Synthesis of 5'-amino-5'-phosphonate analogues of pyrimidine nucleoside monophosphates

The 5'-amino-5'-phosphono derivatives of cytidine, cytosine arabinoside (ara-C), and uridine have been prepared via the corresponding nucleoside aldehydes. Phosphite addition to imines derived from the nucleoside aldehydes and p-methoxybenzylamine was efficient, and use of this amine allowed cleavage of the products to the parent amino phosphonic acids. The phosphite additions proved to be diastereoselective, with the cytidine and uridine derivatives favoring the 5'S stereochemistry and the ara-C derivative favoring the 5'R isomer. The stereochemistry of one cytidine derivative was established by single-crystal diffraction analysis, and detailed comparisons of the (13)C NMR data allowed assignments of the other amino phosphonates.     

Alpha-phosphono lactone analogues of cytidine and cytosine arabinoside diphosphates: synthesis via ring closing metathesis

alpha-Phosphono lactone derivatives of the nucleosides cytidine and cytosine arabinoside have been prepared from the corresponding nucleoside aldehydes. The stereochemical outcome of allylation reactions with these aldehydes was found to be dependent upon both the choice of protecting groups for the 2'- and 3'-hydroxyl groups and, to some extent, the nature of the Lewis acid catalyst employed. Ultimately, conditions were found that favored either the 5'R or 5'S diastereomer from different cytidine aldehydes, and gave some stereoselectivity in additions to an aldehyde derivative of ara-C. The resulting homoallylic alcohols were used as substrates in attempted Knovenagel and Horner-Wadsworth-Emmons condensations, but elimination was found to predominate over lactone formation under the conditions employed. The desired alpha-phosphono lactones could be prepared through a reaction sequence that included ring-closing metathesis on acrylate esters of the homoallylic alcohols, followed by reduction of the resulting alpha,beta-unsaturated lactones and carbon-phosphorus bond formation on enolates generated from the saturated lactones.     

Synthesis and assignment of the absolute configuration of the anti-Helicobacter pylori agents CJ-12,954 and CJ-13,014

The synthesis of the spiroacetal-containing anti-Helicobacter pylori agents (3S,2'S,5'S,7'S)- (ent-CJ-12,954) and (3S,2'S,5'R,7'S)- (ent-CJ-13,014) has been carried out based on the convergent union of a 1:1 mixture of heterocycle-activated spiroacetal sulfones and with (3S)-phthalide aldehyde . The synthesis of the (3R)-diastereomers (3R,2'S,5'S,7'S)- and (3R,2'S,5'R,7'S)- was also undertaken in a similar manner by union of (3R)-phthalide aldehyde with a 1:1 mixture of spiroacetal sulfones and . Comparison of the (1)H and (13)C NMR data, optical rotations and HPLC retention times of the synthetic compounds (3S,2'S,5'S,7'S)- and (3S,2'S,5'R,7'S)- and the (3R)-diastereomers (3R,2'S,5'S,7'S)- and (3R,2'S,5'R,7'S)-, with the naturally occurring compounds, established that the synthetic isomers and were in fact enantiomeric to the natural products CJ-12,954 and CJ-13,014. The (2S,8S)-stereochemistry in protected dihydroxyketone , the precursor to the mixture of spiroacetal sulfones and was established via union of readily available (S)-acetylene with aldehyde in which the (4S)-stereochemistry was established via asymmetric allylation. Deprotection and cyclization of protected dihydroxyketone afforded an inseparable 1:1 mixture of spiroacetal alcohols and that were converted into a 1:1 inseparable mixture of spiroacetal sulfones and . Phthalide-aldehyde was prepared via intramolecular acylation of bromocarbamate in which the (3S)-stereochemistry was established via asymmetric CBS reduction of ketone .     

