残基突变对P53-DNA结合域肽段构象影响的分子动力学模拟

基于分子动力学模拟方法研究了R249S、R248W 和G245S 突变对P53-DNA 结合域肽段(残基230-258)结构的影响. 采用GROMACS 软件包和GROMOS 43A1分子力场, 分别对野生型wtP53肽段、单点突变型P53-R249S肽段、两点突变型P53-R249S/R248W肽段和三点突变型P53-R249S/R248W/G245S肽段进行了4组独立的分子动力学模拟, 每组体系模拟时间为500 ns. 研究结果表明: R249S单残基突变影响肽段残基形成二级结构的情况, 但不改变肽段三维结构的模式, 同时使该肽段结构相对稳定; R249S和R248W两残基同时突变会加剧R249S突变对肽段的影响, 同时导致三维结构发生较大变化, 构象弯曲呈现双turn 结构, 肽段稳定性进一步增大; G245S突变对肽段的影响与R249S和R248W同时突变对其结构的影响相反, 在两残基突变的基础上, G245S突变会使原突变引起的变化减弱甚至消失, 同时使得该肽段结构稳定性减小. 该研究对认识肿瘤致病分子机制和设计新药物有重要意义.     

First optically active molecular electronic wires

[structure: see text]. The optically active molecular electronic wires (S)- and (R)-7 containing an oligo-arylene-ethynylene structure and a chiral 1,1'-binaphthyl unit are synthesized. These molecules are incorporated into nanowell devices by self-assembly on the gold surface. In the nanowell devices, the median currents from the molecules containing both S and R enantiomers are significantly smaller than those from the pure S or R molecule. Compounds (R)- and (S)-7 are also less conductive than the fully conjugated oligo-phenylene-ethynylene-thiol molecules.     

Absolute stereochemistry of amphidinolide C

[structure in text] The absolute configurations at 12 chiral centers in amphidinolide C (1), a potent cytotoxic 25-membered macrolide isolated from a marine dinoflagellate Amphidinium sp., were determined to be 3S, 4R, 6R, 7R, 8R, 12R, 13S, 16S, 20R, 23R, 24R, and 29S by combination of NMR analyses, degradation experiments, and synthesis of the C-1-C-7 segment.     

Relative and absolute configurations of ganefromycin alpha

The full structure of ganefromycin alpha has been determined. The relative configurations were determined from 3JH,H coupling constants and NOE data, while the absolute configurations in moleties A and B were determined separately by difference CD of their acylate derivatives, which showed typical exciton couplets. The configurations of the stereogenic centers in ganefromycin alpha are 8S, 9S, 11R, 12S, 13S, 21S, 22R, 23R, 24R, and 26S.     

Relative and absolute configuration of versipelostatin, a down-regulator of molecular chaperone GRP78 expression

[structure: see text] Versipelostatin is the first compound which specifically inhibits the expression of GRP78 and the resultant robust cell death under stress conditions, in contrast to the weak cytotoxicity under normal conditions. Versipelostatin consists of a macrocyclic aglycone with an alpha-acyltetronic acid and three sugar moieties. The relative and absolute configuration of the aglycone moiety was established to be 4S, 5S, 6R, 9S, 10S, 13S, 16R, 18R, 19R, 20R, 24R, 27R, and 29S utilizing NMR techniques.     

Psymberin, a potent sponge-derived cytotoxin from Psammocinia distantly related to the pederin family

[structure: see text] Bioassay-guided fractionation of the sponge Psammocinia sp. afforded psymberin (1) possessing 5S,8S,9S,11R,13R,15S,16R,17R stereochemistry. Psymberin exhibits structural similarities to the pederin family metabolites. The potent cytotoxicty and unique structural features of 1 make it a promising lead for therapeutic development.     

