 1a―1g and 2a―2j was performed, which indicates that the replacement of the carbamoyl moiety of C3a-ethyl-C5-triazole analogues 1 and 2 with a triazole moiety decreased acetylcholinesterase(AchE) inhibitory activity, whereas the introduction of heterocycles into the triazole ring increased both AChE and butyrylcholinesterase(BchE) inhibitory activities. Structure-activity relationship(SAR) studies of C3a-methyl-C5-triazole analogues 3 reveal the C3a-methyl substituent is important for AChE and BChE inhibition and the introduction of a second ionizable N center improved the binding of the synthetic analogues to both AChE and BChE.     

Synthesis of isogranulatimides A and B analogues possessing a 7-azaindole unit instead of an indole moiety

The synthesis of a new family of isogranulatimides analogues is described in which a 7-azaindole replaces the indole moiety. The key step is the photocyclization of the aza didemnimide intermediates which leads to two isomeric analogues of isogranulatimides A and B. A derivative bearing a carbohydrate part linked to the azaindole via a β-N-glycosidic bond was also prepared.     

Autonomously pairing cysteinyl-linked nucleotide analogues with a unique architecture

We report the efficient pairing in water of the first representative of oligonucleotide analogues in which the backbone is replaced by linking elements between the nucleobases. The architecture of the new analogue demonstrates that the structural differentiation of oligonucleotides into a contiguous backbone and nucleobases, as embodied by the natural nucleic acids and all nucleotide analogues analyzed to date, is not a prerequisite for pairing. UV and circular dichroism analyses of self-complementary and non-self-complementary octanucleotide analogues strongly suggest the fully reversible, sequence-specific association of our new analogues to form a left-handed double helix with an antiparallel strand orientation that is characterized by melting temperatures and free enthalpies higher than those of natural RNA and DNA of the same sequence. The linking element incorporates an L-cysteine moiety that allows a short and efficient synthesis of the monomeric building blocks and, through the choice of either L- or D-cysteine, gives access to either one of the enantiomeric oligomers and thus to left- or right-handed helices.     

Synthesis of new 18-substituted analogues of calcitriol using a photochemical remote functionalization

A novel convergent synthetic approach to new analogues of calcitriol modified at the C-18 position is reported. The key step in the synthesis is the 20-hydroxyl-directed photochemical iodination of the 18-methyl group in the presence of (diacetoxyiodo)benzene. Using this methodology, two new analogues of calcitriol were prepared: the first contains a hydroxylated alkyl side chain attached at C-18 with the natural side chain replaced by an isopropylidene group; the second is a conformationally locked analogue due to an extra oxacycle between the C-18 and C-20 positions.     

L-核苷类抗HIV、HBV活性化合物研究进展

抗病毒新试剂的不断涌现,为HIV、HBV感染者的临床治疗提供了有效的方法.在抗病毒试剂中,核苷类化合物占据了十分重要的地位.本文阐述了核苷类化合物抗病毒的作用机理,介绍了L型核苷的发展历史及一些新型具有抗HIV、HBV生物活性的L型核苷类化合物的分类.同时,通过对一些新型具有抗HIV、HBV生物活性的核苷类化合物如BCH、FTC、OddC、d4A、Fd4C等,D型和L型不同对映异构体抗病毒活性及生物毒性的对比发现,L型异构体比其相应的D型异构体具有抗病毒活性更高、生物毒性更低的特点.药物化学家们对此产生了极大的兴趣,进一步开展了新型L型核苷类化合物设计、合成的相关研究,以便筛选出更安全有效的抗病毒试剂.     

A new method of solvent free O- and N-glycosylation using activated carbon fiber (ACF) as a promoter. Application to the synthesis of saponin and nucleoside analogues

By using activated carbon fiber (ACF) as solid acid promoter, we display a new system for solvent free O- and N-glycosylation, with a simple process which takes place in a drying oven; this method has been applied to the synthesis of sterol and triterpene O-glycosides (saponin analogues), as well as nucleoside analogues.     

新型甾体血管新生抑制剂Cortistatin的结构、生物活性与合成

由于肿瘤的生长与转移高度依赖于血管新生,因此发现和发明新型血管新生抑制剂对肿瘤疾病治疗有重要意义.以Cortistatin A为代表的Cortistatin类海洋天然产物是一类化学结构新颖、具有显著血管新生抑制作用的甾体化合物.它们具有9-(10,19)-abeo-雄甾烷骨架和氧原子桥连七元B环结构,Cortistatin A对人脐静脉内皮细胞(HUVEC)增殖具有nmol/L级的抑制活性和相对其他细胞系大于3300的选择性指数.综述了Cortistatin及其类似物自发现来两年期间的合成进展情况.     

Natural product diversification using a non-natural cofactor analogue of S-adenosyl-L-methionine

Adenosine analogues bearing either 5'-aziridine or 5'-N-mustard electrophiles are methyltransferase-dependent DNA alkylating agents. We present here a novel synthetic cofactor bearing a pendant 5'-amino acid N-mustard. Unlike previously studied synthetic cofactors, this material is very efficiently used by the natural product biosynthetic enzyme rebeccamycin methyltransferase (RebM) to generate a number of new rebeccamycin analogues. These data promote the notion that natural product methyltransferases can be used with non-natural cofactors to enhance the molecular diversity of natural product analogues for drug discovery. To our knowledge, this is the first documentation of a biological methyltransferase, other than DNA methyltransferases, that can exploit such synthetic cofactors.     

