Synthesis of (±)-Homosarkomycin and (±)-Rosaprostol

(±)-Homosarkomycin (2) and (±)-rosaprostol (3) were synthesized from (±)-methyl 2-oxo-bicyclo[3.1.0]hexane-1-carboxylate (1) by using the nucleophilic ring opening reaction on the double-activated cyclopropane ring as the key step.     

Synthesis of (±)-Lamprolobine and (±)-Epilamprolobine

(±)-Lamprolobine, the (+)-enatiomer of which was isolated from the leaves of Lamprolobium fruticosum, and (±)-epilamprolobine were synthesized from δ-valerolactam.     

A small diversity library of α-methyl amide analogs of sulindac for probing anticancer structure-activity relationships

Non-steroidal anti-inflammatory drugs (NSAIDs) have a variety of potential indications that include management of pain and inflammation as well as chemoprevention and/or treatment of cancer. Furthermore, a specific form of ibuprofen, dexibuprofen or the S-(+) form, shows interesting neurological activities and has been proposed for the treatment of Alzheimer’s disease. In a continuation of our work probing the anticancer activity of small sulindac libraries, we have prepared and screened a small diversity library of α-methyl substituted sulindac amides in the profen class. Several compounds of this series displayed promising activity compared with a lead sulindac analog.     

Concise synthesis of (±)-litseaones A and B

A concise synthesis of litseaones A and B, which were isolated from the stem barks of Litsea rubescens and L. pedunculata, is described in this study. Litseaone A was synthesized in just three steps from a known phloroglucinol derivative. The direct conversion of litseaone A into litseaone B was also achieved.     

Synthesis and cytokinin activity of (R)-(+)- and (S)-(−)-dihydrozeatins and their ribosides

(R)-(+)- and (S)-(?)-dihydrozeatins [(R)-(+)- and (S)-(?)-6-(4-hydroxy-3-methylbutylamino)purines, 1a and 1b] and their ribosides {(?)-6-[(R)-4-hydroxy-3-methylbutylamino]- and (?)-6-[(S)-4-hydroxy-3-methyl-butylamino]-9-β-D-ribofuranosylpurines, 3a and 3b} were synthesized and tested for their cytokinin activity by four bioassay systems, the growth of tobacco callus, the seed germination of lettuce, the fr. wt increase of excised radish cotyledons and the retardation of chlorophyll degradation in radish cotyledons. In tobacco callus bioassay, 1a was more active than 1b. The ribosides 3a and 3b were not less active than their corresponding aglycones 1a and 1b. In other bioassays used the activity followed the order: 1a >3a >1b >3b. In tobacco callus bioassay and lettuce seed germination, trans-zeatin [6-(4-hydroxy-3-methylbut-trans-2-enylamino)purine] showed stronger cytokinin activity than 1a.     

Syntheses of (±)-Epoformin (Desoxyepoxydon) and (±)-Epiepoformin (Desoxyepiepoxydon)

Boron is an essential nutrient for plants, but it is toxic in excess. Transgenic rice plants expressing an Arabidopsis thaliana borate efflux transporter gene, AtBOR4, at a low level exhibited increased tolerance to excess boron. Those lines with high levels of expression exhibited reduced growth. These findings suggest a potential of the borate transporter BOR4 for the generation of high-boron tolerant rice.     

Synthesis of ( ± )-Methyl Epijasmonate and ( ± )-Methyl Cucurbate

A novel synthesis of ( ± )-methyl epijasomonate (2) and the first synthesis of ( ± )-methyl cucurbate (4) were achieved starting from 2-allylcyclohexane-1,3-dione (8). The synthetic epimer 2 had a stronger jasmin flavor than the trans-isomer 1 with 95% purity.     