珊瑚中五环半缩醛甾体的结构解析

为研究珊瑚Sinularia sp.中五环半缩醛甾醇的分离与结构,运用普通色谱及高效液相色谱等色谱方法对珊瑚Sinularia sp.中五环半缩醛甾醇化合物进行分离纯化,通过分析该化合物的核磁共振谱与质谱确定其平面结构,测定并比较圆二色光谱计算值确定化合物的立体构型。结果从珊瑚Sinularia sp.中首次分离纯化得到结构独特的五环半缩醛甾醇化合物(8R,9S,10R,13R,14S,17R,18R,20S,22R)-胆甾-1,4-二烯-18-乙酰基-22-氧-3-酮-18,22-环缩醛。     

Feigrisolide C: structural revision and synthesis

[Carbohydrate structure: see text] The original macrodiolide structure proposed for feigrisolide C was incorrect. The true structure of feigrisolide C was identified as (2'S,3'S,6'R,8'R)-homononactoyl (2R,3R,6S,8S)-nonactic acid, which was confirmed by total synthesis.     

First asymmetric total synthesis of Us-7 and -8, novel D-seco Corynanthe-type oxindole alkaloids from Uncaria attenuata: structure revision of Us-7 and determination of absolute stereochemistry

[reaction: see text] Starting from (S)-glycidol, the asymmetric total synthesis of novel D-seco Corynanthe-type oxindoles Us-7 and Us-8 was accomplished. The structure of Us-7 was revised from the reported structure 1 with the (3R,7S) form to structure 22 with (3S,7R), and the absolute stereochemistry at C15 of both alkaloids was established.     

Atmospheric pressure chemical ionization multi-stage mass spectrometry in the characterization of stereoisomeric synthons of cyclopropane amino acids

The mass spectrometric behaviour of (1S,2R)-, (1R,2R)-, (1R,2S)- and (1S,2S)-2-[(S)-2,2-dimethyl-1, 3-dioxolan-4-yl]-1-spiro-?4'[2'-phenyl-5'(4'H)-oxazolone]? cyclopropane (2) and (1S,2R)-, (1R,2R)-, (1R,2S)- and (1S, 2S)-methyl-1-benzamido-2-[(S)-2,2-dimethyl-1, 3-dioxolan-4-yl]cyclopropanecarboxylate (3) was studied under atmospheric pressure ionization conditions and by multi-stage mass spectrometric (MS(n)) experiments performed with an ion trap. Interestingly, by using methanol as solvent, compounds 2 lead to [M + H + CH(3)OH](+) ions which, as proved by collisional experiments, exhibit the same structure of the corresponding compound 3. MS/MS of [MH](+) ions allows a clear characterization of the different stereoisomers, which give rise to specific fragmentation pathways, rationalized with respect to the structure of the neutral molecules.     

Revision of the absolute configuration of the tricyclic sesquiterpene (+)-kelsoene by chemical correlation and enantiospecific total synthesis of its enantiomer

The absolute configuration of the recently identified sesquiterpene (+)-kelsoene was revised by chemical correlation with (R)-(+)-pulegone; the correct structure is (1R,2S,5R,6R,7R,8S)-2,8-dimethyl-6-(1-methylethenyl)tricyclo[5.3.0.0 (2,5)]decane.     

Chemical mediators: the remarkable structure and host-selectivity of depsilairdin, a sesquiterpenic depsipeptide containing a new amino acid

The chemical structure determination of depsilairdin, a highly selective phytotoxin produced by the plant pathogenic fungus Leptosphaeriamaculans/Phoma lingam, is described. The elucidation of the unusual chemical structure used a combination of NMR spectral data and X-ray crystallography. The absolute configuration was established using chemical degradation and synthesis of (3S,6R)-3,6-diisopropyl-2,5-morpholinedione and its (3R,6S) and (3R,6R) stereoisomers. Similar to the fungal pathogen, depsilairdin caused strong lesions only on brown mustard leaves but not on related species. [structure: see text]     

Physicochemical and crystal structure analyses of the antidiabetic agent troglitazone

