Phosphoralaninate Pronucleotides of Pyrimidine Methylenecyclopropane Analogues of Nucleosides: Synthesis and Antiviral Activity

The Z- and E-thymine and cytosine pronucleotides 3d, 4d, 3e, and 4e of methylenecyclopropane nucleosides analogues were synthesized, evaluated for their antiviral activity against human cytomegalovirus (HCMV), herpes simplex virus 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), human immunodeficiency virus type 1 (HSV-1), and hepatitis B virus (HBV) and their potency was compared with the parent compounds 1d, 2d, 1e, and 2e. Prodrugs 3d and 4d were obtained by phosphorylation of parent analogues 1d or 2d with reagent 8. A similar phosphorylation of N⁴-benzoylcytosine methylenecyclopropanes 9a and 9b gave intermediates 11a and 11b. Deprotection with hydrazine in pyridine–acetic acid gave pronucleotides 3e and 4e. The Z-cytosine analogue 3e was active against HCMV and EBV. The cytosine E-isomer 4e was moderately effective against EBV.     

Synthesis Of 2,2,3-Tris(Hydroxymethyl)Methylenecyclopropane Analogues Of Nucleosides

Synthesis of 2,2,3-tris(hydroxymethyl)methylenecyclopropane analogues 16a, 16b, 17a, and 17b is described. Diethyl ester of Feist's acid 18b was hydroxymethylated via carbanion formation using formaldehyde under simultaneous isomerization to cis diester to give intermediate 19. Reduction followed by acetylation gave triacetate 22. Addition of bromine afforded reagent 23, which was used for alkylation-elimination of adenine and 2-amino-6-chloropurine to provide Z,E-isomeric mixtures of 24a and 24b. Deacetylation and separation furnished the Z-isomers 16a, 16c and E-isomers 17a, 17c. Hydrolytic dechlorination of 16c and 17c gave guanine analogues 16b and 17b. None of the analogues exhibited a significant antiviral activity. Adenosine deaminase is refractory toward adenine analogues 16a and 17a.     

Novel steroidal saponins from Dioscorea esculenta (Togedokoro)

Fifteen steroidal saponins 1–15, which include 4 furostanol glycosides 1–3 and 15, and 11 spirostanol glycosides 4–14, were isolated from the tubers and leaves of lesser yam (Dioscorea esculenta, Togedokoro). Their structures were identified by nuclear magnetic resonance and liquid chromatography mass spectroscopy. Four steroidal saponins 9, 11, 14, and 15 were found to be novel compounds.     

Rubralactone,Rubralides A,B and C,and Rubramin Produced by Penicillium rubrum

Rubralactone (1), rubralides A, B and C (2–4), rubramin (5), and 2-formyl-3,5-dihydroxy-4-methylbenzoic acid (6), were isolated from Penicillium rubrum, and their structures established by spectroscopic methods including 2D NMR. The effects on plant growth of 1–6 were examined using the lettuce seedling bioassay. Compound 1 promoted root growth. Compounds 2, 3 and 5 inhibited the growth of lettuce seedlings, but 4 and 6 did not have any inhibitory effect on their growth.     

苦槛蓝叶的黄酮类成分及其荔枝霜疫霉抑制活性研究

为了解苦槛蓝(Myoporum bontioides)的化学成分,采用色谱分离法从叶中分离得到11个化合物,分别鉴定为：5,7,3’-三羟基-4’-甲氧基黄酮(1)、3,5,7,4’-四羟基-3’-甲氧基黄酮(2)、5,7,4’-三羟基-3’,5’-二甲氧基黄酮(3)、木犀草素(4)、山奈酚(5)、鼠李黄素(6)、5,7-二羟基二氢黄酮(7)、7,4’-二羟基二氢黄酮(8)、5,7,3’,4’-四羟基二氢黄酮(9)、5-O-乙酰基-3,7,3’,4’-四羟基二氢黄酮(10)和7-甲氧基香橙素(11)。除化合物4、7、11之外,其他化合物均为首次从苦槛蓝叶中分离得到。菌丝生长速率法测试表明化合物4、7～9和11对荔枝霜疫霉菌具有较好的抑菌活性。     