Identification of novel small-molecule inhibitors of α-methylacyl-CoA racemase (AMACR; P504S) and structure-activity relationships

α-Methylacyl-CoA racemase (AMACR; P504S; EC 5.1.99.4) catalyses epimerization of 2-methylacyl-CoAs and is important for the degradation of branched-chain fatty acids and the pharmacological activation of ibuprofen and related drugs. It is also a novel drug target for prostate and other cancers. However, development of AMACR as a drug target has been hampered by the difficulties in assaying enzyme activity. Consequently, reported inhibitors have been rationally designed acyl-CoA esters, which are delivered as their carboxylate prodrugs. The novel colorimetric assay for AMACR based on the elimination of 2,4-dinitrophenolate was developed for high-throughput screening and 20,387 ‘drug-like compounds’ were screened, with a throughput of 768 compounds assayed per day. Pyrazoloquinolines and pyrazolopyrimidines were identified as novel scaffolds and investigated as AMACR inhibitors. The most potent inhibitors have IC₅₀ values of ~2 µM. The pyrazoloquinoline inhibitor 10a displayed uncompetitive inhibition, whilst 10j displayed mixed competitive inhibition. The pyrazolopyrimidine inhibitor 11k displayed uncompetitive inhibition. This is the first report of the identification of specific drug-like small-molecule AMACR inhibitors by high-throughput screening. Pyrazoloquinolines and pyrazolopyrimidines may also be useful as inhibitors of other CoA-utilizing enzymes.     

A Total Synthesis of (±)-Gibberellin A12 via Methyl (±)-7,16-dioxo-17-norkauran-19-oate

¹⁴C-labelled methionine, xanthosine, and 7-methylxan-thosine were given to excised tea shoots. The methyl group of methionine was incorporated into 7-methylxanthosine (ca. 10%) in the earlier period of incubation after the uptake. About 50% of the radioactivity of xanthosine was rapidly incorporated into caffeine via 7-methylxanthosine, 7-methylxanthine, and theobromine within 24 hr. 7-Methylxanthosine was also converted into caffeine at a high rate. The results suggest that the pathway for caffeine biosynthesis is as follows: xanthosine → 7-methylxanthosine → 7-methylxanthine → theobromine → caffeine.     

Individual and combined effect of (±)-α-hydrastine and (±)-β-hydrastine on spore germination of some fungi

(+/-)-alpha-Hydrastine and (+/-)-beta-hydrastine were isolated from Corydalis longipes; both exhibited considerable efficacy against spore germination of some saprophytic and phytopathogenic fungi. While (+/-)-alpha-hydrastine was effective against most of the fungi, Helminthosporium echinoclova was least affected even at the highest dose (150 ppm). (+/-)-beta-Hydrastine was equally effective against several fungi. Mixture of both compounds was more effective than each one individually. Helminthosporium species were again the most resistant toward the mixture. The effect of both alkaloids independently on germination and development of E. pisi conidia on excised pea leaves was also shown. After pre-inoculation with (+/-)-alpha-hydrastine, the effect was more pronounced than the addition post-inoculation; maximum inhibition occurred at 200 ppm. (+/-)-beta-Hydrastine also reduced germination of conidia but was less effective than (+/-)-alpha-hydrastine. The number of primary and secondary branches of conidia and number of appressoria were not affected significantly by either compound.     

Total synthesis of (±)-elegansidiol, (±)-farnesiferol B,and (±)-farnesiferol D

The racemic total synthesis of elegansidiol, farnesiferol B, and farnesiferol D has been obtained following a Diels–Alder approach. Gillman addition, cross metathesis reaction are the other key steps involved in the target synthesis.     

Microbial Resolution of (±)-1 and 2-Decalols

By microorganisms or esterase they produce, (±)-1 and 2-decalyl acetates were asymmetrically hydrolyzed to (?)-1-(R)-trans,cis-1-decalol (IIa), (+)-1-(S)-cis,cis-1-decalol (IIIb), (+)-1-(R)-cis,trans-1-decalol (IVa) and (+)-1-(S)-trans,trans-2-decalol (VIIb), (?)-cis,cis-2-decalol (IXb) with the acetates of their antipodes, whereas the axial acetates of (±)-decalols were scarecely hydrolyzed.     