The antidiabetic agent troglitazone has two asymmetric carbons located at the chroman ring and the thiazolidine ring and is produced as a mixture of equal amounts of four optical isomers, 2R-5S, 2S-5R, 2R-5R, and 2S-5S. The crystalline powdered drug substance consists of two diastereomer pairs, 2R-5R/2S-5S and 2R-5S/2S-5R. There are many types of crystals obtained from various crystallization conditions. The X-ray structure analysis and the physicochemical analyses of troglitazone were performed. The solvated crystals of the 2R-5R/2S-5S pair were crystallized from several solutions: methanol, ethanol, acetonitrile, and dichloromethane. The ratio of solvent and troglitazone was 1 : 2 (L1/2-form). The monohydrate crystals were obtained from aqueous acetone solution (L1-form). On the other hand, only an anhydrate crystal of the 2R-5S/2S-5R pair was crystallized from various solutions (H0-form). The dihydrous mixed crystal (MA2-form) was obtained from a mixture of the two diastereomer pairs of 2R-5R/2S-5S and 2R-5S/2S-5R in equal amounts by the slow evaporation of aqueous acetone solution. The crystal structure of the MA2-form is similar to the H0-form. When the MA2 crystal was kept under low humidity, it was converted into the dehydrated form (MA0-form) with retention of the single crystal form. The structure of the MA0-form is isomorphous to the H0-form. The MA2-form was converted into the MA0-form and vice versa with retention of the single crystal under low and high humidity, respectively. The crystallization and storage conditions of the drug substances were successfully analyzed.     

A New Jatrophane Diterpenoid Ester from Euphorbia turczaninowii

A new jatrophane diterpenoid ester （2S, 3S, 4R, 5R, 7S, 8R, 13R, 15R） - 3, 5, 7, 8, 15- pentaacetoxy-9, 14-dioxojatropha-6（17）, 11E-diene was isolated from the whole plant of Euphorbia turczaninowii Kar. ＆ Kit.. Its structure was characterized by spectral analysis and confurmed by X-ray crystallographic analysis.     

Megastigmane glucosides from Equisetum debile and E. diffusum

A new megastigmane diglucoside, (3S,5R,6S,7E,9S)-megastigman-7-ene-5,6-epoxy-3,9-diol 3,9-O-beta-D-diglucopyranoside (3), was isolated from the aerial portion of Equisetum debile along with macarangioside D (debiloside A), sammangaoside A, (6R,9S)-3-oxo-alpha-ionol 9-O-beta-D-glucopyranoside, debiloside B, kaempferol 3-O-sophoroside, kaempferol 3,7-O-beta-D-diglucopyranoside, kaempferol 3-O-sophoroside-7-O-beta-D-glucopyranoside, phenylethyl O-beta-D-glucopyranoside, (Z)-3-hexenyl O-beta-D-glucopyranoside, (7S,8R)-dehydrodiconiferyl 4-O-beta-D-glucopyranoside, and L-tryptophan. The absolute configuration at C-6 of the original structure of debilo-side A was revised to 6R-configuration, and was identical with macarangioside D (1). From the aerial portion of E. diffusum, four compounds, sammangaoside A, kaempferol 3-O-sophoroside and L-tryptophan and (3S,5R,6S,7E,9S)-megastigman-7-ene-5,6-epoxy-3,9-diol 3-O-beta-D-glucopyranoside were identified. The spectroscopic data of (3S,5R,6S,7E,9S)-megastigman-7-ene-5,6-epoxy-3,9-diol 3-O-beta-D-glucopyranoside (13) were found to be identical with corchoionoside A (9R-isomeric compound). The structure of corchoionoside A was also discussed. Structure determinations were based on physical data and spectroscopic evidence.     

On the structure of passifloricin A: asymmetric synthesis of the delta-lactones of (2Z,5S,7R,9S,11S)- and (2Z,5R,7R,9S,11S)tetrahydroxyhexacos-2-enoic acid

Stereoselective syntheses of the delta-lactone of (2Z,5S,7R,9S,11S)-tetrahydroxyhexacos-2-enoic acid, the structure reported for passifloricin A, and of its (5R)-epimer are described. The creation of all stereogenic centers relied upon Brown's asymmetric allylation methodology. The lactone ring was created via ring-closing metathesis. The NMR data of both synthetic products, however, were different from those of the natural product. The published structure of passifloricin A is thus erroneous and will require further synthetic work to be unambiguously assigned. [structure: see text]     