Synthesis of novel carbazole chalcones as radical scavenger,antimicrobial and cancer chemopreventive agents

A series of novel carbazole chalcones has been synthesised and evaluated for radical scavenging activity, cytotoxicity and antimicrobial activities. Compounds 12m, 12o and 12c exhibited good 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, compounds 12e, 12m and 12d were excellent hydroxyl radical scavengers and compounds 12a, 12e, 12g, 12n and 12m have shown inhibition of oxidative DNA damage induced by 2,2′-azobis (2-amidinopropane hydrochloride). Compounds 12j, 12i, 12n, 12c, 12m and 12e were most active against the selected cancer cell lines. Compounds 12a, 12e and 12m showed good antibacterial activity and compounds 12h and 12m have shown good antifungal activity. All the compounds were subjected for absorption, distribution, metabolism and excretion (ADME) predictions by computational method and found that these molecules could be considered as potential candidates for oral drug development.     

Conferin,potent antioxidant and anti-inflammatory isoflavone from Caragana conferta Benth

Conferin (1), a new isoflavone, has been isolated from the ethyl acetate soluble fraction of Caragana conferta Benth. along with seven known compounds, namely biochanin A (2), p-hydroxybenzoic acid (3), 3,5- dimethoxybenzoic acid (4), ursolic acid (5), erythrodiol (6), pinoresinol (7), and syringresinol (8), reported for the first time from this species. The structure of the new isoflavone was deduced on the basis of spectroscopic studies. Compounds 1 and 2 were investigated for biological activities and showed significant anti-inflammatory activity in carrageenan induced paw edema of rats. Evaluation of antioxidant activity by the radical scavenging method indicated that compound 1 is a potent antioxidant while 2 is moderately active. It was also shown that the reducing capability of compound 2 was remarkably increased in a concentration dependent manner as compared to 1. Compound 1 showed moderate inhibitory activity against the enzyme lipoxygenase, while 2 showed weak activity.     

Synthesis of 3-fluoro-6-S-(2-S-pyridyl) nucleosides as potential lead cytostatic agents

The 3-deoxy-3-fluoro-6-S-(2-S-pyridyl)-6-thio-β-d-glucopyranosyl nucleoside analogs 7 were prepared via two facile synthetic routes. Their precursors, 3-fluoro-6-thio-glucopyranosyl nucleosides 5a-e, were obtained by the sequence of deacetylation of 3-deoxy-3-fluoro-β-d-glucopyranosyl nucleosides 2a-e, selective tosylation of the primary OH of 3 and finally treatment with potassium thioacetate. The desired thiolpyridine protected analogs 7a-c,f,g were obtained by the sequence of deacetylation of 5a-c followed by thiopyridinylation and/or condensation of the corresponding heterocyclic bases with the newly synthesized peracetylated 6-S-(2-S-pyridyl) sugar precursor 13, which was obtained via a novel synthetic route from glycosyl donor 12. None of the compounds 6 and 7 showed antiviral activity, but the 5-fluorouracil derivative 7c and particularly the uracil derivative 7b were endowed with an interesting and selective cytostatic action against a variety of murine and human tumor cell cultures.     

