A chiron approach towards the synthesis of 3-hydroxy lysine and its derivatives

A general and efficient route towards the synthesis of three derivatives of structurally and functionally important amino acid, lysine is reported. Chemoselective reduction of aldehydic functionality in C-3-azido conjugated aldehyde 4, under Luche condition, is the key step in the synthetic sequence. The lysine derivative, (2S,3R)-2,6-diazido-3-hydroxy-hex-4-ene-oic acid 9 could be used to prepare switch peptide using Staudinger reaction, while the unprotected (2S,3R)-2,6-diamino-3-hydroxy-hexanoic acid hydrochloride 10 is a proven reaction intermediate towards the synthesis of natural product (?)-Balanol.     

A novel synthetic approach to (20R)- and (20S)-21-hydroxy steroids. Synthesis of a marine sterol 21-hydroxycholesterol

A short and efficient synthesis of steroid synthons, di(tert-butyldimethylsilyl) ethers of 3,21-dihydroxy-24-nor-chol-5-en-23-al (8 and 10) and of ethyl 3,21-dihydroxy-25-homo-chola-5,23-dien-25-oate (9 and 11), having natural (20R) and unnatural (20S) configuration from 3β-(tert-butyldimethylsilyloxy)-14α,20ξ-card-5-enolide (2) is reported. Further elongation of the side chain of these synthons provides a new method for the synthesis of (20R) and (20S)-21-hydroxy steroids. The utility of the method was exemplified by the synthesis of a natural marine sterol - 21-hydroxycholesterol (18).     

A fused pyrrolidotriazole derivative from bis(ethylsulphonyl)-(2,3-O-isopropylidene-4-O-methanesulphonyl-α-D-lyxopyranosyl)methane

Reaction of bis(ethylsulphonyl)-(2,3-O-isopropylidene-4-O-methanesulphonyl-α-D-lyxopyranosyl)methane (1) with sodium azide in N,N-dimethylformamide gave 1(S)-hydroxymethyl-2(R),3(S)-isopropylidenedioxypyrrolido-[1,2-c]-4-ethylsulphonyl-1,2,3-triazole (5). The latter was identified by p.m.r. and mass spectrometry, and by degradation to, and unambiguous synthesis of, 4-ethylsulphonyl-1,2,3-triazole (17).     

Synthesis,antimycobacterial and cytotoxic activity of α,β-unsaturated amides and 2,4-disubstituted oxazoline derivatives

The synthesis of six α,β,-unsaturated amides and six 2,4-disubstituted oxazolines derivatives and their evaluation against two Mycobacterium tuberculosis strains (sensitive H37Rv and a resistant clinical isolate) is reported. 2,4-Disubstituted oxazolines (S)-3b,d,e were the most active in the sensitive strain with a MIC of 14.2, 13.6 and 10.8 μM, respectively, and the compounds (S)-3d,f were the most active against resistant strain with a MIC of 6.8 and 7.4 μM. The ex-vivo evaluation of hepatotoxicity on precision-cut rat liver slices was also tested for the α,β-unsaturated amides (S)-2b and (S)-2d,f and for the oxazolines (S)-3b and (S)-3d,f at different concentrations (5, 15 and 30 μg/mL). The results indicate that these compounds possess promising antimycobacterial activity and at the same time are not hepatotoxic. These findings open the possibility for development of new drugs against tuberculosis.     

Synthesis and biological evaluation of enantiomerically pure glyceric acid derivatives as LpxC inhibitors

Inhibitors of the UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC) represent a promising class of novel antibiotics, selectively combating Gram-negative bacteria. In order to elucidate the impact of the hydroxymethyl groups of diol (S,S)-4 on the inhibitory activity against LpxC, glyceric acid ethers (R)-7a, (S)-7a, (R)-7b, and (S)-7b, lacking the hydroxymethyl group in benzylic position, were synthesized. The compounds were obtained in enantiomerically pure form by a chiral pool synthesis and a lipase-catalyzed enantioselective desymmetrization, respectively. The enantiomeric hydroxamic acids (R)-7b (K_i = 230 nM) and (S)-7b (K_i = 390 nM) show promising enzyme inhibition. However, their inhibitory activities do not substantially differ from each other leading to a low eudismic ratio. Generally, the synthesized glyceric acid derivatives 7 show antibacterial activities against two Escherichia coli strains exceeding the ones of their respective regioisomes 6.     