Selective biocatalytic aminolysis of (±)-epichlorohydrin: synthesis and ICAM-1 inhibitory activity of (S)-(+)-3-arylamino-1-chloropropan-2-ols

Regio- and enantioselective synthesis of (S)-(+)-3-arylamino-1-chloropropan-2-ols has been achieved by the epoxide ring opening of (±)-epichlorohydrin with different aromatic amines in the presence of Candida rugosa lipase. Activities of seven model (S)-(+)-3-arylamino-1-chloropropan-2-ols, out of 10 compounds synthesized, have been evaluated for the inhibition of tumor necrosis factor-α TNF-α) induced expression of intercellular adhesion molecule-1 (ICAM-1), which is one of the factors responsible for the modulation of inflammation in biological systems; (S)-(+)-1-chloro-3-(2'-chlorophenylamino)-propan-2-ol has been found to exhibit highest activity, that is, 86% inhibition of TNF-α induced expression of ICAM-1 at a concentration of 40 μg/ml.     

High-performance liquid chromatographic assay of (±)-ethopropazine and its enantiomers in rat plasma

Two high-performance liquid chromatographic (HPLC) methods are described for determination of (±)-ethopropazine (ET) in rat plasma. After deproteination and liquid–liquid extraction, assay of (±)-ET was performed using either a C₁₈ column (non-stereospecific assay) or an (α-R-naphthyl)ethylurea column (stereospecific assay). The UV detection was at 250 nm. Mean recovery was >85%. Both assays demonstrated excellent linear relationships between peak height ratios and plasma concentrations; quantitation limits were ≤25 ng/ml, based on 100 μl rat plasma. Accuracy and precision were <17% with both methods. Both methods were applied successfully to the measurement of ET plasma concentrations in rats given the drug intravenously.     

(–)-Germacrene D receptor neurones in three species of heliothine moths: structure-activity relationships

Specificity of olfactory receptor neurones plays an important role in food and host preferences of a species, and may have become conserved or changed in the evolution of polyphagy and oligophagy. We have identified a major type of plant odour receptor neurones responding to the sesquiterpene germacrene D in three species of heliothine moths, the polyphagous Heliothis virescens and Helicoverpa armigera and the oligophagous Helicoverpa assulta. The neurones respond with high sensitivity and selectivity to (–)-germacrene D, as demonstrated by screening via gas chromatography with numerous mixtures of plant volatiles. Germacrene D was present in both host and non-host plants, but only in half of the tested species. The specificity of the neurones was similar in the three species, as shown by the "secondary" responses to a few other sesquiterpenes. The effect of (–)-germacrene D was about ten times stronger than that of the (+)-enantiomer, which again was about ten times stronger than that of (–)--ylangene. Weaker effects were obtained for (+)--ylangene, (+)--copaene, -copaene and two unidentified sesquiterpenes. The structure-activity relationship shows that the important properties of (–)-germacrene D in activating the neurones are the ten-membered ring system and the three double bonds acting as electron-rich centres, in addition to the direction of the isopropyl-group responsible for the different effects of the germacrene D enantiomers.Abbreviations -copaene (tricyclo[4.4.0.0.]dec-3-ene, 1,3-dimethyl-8-(1-methylethyl)-) - -copaene (tricyclo[4.4.0.0.]decane, 1-methyl-3-methylene-8-(1-methylethyl)-) - GC gas chromatograph - GC-MS linked gas chromatography mass spectrometry - GC-SCR linked gas chromatography single cell recording - GD germacrene D (1,6-cyclodecadiene, 1-methyl-5-methylene-8-(1-methylethyl-, E,E)) - -ylangene (tricyclo[4.4.0.0]dec-3-ene, 1,3-dimethyl-8-(1-methylethyl)-) - -ylangene (tricyclo[4.4.0.0.]decane, 1-methyl-3-methylene-8-(1-methylethyl)-)     

