Alkaloids from Houttuyniae Cordata

The crude extract of Houttuyniae cordata showed potent anti-platelet and cytotoxic activities. The constituents of this plant, two pyridine alkaloids 1 and 2, along with three aporphine related alkaloids, cepharanone B (3), cepharadione B (4) and 7-choloro-6-demethyl cepharadione B (5) were characterized by spectral methods. Among them, long chain substituted pyridine alkaloids 1 and 2 are rare in nature, and the 7-choloro-6-demethyl cepharadione B (5) is isolated for the first time.     

A stereoselective synthesis of (2S,4R)-δ-hydroxyleucine methyl ester: a component of cyclomarin A

(2S,4R)-δ-Hydroxyleucine methyl ester, the N-demethyl analogue of an amino acid contained within the macrocycle of cyclomarin A, was successfully synthesized using Davis’ asymmetric Strecker reaction.     

STEREOSELECTIVE SYNTHESIS OF 9-METHYLENE-13-DEMETHYL ANALOGS OF NATURAL RETINOIDS

9-Methylene-13-demethyl analogs of retinol, retinal and retinoic acid, methyl ester were synthesised via new synthons β-methylenealdehydes.     

Synthesis of optically active methyl 7 beta-hydroxykaurenoate with potent neuroprotective activity

(-)-Methyl 7 beta-hydroxykaurenoate (3) and its 4-demethyl acetate (-)-4 were both synthesized via methods that contained radical cyclization and intramolecular Diels-Alder reactions as key steps. Both compounds displayed potent neuroprotective activity against N-methyl-D-aspartate toxicity in cultured cortical neurons.     

Structure of brefeldin A

On the basis of X-ray crystal structure analysis, CD. measurements, and asymmetric synthesis the absolute configuration of brefeldin A has been determined.     

Steric barrier to bathorhodopsin decay in 5-demethyl and mesityl analogues of rhodopsin

Absorbance difference spectra were recorded from 20 ns to 1 micros after 20 degrees C photoexcitation of artificial visual pigments derived either from 5-demethylretinal or from a mesityl analogue of retinal. Both pigments produced an early photointermediate similar to bovine bathorhodopsin (Batho). In both cases the Batho analogue decayed to a lumirhodopsin (Lumi) analogue via a blue-shifted intermediate, BSI, which formed an equilibrium with the Batho analogue. The stability of 5-demethyl Batho, even though the C8-hydrogen of the polyene chain cannot interact with a ring C5-methyl group to provide a barrier to Batho decay, raises the possibility that the 5-demethylretinal ring binds oppositely from normal to form a pigment with a 6-s-trans ring-chain conformation. If 6-s-trans binding occurred, the ring C1-methyls could replace the C5-methyl in its interaction with the chain C8-hydrogen to preserve the steric barrier to Batho decay, consistent with the kinetic results. The possibility of 6-s-trans binding for 5-demethylretinal also could account for the unexpected blue shift of 5-demethyl visual pigments and could explain why 5-demethyl artificial pigments regenerate so slowly. Although the mesityl analogue BSI's absorption spectrum was blue-shifted relative to its pigment spectrum, the blue shift was much smaller than for rhodopsin's or 5-demethylisorhodopsin's BSI. This suggests that increased C6-C7 torsion may be responsible for some of BSI's blue shift, which is not the case for mesityl analogue BSI either because of reduced spectral sensitivity to C6-C7 torsion or because the symmetry of the mesityl retinal analogue precludes having 6-s-cis and 6-s-trans conformers. The similarity of the mesityl analogue BSI and native BSI lambda(max) values supports the idea that BSI has a 6-s angle near 90 degrees, a condition which could disconnect the chain (and BSI's spectrum) from the double bond specifics of the ring.     

A synthesis of (±)-brefeldin A

A macrolide antibiotic, brefeldin A, was synthesized from trans-4-oxocyclopentane-1,2-dicarboxylic acid in a stereoselective manner, the intermediary hydroxy acid being lactonized by the mixed 2,4,6-trichlorobenzoic acid anhydride—4-dimethylaminopyridine method.     

Chiral analyses of dextromethorphan/levomethorphan and their metabolites in rat and human samples using LC-MS/MS