Co‐Assembled Supramolecular Nanostructure of Platinum(II) Complex through Helical Ribbon to Helical Tubes with Helical Inversion

We demonstrated the morphology transformation of co‐assemblies based on terpyridine‐based ligands ( 1R and 1S ) possessing R‐ or S‐alanine analogues and their platinum(II) complex ( 2R‐Pt and 2S‐Pt ). The right‐handed helical ribbon of the co‐assembly formed with 0.5 equivalents of 2R‐Pt to 1R was converted into the left‐handed helical ribbon with 0.6 equivalents of 2R‐Pt . The left‐handed helical ribbon structure of the co‐assembly became a tubular structure in the presence of 0.8–1.0 equivalents of 2R‐Pt . The morphology transformation via helical inversion at the supramolecular level was due to an orientation change of the amide groups caused by non‐covalent Pt???Pt interactions between the terpyridine of 2R‐Pt and that of 2R‐Pt . This study provides insights into controlling the morphology of the transformation of helical ribbons into tubular structures through helicity inversion in co‐assembled supramolecular nanostructures based on platinum(II) complexes.     

Reduction products of the alkaloid norfluorocurarine

The alkaloid norfluorocurarine was reduced under various conditions to produce the novel bisindoline derivative 2,16-dihydro-19-oxo-C-dihydrotoxiferine and the previously known natural derivatives deoxydihydro-, deoxytetrahydro-, and tetrahydronorfluorocurarine. The structures of the synthesized compounds were identified using IR and UV spectroscopy; of newly produced 2,16-dihydro-19-oxoC-dihydrotoxiferine and deoxydihydronorfluorocurarine, also by x-ray structure analysis. Determination of the absolute configuration of N(α)-methylfluorocurarine chloride dihydrate by x-ray methods enabled the configuration of the 3S,7R,15S asymmetric centers in norfluorocurarine and 2S,3S,7R,15S in deoxydihydronorfluorocurarine to be determined. Also, the absolute configuration of 2,16-dihydro-19-oxoC-dihydrotoxiferine was determined as 2S,3S,7R,15R,16R in one part of the bisindoline and 3'S,7'R,15'S in the other.     

A new 5,11-epoxymegastigmane glucoside from Acanthus ilicifolius

From a China mangrove plant Acanthus ilicifolius Linn., a new compound, 5,11-epoxymegastigmane glucoside (1) was isolated along with one known compound of megastigmane glucosides, (6S, 9S)-roseoside (2). The structure of compound 1 was determined on the basis of 1D- and 2D-NMR techniques (DEPT, COSY, HMBC, HMQC, NOESY) and HR-FABMS. The structure of 1 was established as (1S, 3S, 5R, 6R, 7E)-5,11-epoxy-3-hydroxymegastigman-7-en-9-one-3-O-beta-D-glucopyranoside.     

Total synthesis of (-)-crambidine and definition of the relative configuration of its unique tetracyclic guanidinium core

Total syntheses of the 3S,8S,10S,19R,43S isomer 4a and the 3S,8S,10S,19R,43R isomer 4b of the unique crambescidin alkaloid crambidine are reported. These studies confirm the tetracyclic structure proposed by Braekman and co-workers for crambidine, and establish the rel-3R,8R,10R,19S relative configuration for this moiety. Natural crambidine is most likely the 3S,8S,10S,19R,43S isomer 4a. These syntheses were completed in five steps and approximately 14% overall yield from 1-iminohexahydro[1,2-c]pyrimidine carboxylic ester 10, an intermediate in our earlier total synthesis of 13,14,15-isocrambescidin 800 (3). The signature step in the total syntheses of crambidine and several stereoisomers is chemoselective dehydrogenation of the tethered Biginelli adduct 10 or the derived tetracyclic intermediate 17. Additionally, these studies reveal the unprecedented ring-chain isomerization of the crambidine ring system exemplified by the interconversion of isomers 15a and 15b.