Independent generation of C5'-nucleosidyl radicals in thymidine and 2'-deoxyguanosine

The synthesis of the C5' tert-butyl ketone of thymidine 1a and 2'-deoxyguanosine 2 is achieved by reaction of 5'-C-cyano derivatives with tert-butyl lithium followed by acid hydrolysis. The 5'R configuration is assigned by X-ray crystal structure determination of an opportunely protected derivative of 1a. The (5'S)-isomers of both nucleosides are not stable, and a complete decomposition occurs in the reaction medium. The photochemistry of 1a and 2 effectively produced the thymidin-5'-yl radical and the 2'-deoxyguanosin-5'-yl radical, respectively. In the thymidine system, the C5' radical is fully quenched in the presence of a physiological concentration of thiols. In the 2'-deoxyguanosine system, the C5' radical undergoes intramolecular attack onto the C8-N7 double bond of guanine leading ultimately to the 5',8-cyclo-2'-deoxyguanosine derivative. The cyclization of the 2'-deoxyguanosin-5'-yl radical occurs with a rate constant of ca. 1x10(6) s-1 and is highly stereoselective affording only the (5'S)-diastereomer.     

Synthesis of pipecolic acid-based spiro bicyclic lactam scaffolds as beta-turn mimics

A series of 6.5.5 spiro bicyclic lactam scaffolds were synthesized from pipecolic acid in a sequence of reactions that was initiated with the alpha-allylation of tert-butoxycarbonyl pipecolic acid. Oxidative cleavage of the olefin to give an aldehyde followed by condensation with D-cysteine methyl ester gave a mixture of pipecolyl thiazolidines. Cyclization of the pipecolyl thiazolidines with Mukaiyama's reagent yielded the spiro bicyclic lactams 4a-d. Epimerization of the 7'a bridgehead carbon under acidic conditions was observed for those spiro bicyclic lactam scaffolds with an S stereochemistry at this position. The 6.5.5 spiro bicyclic lactam scaffold with the 3'S,6'R,7'aR stereochemistry mimicked a type II beta-turn, while the scaffold with the 3'S,6'S,7'aR stereochemistry mimicked a right-handed poly-d-proline II helix.     

Improved preparation of (1S,3’R,4’S,5’S,6’R)-5-chloro-6-[(4-ethylphenyl)methyl]-3’,4’,5’,6’-tetrahydro-6’-(hydroxymethyl)-spiro[isobenzofuran-1(3H),2’-[2H]pyran]-3’,4’,5’-triol

A convenient approach for the preparation of(1S,3’R.4’S,5’S,6’R)-5-chloro-6-[(4-ethylphenyl)methyl]- 3’,4’,5’,6’-tetrahydro-6’-(hydroxymethyl)-spiro[isobenzofuran-1(3H),2’-[2H]pyran]-3’,4’,5’-triol is developed. The targeted compound was synthesized from 2-bromo-4-methylbenzoic acid in nine steps and the isomers of undesired ortho-products were avoided during the preparation.     

Intermolecular interactions in (arene)chromium carbonyl compounds: prediction of chiral crystal packing from racemate structure

Six X-ray crystal structures are reported, all containing substituted triphenylmethanol derivative 4 either alone or as its mono or bis(chromium tricarbonyl) complexes. All four chromium complexes studied crystallize with two independent molecules in the crystallographic asymmetric unit. It is demonstrated that from the X-ray crystal structure of the acentric racemic (+/-)-(1pR,1' 'R)(1pS,1' 'S)-[Cr(CO)(3)(eta(6)-t-BuC(6)H(3)(CMeOMe)CPh(2)OH)], (+/-)-3, it is possible to deduce the 4-fold helical structure of the chiral (-)-(1pR,1' 'R) isomer, (-)-3. The bimetallic derivatives demonstrate the ability to control intermolecular interactions by the positioning of relative stereochemistry.     