In order to develop an analytical method for the discrimination of dextromethorphan (an antitussive medicine) from its enantiomer, levomethorphan (a narcotic) in biological samples, chiral analyses of these drugs and their O-demethyl and/or N-demethyl metabolites in rat plasma, urine, and hair were carried out using LC-MS/MS. After the i.p. administration of dextromethorphan or levomethorphan to pigmented hairy male DA rats (5 mg/kg/day, 10 days), the parent compounds and their three metabolites in plasma, urine and hair were determined using LC-MS/MS. Complete chiral separation was achieved in 12 min on a Chiral CD-Ph column in 0.1% formic acid–acetonitrile by a linear gradient program. Most of the metabolites were detected as being the corresponding O-demethyl and N, O-didemethyl metabolites in the rat plasma and urine after the hydrolysis of O-glucuronides, although obvious differences in the amounts of these metabolites were found between the dextro and levo forms. No racemation was observed through O- and/or N-demethylation. In the rat hair samples collected 4 weeks after the first administration, those differences were more clearly detected and the concentrations of the parent compounds, their O-demethyl, N-demethyl, and N, O-didemethyl metabolites were 63.4, 2.7, 25.1, and 0.7 ng/mg for the dextro forms and 24.5, 24.6, 2.6, and 0.5 ng/mg for the levo forms, respectively. In order to fully investigate the differences of their metabolic properties between dextromethorphan and levomethorphan, DA rat and human liver microsomes were studied. The results suggested that there might be an enantioselective metabolism of levomethorphan, especially with regard to the O-demethylation, not only in DA rat but human liver microsomes as well. The proposed chiral analyses might be applied to human samples and could be useful for discriminating dextromethorphan use from levomethorphan use in the field of forensic toxicology, although further studies should be carried out using authentic human samples.     

A new phenanthroindolizidine alkaloid from Tylophora indica

A new phenanthroindolizidine alkaloid, 3-O-demethyl tylophorinidine (VI), was isolated from the aerial (leaves and stem) parts of Tylophora indica and characterized using different spectral techniques. Gel chromatography and reverse phase preparative HPLC were used for sample purification. The new alkaloid, VI, was screened for anticancer activity against a panel of different cancer cell lines and it showed significant anticancer activity with IC₅₀ value in the range of 0.89?C1.40 ??M.     

Minor components with the γ-cyclogeranil geraniol skeleton from Bellardia trixago (L.) all.

Trixagol 1 and fourteen derivatives with the skeleton of γ-cyclogeranil geraniol were isolated from Bellardia trixago, the structures were determined by spectroscopic methods and confirmed by partial synthesis. Furthermore. 3,4-dihydro-γ-ionone, α-ambrinol, β-sitosterol and three flavonoids 5-O-demethyl tangeretin, 5-hydroxy auranetin and 3′-methoxy calycopterin were also isolated.     

Enantioselective total synthesis of 13-O-brefeldin A

An enantioselective route to the title compound, a heteroatom substituted close analogue of natural brefeldin A, is described. As a key step in the whole synthesis, concatenation of the lower chain and the cyclopentanone-upper chain moiety was achieved using a Rh-catalyzed Michael addition of a vinyl boronic acid to an enone, which effectively eliminated the problems encountered with the corresponding cuprate protocol and exemplified the potential of the strategy in synthesizing similar analogues.     

Brefeldin A全合成研究新进展

Brefeldin A(布雷菲德菌素甲)是一种天然抗生素, 最早发现于1958年, 许多种微生物中都能产生该化合物. 由于其有趣的结构和显著的抗真菌、抗病毒、抗肿瘤等生物活性, 该化合物很早就引起合成化学家们的注意. 到目前为止, 文献中有报道的全合成和表观合成已有30多种. 对近十年来的全合成及部分表观合成进行了综述, 对各路线的主要优缺点也进行了简要的分析. 一些类似物的合成也一并予以简介.     

Sarkomycin A methyl esters and functionalized cyclopentane blocks for brefeldin A

Sarkomycin A methyl esters and functionalized cyclopentane blocks for brefeldin A were synthesized starting from diastereoisomeric (1R,2S)- and (1S,2R)-2-hydroxymethyl-N-[(1R)-1-phenylethyl]cyclopent-3-ene-1-carboxamides.     

New brefeldins and penialidins from marine fungus Penicillium janthinellum DT-F29

A fermentation of marine fungus Penicillium janthinellum DT-F29 on solid rice medium led to the isolation of three new compounds, brefeldin D (1) and penialidins D-E (5–6), along with other five known brefeldins and penialidins. The structures of above compounds were determined on the basis of MS and NMR analysis.     

Synthesis and properties of poly(dimethylxylylenylamides)

Poly(dimethylxylylenylamides) were synthesized from six different diphenylenediamenes and two dimethyl-substituted xylylenyldiacid chlorides by solution polycondensation at low temperature. The model compound 2,5-demethyl1,4-benzediacetanilide was synthesized and characterized by infrared (IR) and nuclear magnetic resonance (NMR) spectroscopy. The polyamides were characterized by IR and viscosity measurements. Some of the polyamides showed crystalline behavior in the x-ray diffractograms. The polyamdes have decomposition temperatures in the range 370–310°C in air and are soluble in all amide solvents. The effects of subsituents on crystallinity, thermal stability, and solubility of the polymides are also discussed.     