Eudistomidin G,a new β-carboline alkaloid from the Okinawan marine tunicate Eudistoma glaucus and structure revision of eudistomidin B

A new β-carboline alkaloid, eudistomidin G (1), has been isolated from the Okinawan marine tunicate Eudistoma glaucus, and the structure was elucidated from spectroscopic data. Furthermore, the structure of eudistomidin B (2), which has been isolated from the same tunicate, was revised from 2a to 2b by detailed analyses of spectroscopic data. Asymmetric synthesis of the revised structure (2b) of eudistomidin B (2) and its (1S,10S)-diastereomer (2c) has been accomplished with the Noyori catalytic asymmetric hydrogen-transfer reaction. The absolute configuration of eudistomidin B (2) was confirmed to be 2b possessing (1R,10S)-configuration, from comparison of the ¹H NMR data, CD spectra, [α]_D values, and HPLC analysis of 2b, 2c, and natural eudistomidin B.     

Synthesis and antimalarial evaluation of a screening library based on a tetrahydroanthraquinone natural product scaffold

As part of a research program aimed at discovering new antimalarial leads from Australian macrofungi a unique fungi-derived prefractionated library was screened against a chloroquine-sensitive Plasmodium falciparum line (3D7) using a radiometric growth inhibition assay. A library fraction derived from a Cortinarius species displayed promising antimalarial activity. UV-guided fractionation on the CH₂Cl₂/MeOH extract from this fungus resulted in the isolation of four known compounds: (1S,3R)-austrocortirubin (1), (1S,3S)-austrocortirubin (2), 1-deoxyaustrocortirubin (3), and austrocortinin (4). Compound 2 was used as a natural product scaffold in the parallel solution-phase synthesis of a small library of N-substituted tetrahydroanthraquinones (5–15). All compounds (1–15) were tested in vitro against P. falciparum 3D7 parasites and (1S,3S)-austrocortirubin (2), the major fungal constituent, was shown to be the most active compound with an IC₅₀ of 1.9 μM. This compound displayed moderate cytotoxicity against neonatal foreskin fibroblast (NFF) cells with an IC₅₀ of 15.6 μM.     

Two new isodrimene sesquiterpenes from the fungal culture broth of Polyporus arcularius

Two new isodrimene sesquiterpene derivatives, 2(S)-hydroxyalbicanol (1, =(2S,4aS,8S,8aS)-8-(hydroxymethyl)-4,4,8a-trimethyl-7-methylenedecahydronaphthalen-2-ol) and 2(S)-hydroxyalbicanol 11-acetate (2, =((1S,4aS,7S,8aS)-7-hydroxy-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)methyl acetate) were isolated from the culture broth of the fungus Polyporus arcularius, together with two phenylpropanediols, (1S,2S)- and (1R,2S)-1-phenyl-1,2-dihydroxypropane (3, 4). Compound 3 is reported as a naturally occurring compound for the first time. The structures of the compounds were elucidated on the basis of spectroscopic analysis. Compound 1 exhibited growth inhibition of lettuce seedlings with IC₅₀ values of 1.3 mM to hypocotyl and 1.7 mM to radicle.     

Neoflavanoids of Dalbergia melanoxylon

The heartwood of Dalbergia melanoxylon has yielded new examples of known neoflavanoid types. The isolates included 4-phenylcoumarins, (S)-4-methoxydalbergiones and benzophenones which have the corresponding oxygenation pattern. The structures of the extractives have been examined by physical methods, and confirmed by conversion to known compounds or by independent synthesis. A 2-cinnamylphenol (6) and 3-cinnamylflavan (7) were the only products in a condensation reaction in the attempted synthesis of the 4-methoxydalbergione (1b).     