New ent-kaurane diterpenes with chiral epoxyangelate moieties from Wedelia prostrata

Four new ent-kaurane diterpenes with chiral epoxyangelate moieties, (2′R,3′R)-3 a- (2′,3′-epoxyangeloyloxy)-kaur-16-en-19-oic acid (1), (2′S,3′S)-3 a- (2′,3′-epoxyangeloyloxy)-kaur-16-en-19-oic acid (2), (2′S,3′R)-3 a- (2',3'-epoxyangeloyloxy)-kaur-16-en-19-oic acid (3) and (2′R,3′S)-3α- (2′,3'-epoxyangeloyloxy)-kaur-16-en-19-oic acid (4), along with eight known diterpenes (5-12), were isolated from Wedelia prostrata. The absolute configurations of the new structures were determined by X-ray crystallography,ECD calculations and chemical methods. All compounds were evaluated for their cytotoxicity activities on human HepG-2 cells,with IC_(50) values of 11.72 ±0.22 μmol/L to 54.75±1.12 μmol/L.     

Lignans and neolignans from Myristica argentea Warb

The petrol extract from mace of Myristica argentea Warb. afforded six phenylpropenes, three lignans, three neolignans and a dilignan, bis erythro-argenteane (4) or rel-(8R,8'S,8"S,8"'R)-5',5"'-bis(7-(3,4-methylenedioxyphenyl)-7'-(4'-hydroxy-3'-methoxyphenyl)-8.8'-lignane]. The last-named compound is a new natural product.     

Solar one-way photoisomerisation of 5',8-cyclo-2'-deoxyadenosine

Under sunlight irradiation (5'S)-5',8-cyclo-2'-deoxyadenosine 2 photoisomerises to the (5'R) isomer 1, which is the more easily repaired damage when these cyclopurine lesions are formed in DNA.     

A stereodivergent,two-directional synthesis of stereoisomeric C-linked disaccharide mimetics

Dipyranones, such as 1,2-bis[(2R,3S,6S)-3-hydroxy-6-methoxy-3-oxo-6H-pyran-2-yl]ethane, were exploited as templates for the synthesis of some novel C-linked disaccharide analogues. Efficient methods, such as stereoselective reduction and dihydroxylation, were developed for two-directional functionalisation of these templates. Peracetylated derivatives of ten stereoisomeric disaccharide analogues [acetic acid 4,5-diacetoxy-6-methoxy-[(3',4',5'-triacetoxy-6'-methoxytetrahydropyran- 2'-yl)ethyl]tetrahydropyran-3-yl esters] were synthesised from a virtual library of 136 compounds; furthermore, an additional eight stereoisomers could have been synthesised simply by using the enantiomeric ligand in the enantioselective step. The ability of (2S,3S,4R,5R,6R)-6-methoxy-2-[2'-((2'R,3'R,4'S, 5'R,6'S)-3',4',5'-trihydroxy-6'-methoxytetrahydropyran-2'-yl) ethyl]tetrahydropyran-3,4,5-triol to bind to the repressor protein, LacI, was estimated to be similar to that of isopropyl-beta-thiogalactoside. The disaccharide mimetics were concluded to be a new and interesting class of C-linked disaccharide mimetics with promising, though largely unstudied, biological activity.     

Antimicrobial C-glucoside from aerial parts of Diospyros nigra

A new C-alkylglucoside, diospyrodin [beta-1C-(1'S*,2'R*,3'R*,4'S*-1',2',3',4',5'-pentahydroxypentyl)-glucopyranoside] (1) has been isolated as its nonaacetate from the leaves and stems of Diospyros nigra. Its structure was elucidated on the basis of chemical and spectral properties and a single crystal X-ray analysis. It showed antimicrobial activity against Gram-positive and Gram-negative bacteria.     