Modification of 3-substituents in (bacterio)chlorophyll derivatives to prepare 3-ethylated, methylated, and unsubstituted (nickel) pyropheophorbides and their optical properties

Methyl mesopyropheophorbide-a possessing an ethyl group at the 3-position, its 3(1)-demethyl analogue (3-methyl homologue), and its 3(1)-deethyl analogue (3-unsubstituted chlorin) were prepared by modifying naturally occurring (bacterio)chlorophylls bearing 3-vinyl, formyl, acetyl, and 1-hydroxyethyl groups. These synthetic 3-(un)substituted chlorophyll derivatives and their nickel complexes are probable intermediates during degradation of (bacterio)chlorophylls to chemically stable porphyrinoids. The optical properties (visible absorption, circular dichroism, and fluorescence emission) of the catabolic candidates in a solution were measured, and the substitution effect was investigated.     

New analogues of brefeldin A from sediment-derived fungus Penicillium sp. DT-F29

Four new analogues of brefeldin A named 7, 7-dimethoxybrefeldin C (3), 6β-hydroxybrefeldin C (4), 4-epi-15-epi-brefeldin A (5), 4-epi-8α-hydroxy-15-epi-brefeldin C (6), together with four known analogues (1, 7?9) were isolated from a fermentation of the sediment-derived fungus Penicillium sp. DT-F29. The structures of these compounds were elucidated on the basis of extensive spectroscopic and chemical methods. In the bioactivity assays, only compounds 1 and 8 showed significant inhibitory activities against human lung adenocarcinoma cell. In addition, compound 1 was first reported for the potent ability to reactivate latent HIV with EC₅₀ value of 0.03 μM.     

Conformational Properties of 3-Phenylpiperidine and 3-Phenylpyrrolidine Opioid Analgesics

Conformational energy calculations have been performed on 3-phenylpiperidine and 3-phenylpyrrolidine opioids using the MM2 method. Phenyl equatorial conformers were found to be preferred for 1,2,3-trimethyl-3-phenylpiperidines while phenyl axial conformers were preferred for the 2-demethyl derivative and 1-methyl-3-isobutyl-3-phenylpyrrolidine. These conformational differences may account for differences in their structure-activity relationships. The geometries of these compounds were superimposed onto a rigid phenyl-axial opioid with the result that the more active antipodes of alpha-2,3-dimethyl-3-phenylpiperidine and 3-isobutyl-3-phenylpyrrolidine antagonists were found to be a better fit. However, for the beta derivative, which has not yet been resolved, the opposite antipode was found to be a better fit though the orientation of NH bond was quite different. There is a good agreement between the computed molecular geometries and those observed by x-ray crystallography.     

Isolation and purification of macrocyclic components from Penicillium fermentation broth by high‐speed counter‐current chromatography

In this paper, high‐speed counter‐current chromatography (HSCCC), assisted with ESI‐MS, was first successfully applied to the preparative separation of three macrolide antibiotics, brefeldin A (12.6 mg, 99.0%), 7′‐O‐formylbrefeldin A (6.5 mg, 95.0%) and 7′‐O‐acetylbrefeldin A (5.0 mg, 92.3%) from the crude extract of the microbe Penicillium SHZK‐15. Considering the chemical nature and partition coefficient (K) values of the three target compounds, a two‐step HSCCC isolation protocol was developed in order to obtain products with high purity. In the two‐step method, the crude ethyl acetate extract was first fractionated and resulted in two peak fractions by HSCCC using solvent system n‐hexane/ethyl acetate/methanol/water (HEMWat) (3:7:5:5 v/v/v/v), then purified using solvent systems HEMWat (3:5:3:5 v/v/v/v) and HEMWat (7:3:5:5 v/v/v/v) for each fraction. The purities and structures of the isolated compounds were determined by HPLC, X‐ray crystallography, ESI‐MS and NMR. The results demonstrated that HSCCC is a fast and efficient technique for systematic isolation of bioactive compounds from the microbes.     

4-Oxo-2-cyclopentenyl Acetate—A Synthetic Intermediate

The present day importance of cyclopentenone derivatives in preparative organic chemistry and especially in natural product chemistry is demonstrated by the stereoselective synthesis of substituted and annelated cyclopentanone derivatives. It has been found that 4-oxo-2-cyclopentenyl acetate (“4-acetoxy-2-cyclopenten-1-one”) can be used in many reactions as a substitute for cyclopentadienone, which is itself too unstable to be isolated. A large variety of polyfunctionalized cyclopentanone derivatives, as well as carbocyclic and heterocyclic annelation products, can thus be obtained in a simple way. Various stereoselective transformations of the adducts so formed are presented, using the total synthesis of brefeldin A—a typical natural product of this series—as example. Several methods for the synthesis of 4-oxo-2-cyclopentenyl acetate are outlined and, in addition, the more important methods for the enantioselective synthesis of other 4-substituted 2-cyclopenten-1-ones are discussed.