Identification of RC-33 as a potent and selective σ1 receptor agonist potentiating NGF-induced neurite outgrowth in PC12 cells. Part 2: g-Scale synthesis,physicochemical characterization and in vitro metabolic stability

Strong pharmacological evidences indicate that σ1 receptors are implicated in the pathophysiology of all major CNS disorders. In the last years our research group has conducted extensive studies aimed at discovering novel σ1 ligands and we recently selected (R/S)-RC-33 as a novel potent and selective σ1 receptor agonist. As continuation of our work in this field, here we report our efforts in the development of this new σ1 receptor agonist. Initially, we investigated the binding of (R) and (S) enantiomers of RC-33 to the σ1 receptor by in silico experiments. The close values of the predicted affinity of (R)-RC-33 and (S)-RC-33 for the protein evidenced the non-stereoselective binding of RC-33 to the σ1 receptor; this, in turn, supported further development and characterization of RC-33 in its racemic form. Subsequently, we set-up a scaled-up, optimized synthesis of (R/S)-RC-33 along with some compound characterization data (e.g., solubility in different media and solid state characterization by thermal analysis techniques). Finally, metabolic studies of RC-33 in different biological matrices (e.g., plasma, blood, and hepatic S9 fraction) of different species (e.g., rat, mouse, dog, and human) were performed. (R/S)-RC-33 is generally stable in all examined biological matrices, with the only exception of rat and human liver S9 fractions in the presence of NADPH. In such conditions, the compound is subjected to a relevant oxidative metabolism, with a degradation of approximately 65% in rat and 69% in human.Taken together, our results demonstrated that (R/S)-RC-33 is a highly potent, selective, metabolically stable σ1 agonist, a promising novel neuroprotective drug candidate.     

6′-Methyl-5′-homoaristeromycin: A structural variation of the anti-orthopox virus candidate 5′-homoaristeromycin

The synthesis of 6′-methyl-5′-homoaristeromycin is described from a known 6′-ethyl ester. Antiviral analysis showed the (S)-6′ stereoisomer retained the vaccinia activity of the parent 5′-homoaristeromycin (1) while the (R)-6′ isomer was less active. Both were weaker than 1 towards cowpox. The diastereomers were equally active versus Epstein Barr virus while (S)-6′ was three times more active toward vesicular stomatitis virus than (R)-6′. The diastereomers were inactive towards numerous other viruses. The CC₅₀ for both diastereomers was >300 μM.     

Synthesis of four stereoisomers of 4-amino-2-(hydroxymethyl)tetrahydrofuran-4-carboxylic acid

The 5-benzyl ether, 15, of a 1,2,4,5-pentanetetrol of known 2S configuration was made by a multistep synthesis from d-ribose. Ring-closure of the 1-O-tosyl derivative, 17, with retention of configuration, followed by oxidation, gave the 2S enantiomer, 22, of 2-benzyloxymethyl-4-oxotetrahydrofuran. The latter was converted by a hydantion synthesis into the 4-amino-4-carboxylic acid (mixture of 2S,4R and 2S,4S isomers, 28 and 29). Spontaneous lactonization of the 2S,4R diastereomer proved it to have the “cis” configuration. The remaining, 2S,4S diastereomer then must be “trans” it is identical with a natural compound recently isolated from an acid hydrolyzate of diabetic urine. In a parallel synthesis, the 4-O-mesyl derivative (de-O-isopropylidenated 19) was cyclized, with inversion at ring-position 2, leading after oxidation to the 2R enantiomer, 25, of the 4-oxotetrahydrofuran. The hydantoin synthesis this time yielded a mixture of the 2R,4R and 2R,4S amino-acids. Spontaneous lactonization of the latter showed it to have the “cis” configuration. Absolute configurations were assigned to the four optically active products, based on the known absolute configuration of d-ribose and the known mechanisms of the synthetic reactions.     