Exploring the self-assembly of glycopeptides using a diphenylalanine scaffold

Diphenylalanine, a key building block for organic nanotechnology, forms discrete, rigid and hollow nanotubes that are assembled spontaneously upon their dilution from organic phase into aqueous solution. Here we report the efficient preparation of several S-linked glycosylated diphenylalanine analogues bearing different monosaccharide, di-saccharide and sialic acid residues. The self-assembly studies revealed that these glycopeptides adopted various structures and glycosylation could be a tool to manipulate the self-assembly process. Moreover, the solubility of these analogues was found to be much greater than diphenylalanine, which could open new applications based on these nanostructures.     

Pharmacophore mapping in the laulimalide series: total synthesis of a vinylogue for a late-stage metathesis diversification strategy

An efficient synthesis of the macrocyclic core of laulimalide with a pendant vinyl group at C20 is described, allowing for late-stage introduction of various side chains through a selective and efficient cross metathesis diversification step. Representative analogues reported herein are the first to contain modifications to only the side chain dihydropyran of laulimalide and des-epoxy laulimalide. This step-economical strategy enables the rapid synthesis of new analogues using alkenes as an inexpensive, abundantly available diversification feedstock.     

Synthesis of granulatimide analogues bearing a maleimide instead of an imidazole heterocycle

A synthesis in a few steps of a new family of granulatimide analogues was performed. In the new compounds, the aromatic framework of granulatimide is modified by replacement of the imidazole unit by a maleimide moiety. The synthesis of a water-soluble analogue is also presented.     

Screening and Identification of a Targeting Peptide to nGLP-1R from Phage Display Peptide Library

<正>In order to provide the structure information for designing new exendin-4 analogues,a phage display peptide library was screened by targeting the N-terminal extracellular domain of GLP-1R(nGLP-1R).After four rounds of selection,nine sequences were obtained,four of them have higher affinity for nGLP-1R than the others.We chose two of them named X and Y peptides.Isletβ-cell proliferation assay suggested that X and Y peptides didn't have any activity to increase isletβ-cell proliferation.In other words,X and Y peptides were not agonists to GLP-1R.However, the conservative motifs of X and Y peptides provided us useful information to design new exendin-4 analogues.     

Synthesis of 2'-amino-LNA: a new strategy

In this paper we present revised and significantly improved synthetic routes to 2'-amino-LNA (locked nucleic acid). The optimal route is convergent with the synthesis of LNA monomers ("2'-oxy-LNA") via a common intermediate obtained by a mild deacetylation for the liberation of the 2'-hydroxy group to give compound 23 without the concomitant ring closure that affords the 2'-oxy-LNA skeleton. After inversion of the stereochemistry at C2' and triflate formation at the 2'-hydroxy group a new common intermediate 16 is obtained which gives easy access to a range of other analogues exemplified by the introduction of a sulfur nucleophile leading to the 2'-thio-LNA structure. After substitution of the triflate with azide a basic reduction affords the desired 2'-amino-LNA structure, i.e., compound 18. This new synthesis strategy towards 2'-amino-LNA improves the overall yield significantly and converges the syntheses of 2'-oxy-LNA and LNA analogues.     

Stereoselective Fluorination Alters the Geometry of a Cyclic Peptide: Exploration of Backbone‐Fluorinated Analogues of Unguisin A

New methods for enhancing the efficiency of peptide cyclization, and for fine‐tuning the conformations of cyclic peptides, are valuable from a drug development perspective. Herein stereoselective fluorination is investigated as a new strategy for achieving these goals. Four vicinal difluorinated analogues of the natural cyclic heptapeptide unguisin A have been efficiently synthesized. The analogues are found to adopt dramatically different secondary structures, controlled by the fluorine stereochemistry.     

Pd-catalyzed carbocyclization-Negishi cross-coupling cascade: a novel approach to 1alpha,25-dihydroxyvitamin D3 and analogues

[reaction: see text] A mild palladium-catalyzed cascade has been used for the synthesis of the hormone 1alpha,25-dihydroxyvitamin D3 (calcitriol, 1a) and its analogues 1b and 1c. This one-pot process involves two consecutive transformations at room temperature: An initial palladium-catalyzed 6-exo-cyclocarbopalladation of vinyl triflates followed by a Negishi cross-coupling reaction with an alkenyl zinc. This novel strategy opens new possibilities for the preparation of a variety of new vitamin D analogues of therapeutic potential, particularly with modifications at the triene and/or ring-A.     

Using a differential refractive index detector as a pressure transducer for online viscometry in exclusion chromatography

A macrocyclic glycopeptide, ristocetin A, was used as chiral stationary phase for the high-performance liquid chromatographic separation of enantiomers of 28 unnatural amino acids, such as analogues of phenylalanine, tyrosine and tryptophan, and analogues containing 1,2,3,4-tetrahydroisoquinoline, tetraline or 1,2,3,4-tetrahydro-2-carboline skeletons. Excellent resolutions were achieved for most of the investigated compounds by using reversed-phase or a new polar-organic mobile phase system. The conditions of separation were optimized by variation of the mobile phase composition, temperature and flow-rate.     

Synthesis,Properties and Reactivity Studies of a Hetero-dicopper Complex Consisting of a Porphyrin and a Bispyridylamine Moiety Connected by a Xanthene Backbone

Synthesis, characterization and reactivity studies of a hetero-dicopper complex, particularly towards oxygen reduction are presented. A bischlorido copper(II) trishistidine-type coordination unit is positioned directly above a copper porphyrin unit. The close distance between the two coordination fragments is secured by a rigid xanthene backbone. Surprisingly, the dinuclear complex is not active towards oxygen reduction unlike the earlier published mononuclear analogues with a bispyridylamine copper center. However, the compound architecture of this multinuclear metal complex is interesting and can play an important role in the development of new catalysts for ORR.