Synthesis and Antiviral Evaluation of Novel 2,3-Dihydroxypropyl Nucleosides from 2- and 4-Thiouracils

Regioselective alkylation of 2-thiouracils 1a–c and 4-thiouracils 7a,b with 2,3-O-isopropylidene-2,3-dihydroxypropyl chloride (2) afforded 2-{[(2,2-Dimethyl-1,3-dioxolan-4-yl) methyl]thio}pyrimidin-4(1H)-ones 3a–c and 4-{[(2,2-Dimethyl-1,3-dioxolan-4-yl)methyl]thio} pyrimidin-2(1H)-ones 8a,b, respectively. Further alkylation with 2 and/or 2,3-O-isopropylidine-1-O-(4-toluenesulfonyl)-glycerol (4) gave the acyclo N-nucleosides 5a–c and 9a,b whose deprotection afforded 6a–c and 10a,b. 2-(Methylthio)pyrimidin-4(1H)-ones 11a–c and 4-(methylthio)pyrimidin-2(1H)-ones 14a,b were treated with 2 and/or 4 to give 12a–c and 15a,b which were deprotected to give 13a–c and 16a,b. Pyrimidine-2,4(1H,3H)-dithiones 17a–c were treated with two equivalents of 2 to give 2,4-bis{[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]thio}pyrimidines 18a–c. Deprotection of compounds 18a–c gave 2,4-bis[(2,3-dihydroxypropyl)thio]pyrimidines 19a-c. The activity of the deprotected nucleosides against Hepatitis B virus was evaluated and showed moderate inhibition activity against HBV with mild cytotoxicity.     

Synthesis of (±)-Muscone from Ethyl 6-Methyl-8-oxopentadecanedioate

(±)-Muscone (3-methylcyclopentadecanone) (8) was synthesized from ethyl 6-methyl-8-oxopentadecanedioate (1) in a 31.9% over-all yield. Ethylene ketal (2) of 1 was cyclized to the acyloin mixture (3) by the acyloin condensation. Reduction of 3 gave 9,9-ethylenedioxy-7-methylcyclopentadecane-1,2-diol (4) which afforded 1,2-ditosyloxy derivative (5). By detosylation according to the Tipson-Cohen procedure, 5 was converted to 9,9-ethylenedioxy-7-methylcyclopentadec-1-ene (6) which was hydrogenated to 8.     

Synthesis of novel sulfonamide analogs containing sulfamerazine/sulfaguanidine and their biological activities

Sulfamerazine and sulfaguanidine are clenched with p-nitrobenzoyl chloride and the products obtained are reduced to Na_xS in ethanol–water. Novel sulfonamides (6a–g and 9a–g) were synthesized by the reaction of these reduced products (4 and 8) with various sulfonyl chlorides (5a–g). The structures of these compounds were characterized using spectroscopic analysis (IR, ¹H-NMR, ¹³C-NMR and HRMS) technique. Antimicrobial activity of sulfonamides (3, 4, 7, 8, 6a–g and 9a–g) was evaluated by the agar diffusion method. These compounds showed antimicrobial activity against tested microorganism strains (Gram-positive bacteria, clinic isolate and yeast and mold). Compounds 9d, 9e, 9a, 6d and 6e showed particularly antimicrobial activity against tested Gram-positive (Bacillus cereus and B. subtilis) and Gram-negative (Enterobacter aerogenes) bacteria.     

MOLECULAR AND PHARMACOLOGICAL CHARACTERISATION OF THE MSH-R ALLELES IN SWISS CATTLE BREEDS

ABSTRACT

The coat colour in mammals is determined by the relative amounts of eumelanin (black/brown) and phaeomelanin (red/yellow), produced in melanocytes, which are controlled by melanocyte stimulating hormone receptor (MSH-R). Melanocyte stimulating hormone receptor is activated by α-melanocyte-stimulating hormone (α-MSH). Stimulated MSH-R activates adenylyl cyclase (AC), thereby increasing the amount of cyclic AMP in the cell, which activates the enzyme tyrosinase resulting in eumelanin synthesis. In this study the complete coding sequences of five alleles of the MSH-R gene found in Holstein, Red Holstein, Simmental, and Brown Swiss cattle were cloned into a mammalian expression vector and transfected into human embryonic kidney (HEK) 293 cells. The expressed receptors were analyzed for their ability to increase intracellular cAMP in response to stimulation by α-MSH. The recessive red allele (e) found in Red Holstein and Simmental and the dominant black allele (E^D) found in Holstein were unresponsive to a wide range of α-MSH concentrations. Two alleles from Brown Swiss (E^d1, E^d2) and one allele found in the Simmental breed (e^f) responded to stimulation by α-MSH in a dose-dependent manner. When compared to E^d1 and E^d2, the cells transfected with the e^f MSH-R allele, however, reached the corresponding intracellular cAMP concentrations at a 10-fold higher concentration of α-MSH. In conjunction with the mode of inheritance of coat colour, the results indicate that the e MSH-R allele is a non-functional receptor, E^D is constitutively activated receptor, and E^d1 and E^d2 are hormonally activated receptors. The delay in e^f MSH-R response may explain the similarity between the e and e^f phenotypes.     