Heterocycles 32. Efficient kinetic resolution of 1-(2-arylthiazol-4-yl)ethanols and their acetates using lipase B from Candida antarctica

In this paper we describe the chemoenzymatic synthesis of new enantiomerically enriched (R)- and (S)-1-(2-arylthiazol-4-yl)ethanols and their acetates by enzymatic enantioselective acetylation of the racemic alcohols rac-2a–d and by methanolysis of the corresponding racemic esters rac-3a–d mediated by lipase B from Candida antarctica (CaL-B) in non-aqueous media. In terms of stereoselectivity and activity, both procedures, acylation and alcoholysis, gave similar good results (50% conversion, E ≫ 200). The absolute configuration of the kinetic resolution products was determined by a detailed ¹H NMR study of the Mosher's derivatives of (S)-2b.     

Design,synthesis and cytotoxicity of novel 3′-N-alkoxycarbonyl docetaxel analogs

By-product 9a exhibited potent cytotoxicity against both SK-OV-3 and A549 cell lines. The structure of 9a was characterized using 1D and 2D NMR experiments and confirmed by synthesis to afford a diastereomeric mixture (16a) that was identical to 9a, as well as a pair of diastereomers (R)-16b and (S)-16c. The preliminary SAR study demonstrated that analogs with an (R)-configuration were slightly more potent than analogs with an (S)-configuration. In addition, α,α-gem-dimethyl analogs 16g–i were the most potent analogs in this series, exhibiting similar potency to docetaxel and greater potency than Taxol against the SK-OV-3 cell line. For the A549 cell line, analogs 16g–i were more potent (>65-fold) than both docetaxel and Taxol.     

S1P1-selective agonist prodrug IMMH002 is phosphorylated in rats to form an S-configured enantiomer: Synthesis,verification, and biological activity of the in vivo active metabolite

IMMH002 (1), a prodrug for a sphingosine-1-phosphate receptor 1 (S1P₁) agonist, is converted to the monophosphate ester, which has an immunomodulatory effect. Starting from prochiral amino alcohol 1, racemic and enantiomerically pure phosphates of 1 were synthesized. Pure enantiomers were obtained after the chiral resolution of the key intermediate by chiral high-performance liquid chromatography and the absolute configuration was determined by circular dichroism. In the in vitro homogeneous time-resolved fluorescence-IP1 functional assay, the (S)-enantiomer showed much higher S1P₁ activity and selectivity than the (R)-enantiomer. In the pharmacokinetic study, the ex vivo o-phthaldialdehyde derivatization protocol showed that the phosphate of 1 in rats was the S-configured enantiomer with >99% enantiomeric excess.     

Sesquiterpenoids from the Chinese endangered plant Manglietia aromatica

One new bourbonane-type (1) and one new cadinane-type (2) sesquiterpenoids, along with one known aromodendrane-type (3) and five known megastigmane-type (4–8) compounds, were isolated from the leaves and twigs of Manglietia aromatica, a Chinese endangered plant that has not been previously phytochemically investigated. The structures and absolute configurations of the new isolates, (1R,4S,5S,6S,7S,10S)-4-hydroxy-bourbon-8-one (1) and (1R,6S,7S)-1-hydroxy- cadin-4,9-dien-8-one (2), were established by means of spectroscopic methods and a combination of experimental and calculated electronic circular dichroism (ECD). Among the isolates, compound 2 was found to show a moderate inhibitory effect against the human protein tyrosine phosphatase 1 B (PTP1B) enzyme, a target for the treatment of type-II diabetes and obesity, with an IC₅₀ value of 83.5 μM.     

Synthesis and biological evaluation of novel N-substituted nipecotic acid derivatives with a trans-alkene spacer as potent GABA uptake inhibitors

Our study presents the synthesis and structure-activity relationship (SAR) of novel N-substituted nipecotic acid derivatives closely related to DDPM-1457 [(S)-2a], a chemically stable analog of (S)-SNAP-5114 (1), in the pursuit of finding new and potent mGAT4 selective inhibitors. Iminium ion chemistry served as key step for the preparation of the desired, new N-substituted nipecotic acid derivatives containing a variety of different heterocycles attached to the nipecotic acid moiety via a trans-alkene spacer. The target compounds were characterized with regard to their potency at and subtype selectivity for the GABA transporters mGAT1-mGAT4.     