4',5'-SUBSTITUTED METHYLANGELICINS: PHOTOCYCLOADDUCTS WITH PYRIMIDINE BASES OF DNA

The isolation and characterization of photocycloadducts with pyrimidine bases from DNA samples irradiated (365 nm) in the presence of four 4',5'-substituted methylangelicins was performed. All these furocoumarins yielded mainly the cis-syn furan-side cycloadduct with thymine. For 4',5'-dimethyl-, 5,4',5'-trimethyl- and 6,4',5'-trimethylangelicin this adduct was accompanied by two pyrone-side adducts ( cis-syn and cis-anti ), whereas the 4,4',5'-trimethyl derivative gave the furan-side adduct with cytosine.
The characterization of the regio- and stereochemistry of the adducts was accomplished by ¹H NOE (nuclear Overhauser effect) and ¹H-¹³C HMBC (heteronuclear multiple-bond connectivity) spectroscopies.
The formation of different cycloadducts in DNA by the various derivatives highlights the role of the methyl groups in determining the regio- and stereochemistry of the cycloaddition.     

Addition of difluorocarbene to 4',5'-unsaturated nucleosides: synthesis and deoxygenation reactions of difluorospirocyclopropane nucleosides

Synthetic routes to 4'-(2,2-difluorospirocyclopropane) analogues of adenosine, cytidine, and uridine are described. Treatment of 2',3'-O-isopropylidene-4',5'-unsaturated compounds derived from adenosine and uridine with difluorocarbene (generated from PhHgCF3 and NaI) gave diastereomeric mixtures of the 2,2-difluorospirocyclopropane adducts. Stereoselectivity resulting from hindrance by the isopropylidene group favored addition at the beta face. Removal of base and sugar protecting groups gave new difluorospirocyclopropane nucleoside analogues. The protected uridine analogue was converted into its cytidine counterpart via a 4-(1,2,4-triazol-1-yl) intermediate. Stannyl radical-mediated deoxygenation of the 3'-O-TBS-2'-thionocarbamate derivatives gave the 2'-deoxy products of direct hydrogen transfer. In contrast, identical treatment of the 2'-O-TBS-3'-thionocarbamate isomers resulted in opening of the vicinal difluorocyclopropane ring upon generation of a C3' radical followed by homoallylic hydrogen transfer to give 4'-(1,1-difluoroethyl)-3',4'-unsaturated nucleoside derivatives. Structural aspects and biological effect considerations are discussed.     

Isolation and characterization of dinochrome A and B,anti-carcinogenic active carotenoids from the fresh Water red tide Peridinium bipes

Two epimeric carotenoids, named dinochromes A (2) and B (3), were isolated from the fresh water red tide Peridinium bipes, as anti-carcinogenic compounds. The stereostructure of dinochrome A and B were characterized to be (3S,5R,6R,3'S,5'R,8'R)- and (3S,5R,6R,3'S,5'R,8'S)-5',8'-epoxy-6,7-didehydro-5,6,5',8'-tetrahydro-beta,beta-carotene-3,5,3'-triol 3-O-acetate, respectively by (1)H- and (13)C-NMR, and circular dichroism (CD) data. Dinochromes A (2) and B (3) inhibit 12-O-tetradecanoyl phorbol 13-acetate (TPA)-stimulated (32)P-incorporation into the phosholipids of HeLa cells. Furthermore, dinochrome A was found to inhibit the proliferation of human malignant tumor cells, such as GOTO, OST and HeLa cells.     

Synthesis of 3'-deoxynucleosides with 2-oxabicyclo[3.1.0]hexane sugar moieties: addition of difluorocarbene to a 3',4'-unsaturated uridine derivative and 1,2-dihydrofurans derived from D- and L-xylose1

Syntheses of 3'-deoxy analogues of adenosine, cytidine, and uridine with a 2,2-difluorocyclopropane ring fused at C3'-C4' are described. Treatment of a 2',5'-protected-3',4'-unsaturated derivative of uridine with difluorocarbene [generated from (CF3)2Hg and NaI] gave a diastereomeric mixture of the 3',4'-difluoromethylene compounds (alpha-L-arabino/beta-D-ribo, approximately 5:4). The limited stereoselectivity for addition at the beta face results from competitive steric hindrance by an allylic 4-methoxybenzyloxy group at C2' on the alpha face and a homoallylic nucleobase at C1' on the beta face. Protected uracil derivatives were converted into their cytosine counterparts via 4-(1,2,4-triazol-1-yl) intermediates. Treatment of 1,2-dihydrofurans derived from D- and L-xylose with difluorocarbene resulted in stereospecific addition at the beta face (anti to the 1,2-O-isopropylidene group on the alpha face). Glycosylations with activated enantiomeric sugar derivatives with the fused difluorocyclopropane ring on the beta face gave protected adenine nucleosides, whereas attempted glycosylation with an alpha-fused derivative gave multiple products. Removal of base- and sugar-protecting groups gave new difluoromethylene-bridged nucleoside analogues.     