New triterpene oligoglycosides from the Caribbean sponge Erylus formosus

Seven new triterpene glycosides, erylosides R₁ (1), T₁ (3), T₂ (4), T₃ (5), T₄ (6), T₅ (7), and T₆ (8) along with the known formoside (2) were isolated from the sponge Erylus formosus collected along the Caribbean coast of Mexico. Glycoside 1 was determined as a trisaccharide, glycoside 2 as a tetrasaccharide while glycosides 3–8 were hexasaccharide. Their carbohydrate chains were unprecedented and have never been found in oligosaccharides from other biological sources, except Erylus spp. Three carbohydrate chains in the glycosides 3 and 6, 4 and 7, 5 and 8 correspondingly are new. The glycosides 1–5 have penasterol as aglycone while glycosides 6–8 proved to be glycoconjugates of 24-methylene-14-carboxy-lanost-8(9)-en-3β-ol.     

SYNTHESIS AND ANTIVIRAL EVALUATION OF N-GLYCOSIDES DERIVED FROM 6-AMINO-3-ARYL-2-METHYL-4-(3H)-QUINAZOLINONES

Reaction of monosaccharides (D-glucose, D-galactose, D-xylose or L-arabinose) with 6-amino-3-aryl-2-methyl-4-(3H) quinazolinones (1a–c) in boiling methanol yielded the corresponding N-glycopyranosides 3a–c, 4a–c, 5a,b and 6a,b. The N-glycopyranosides 3a–c, 4a–c, 5a,b and 6a,b were acetylated with acetic anhydride and pyridine to give the corresponding acetate derivatives 7a–c, 8a–c, 9a,b and 10a,b. The structures of all these glycosides were assessed by elemental analysis, IR, NMR and mass spectra. Some of these products were tested for anticancer and anti-AIDS activity.     

Synthesis and antioxidant,cytotoxicity and antimicrobial activities of novel curcumin mimics

Claisen-Schmidt condensation of 3-(1,2,3,6-tetrahydro-1-methylpyridin-4-yl)-2,4,5- trimethoxybenzaldehyde 3 and various aromatic, heterocyclic and alicyclic amides of 3- aminoacetophenone 6(a–s) afforded novel curcumin mimics. All the synthesized compounds were characterized by IR, ¹H NMR, Mass spectroscopy and evaluated for antioxidant, cytotoxicity and antimicrobial activity. Out of the 20 compounds screened, compounds 7i, 7l, 7q, and 7n have shown excellent radical scavenging activity, compounds 7o, 7t, 7f, and 7r have shown significant xanthine oxidase inhibition, and compounds 7a, 7k and 7l were found to be potent inhibitors of selected cancer cell lines. Compounds 7h, 7t, 7l, 7i, and 7e have shown good antibacterial activity, whereas compounds 7j, 7f, 7o, 7h, and 7t exhibited significant antifungal activity.     