Terpenoids from Russula lepida and R. amarissima (Basidiomycota,Russulaceae)

Four aristolane sesquiterpenes were isolated from the fruiting bodies of Russula lepida and R. amarissima, namely (1R,2S)-1,2-dihydroxyaristolone (6), (2S,11S)-2,12-dihydroxy-aristolone (7), (1R,2S,11S)-1,2,12-trihydroxyaristolone (8), (1S,2S,11S)-1,2,12-trihydroxy-aristolone (9). In addition, a seco-cucurbitane triterpene, i.e. 3,4-secocucurbita-4,24E-diene-3-hydroxy-26-carboxylic acid (14) was isolated from both species. The configuration at C-2 of the already known rulepidol (2-hydroxyaristolone, 5) was corrected as S instead of R. Several more aristolane and nardosinane sesquiterpenes, as well as cucurbitane triterpenes, already reported both from European and Chinese samples of R. lepida, were also isolated. Compound 14 showed moderate cell growth inhibitory activity.     

Synthesis of C-glycopyranosylfuran derivatives by reaction of dialdehydes with cyanoacetamide

The reaction of diglycol- and thiodiglycol-aldehyde (1a,b) with cyanoacetamide yields cis-3,5-diacetoxy-4-carbamoyl-4-cyano-tetrahydropyran (2a) and -tetrahydrothiopyran (2b). When this reaction is applied to (2S)-2-(3-ethoxycarbonyl-2-methyl-5-furyl)-3,5-dihydroxy-1,4-dioxane (1c), (2S)-3,5-dihydroxy-2-(3-methoxycarbonyl-2-methyl-5-furyl)-1,4-dioxane (1d), and (2S,3R,5S)-2-(3-acetyl-2-methyl-5-furyl)-3,5-dihydroxy-1,4-dioxane (1e), 5-(3-carbamoyl-3-cyano-3-deoxy-β-d-xylo-pentopyranosyl)-3-ethoxycarbonyl-2-methylfuran (2c), 5-(2,4-di-O-acetyl-3-carbamoyl-3-cyano-3-deoxy-β-d-xylo-pentopyranosyl)-3-methoxycarbonyl-2-methylfuran (2e), and 3-acetyl-5-(2,4-di-O-acetyl-3-carbamoyl-3-cyano-3-deoxy-β-d-xylo-pentopyranosyl)-2-methylfuran (2f), respectively, are formed with (4S,5S)-4-carbamoyl-4-cyano-2-(3-ethoxycarbonyl-2-methyl-5-furyl)-5-hydroxy-5,6-dihydropyran (3a) and (4S,5S)-4-carbamoyl-4-cyano-5-hydroxy-2-(3-methoxycarbonyl-2-methyl-5-furyl)-5,6-dihydropyran (3b) as minor products. The dehydration of 2a,b, 5-(2,4-di-O-acetyl-3-carbamoyl-3-cyano-3-deoxy-β-d-xylo-pentopyranosyl)-3-ethoxycarbonyl-2-methylfuran (2d), 2e, and 2f yields cis-3,5-diacetoxy-4,4-dicyano-tetrahydropyran and -tetrahydrothiopyran (2l,m), and the 5-(2,4-di-O-acetyl-3,3-dicyano-3-deoxy-β-d-erythro-pentopyranosyl) derivatives (2n–p) of 3-ethoxycarbonyl-2-methylfuran, 3-methoxycarbonyl-2-methylfuran, and 3-acetyl-2-methylfuran, respectively.     

Synthesis and evaluation of opioid receptor-binding affinity of elaeocarpenine and its analogs

Both enantiomers of elaeocarpenine (1) and its analogs, 21, 22, 25, and 27, were synthesized from bicyclic aldehydes 8–10 via a flexible route previously established for total synthesis of grandisines, and their binding affinities for μ-, κ- and δ-opioid receptor subtypes were evaluated. We found that (9R)-1 exhibited higher affinity than (9S)-1 for all the subtypes, but the enantiomers showed little subtype selectivity. Analogs 21 having a pyrrolizidine skeleton and 27 having a stemona-type skeleton in place of the indolizidine unit of (9S)-1 showed μ-selective and μ-, κ-selective binding, respectively.