Isozyme variation and species relationships in peanut and its wild relatives (Arachis L. — Leguminosae)

Summary Arachis hypogaea (peanut or groundnut) is an AABB allotetraploid whose precise ancestry is not yet clear. Its closest diploid relatives are the annual and perennial wild species included with it in the section Arachis. Variation in these species for 11 different enzymes was studied by starch-gel electrophoresis. Differences attributed to at least 13 genetic loci were found among eight enzymes, while three enzymes appeared uniform throughout the section. Values for Nei's genetic distance were calculated for all pairs of species and were used to estimate relationships. All diploid species, apart from two whose validity had previously been questioned, could be distinguished by their overall zymotypes, but few contained unique alleles. When species were grouped by their mean genetic distances, they formed two clusters, which agreed reasonably well with the division of the section into annual versus perennial species. The single B-genome species was an outlier within the annual group. A. hypogaea showed fixed heterozygosity at four loci (in ssp. hypogaea) or six loci (in ssp. fastigiata), which agrees with previous conclusions that the peanut is an allotetraploid. None of the diploids included in this survey could be conclusively identified as donors of either the A or the B genome to the tetraploids. The two subspecies of A. hypogaea differed consistently in two of the thirteen putative loci studied. This may call into question the simple hypothesis that A. hypogaea originated from just two diploid species.     

An Efficient Synthetic Method for (±)-Malyngolide and Its Optical Resolution

A convenient synthetic method for (±)-malyngolide (1), an antibiotic from the marine bluegreen alga Lyngbya majuscula GOMONT, is described. The compound (±)-1 was synthesized from 2-methylglutaric anhydride (starting material) in four steps, involving the TBHP-based osmium-catalyzed procedure for vicinal dihydroxylation of the methylene unit in unsaturated carboxylic acid as the key step. The optical resolution of (±)-l was accomplished by HPLC, in which diastereomeric (+)-2-(4-chlorophenyl)isovaleric acid [(+)-CPIA] esters of (±)-l derived from (+)-CPIA-C1 could be easily separated, and subsequent hydrolysis of each ester gave the enantiomeri-cally pure (?)-l and (+)-l, respectively. A synthetic method for α-methylene malyngolide, which is to be expected for biological activity, is also described.     

A Total Synthesis of (±)-Pachyrrhizone

We examined whether developing cotyledons of soybean seed had photosynthetic activities. The cotyledons evolved oxygen under illumination and the activity was inhibited by 3-(3′,4′-dichlorophenyl)-1,1-dimethylurea. The rate of oxygen evolution decreased during the development of seeds; about 30μ miol O₂ · mg chlorophyll^-1 · hr^-1 at the early developing stage and about 10μ miol O₂-mg chlorophyll^-1 · hr^-1 at the late developing stage. The rate of oxygen uptake remained at an almost constant level of 40^mol 0₂-mg chlorophyll^-1 · hr^-1 throughout the development. Photosynthetic ¹⁴CO₂-fixation by the cotyledon was observed. Ribulose bisphosphate carboxylase was immunochemically detected in the developing cotyledons. These results show that functional photosynthetic apparatus is present in the developing cotyledons of soybean seeds.     

Synthesis and structure-activity relationships of 4,5-fused pyridazinones as histamine H₃ receptor antagonists

Three series of novel 4,5-fused pyridazinones were synthesized as histamine H(3) receptor antagonists. The 2,5,6,7-tetrahydrocyclopenta[d]pyridazin-1-one 5q and 5,6,7,8-tetrahydro-2H-phthalazin-1-one 5u displayed high affinity at both rat and human H(3) receptors, and showed potent antagonist and full inverse agonist activity in functional assays.