NMR confirmation that tryptophan dehydrogenation occurs with syn stereochemistry during the biosynthesis of CDA in Streptomyces coelicolor

Doubly labeled (2'S,3'R)-[3'-2H1,13C1]-tryptophan was fed to the Trp-His auxotrophic Streptomyces coelicolor strain WH101. Mass spectrometry showed single and double incorporation of the labeled Trp into the calcium-dependent lipopeptide antibiotic (CDA4a). From 13C NMR spectroscopy, it was apparent that the C3'-signal of the (Z)-2',3'-dehydrotryptophan (position 11 in CDA4) was a 1:1:1 triplet indicating that the deuterium atom in the pro-R position of the methylene group is retained during Trp-oxidation. This provides definitive proof that Trp dehydrogenation occurs through the loss of the 2' and pro-3'S hydrogen atoms with overall syn stereochemistry.     

Purine 5',8-cyclonucleoside lesions: chemistry and biology

5',8-Cyclo-2'-deoxyadenosine and 5',8-cyclo-2'-deoxyguanosine in their 5'R and 5'S diastereomeric forms are tandem-type lesions observed among the DNA modifications and identified in mammalian cellular DNA in vivo. These lesions result from the chemistry of the C5' radicals generated by the attack of HO˙ radicals to 2-deoxyribose units. Quantitative determination of these lesions in biological samples as biomarkers of free radical damage is a challenge. Results reported for irradiated samples of calf thymus DNA have been critically reviewed, underlining the need of further research for the potential involvement of these lesions in human health (76 references).     

Neolignans from Piper futokadsura and their inhibition of nitric oxide production

From a MeOH extract of the aerial part of Piper futokadsura, the tetrahydrofuran lignans, futokadsurin A [(7S,8S,7'S,8'R)-3,4,3'-trimethoxy-4'-hydroxy-7,7'-epoxylignan], futokadsurin B [(7R,8R,7'R,8'S)-3,4-dimethoxy-3',4'-methylenedioxy-7,7'-epoxylignan], and futokadsurin C [(7R,8R,7'S,8'S)-3,4-methylenedioxy-3',4'-dimethoxy-7,7'-epoxylignan] were isolated, together with nine known neolignans. In addition, L-tryptophan, pellitorine, phytol, elemicin, and 1,2,4-trimethoxyphenyl-5-aldehyde were isolated. The structures of the new compounds were elucidated using spectroscopic methods. These lignans inhibited nitric oxide production by a murine macrophage-like cell line (RAW 264.7), which was activated by lipopolysaccharide and interferon-gamma.     

NEOLIGNANS FROM PIPER KADSURA(Ⅱ)

Two new bicyclo[3,2,1]octanoid neolignans,named as kadsurenin I andkadsurenin J were isolated from Piper kadsura(Choiey)Ohwi.Based on the spectros-copic analysis(UV,IR,MS and NMR)and chemical derivatization,their structures wereestablished as 7R,8R,1'R,2'S,3'R-Δ~s'-3,4,5'-trimethoxy-2'-hydroxy-1',2',3',4'-tetrahydro-4'-oxo-7.3',8.1'-neolignan and 7R,8R,1'R,2'S,3'R-Δ~s'-3,4,5'-trimethoxy-2'-acetoxy-1',2',3',4'-tetrabydro-4'-oxo-7.3',8.1'-neolignan respectively.