Nomenclatural changes in <Emphasis Type="Italic">Lithospermum</Emphasis> (Boraginaceae) and related taxa following a reassessment of phylogenetic relationships

Lithospermum (Boraginaceae) comprises approximately 40 species in both the Old and New Worlds, with a center of diversity in the southwestern United States and Mexico. Using ten cpDNA regions, a phylogeny of Lithospermum and related taxa was reconstructed. Lithospermum (including New World and Old World species) and related New World members of Lithospermeae form a monophyletic group, with Macromeria, Onosmodium, Nomosa, Lasiarrhenum, and Psilolaemus nested among species of Lithospermum. New World Lithospermeae also is a monophyletic group, with Eurasian species of Lithospermum sister to this group. Because Lithospermum is not monophyletic without the inclusion of the other New World genera, species from these genera are transferred to Lithospermum, and appropriate nomenclatural changes are made. New combinations are Lithospermum album, Lithospermum barbigerum, Lithospermum dodrantale, Lithospermum exsertum, Lithospermum helleri, Lithospemum leonotis, Lithospermum notatum, Lithospermum oaxacanum, Lithospermum pinetorum, Lithospermum rosei, Lithospermum trinverium, and Lithospermum unicum; new names are Lithospermum chiapense, Lithospermum johnstonii, Lithospermum macromeria, Lithospermum onosmodium, Lithospermum rzedowskii, and Lithospermum turneri.     

<Emphasis Type="Italic">Alansmia</Emphasis>, a new genus of grammitid ferns (Polypodiaceae) segregated from <Emphasis Type="Italic">Terpsichore</Emphasis>

Alansmia, a new genus of grammitid ferns is described and combinations are made for the 26 species known to belong to it. Alansmia is supported by five morphological synapomorphies: setae present on the rhizomes, cells of the rhizome scales turgid, both surfaces of the rhizome scales ciliate, laminae membranaceous, and sporangial capsules setose. Other diagnostic characters include pendent fronds with indeterminate growth, concolorous, orange to castaneous rhizome scales with ciliate or sometimes glandular margins, hydathodes often cretaceous, and setae simple, paired or stellate. The group also exhibits the uncommon characteristic of producing both trilete and apparently monolete spores, sometimes on the same plant. New combinations are made for Alansmia alfaroi, A. bradeana, A. canescens, A. concinna, A. contacta, A. cultrata, A. dependens, A. diaphana, A. elastica, A. glandulifera, A. heteromorpha, A. immixta, A. kirkii, A. lanigera, A. laxa, A. longa, A. monosora, A. reclinata, A. semilunaris, A. senilis, A. smithii, A. spathulata, A. stella var. stella, A. stella var. flava, A. turrialbae, A. variabilis, A. xanthotrichia. Lectotypifications are made for Alansmia concina, A. variabilis, Polypodium ciliare, P. flexile, and P. ovalescens. The genus is named in honor of pteridologist Alan R. Smith.     

Synthesis,antitumour and antioxidant activities of novel α,β-unsaturated ketones and related heterocyclic analogues: EGFR inhibition and molecular modelling study

New α,β-unsaturated ketones 4a,b; 5a–c; and 6a,b; as well as 4-H pyran 7; pyrazoline 8a,b; isoxazoline 9; pyridine 10–11; and quinoline-4-carboxylic acid 12a,b derivatives were synthesized and evaluated for in vitro antitumour activity against HepG2, MCF-7, HeLa, and PC-3 cancer cell lines. Antioxidant activity was investigated by the ability of these compounds to scavenge the 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation (ABTS^?+). Compounds 6a, 6b, 7, and 8b exhibited potent antitumour activities against all tested cell lines with [IC₅₀] ?5.5–18.1 µΜ), in addition to significantly high ABTS^?+ scavenging activities. In vitro EGFR kinase assay for 6a, 6b, 7, and 8b as the most potent antitumour compounds showed that; compounds 6b, and 7 exhibited worthy EGFR inhibition activity with IC₅₀ values of 0.56 and 1.6?µM, respectively, while compounds 6a and 8b showed good inhibition activity with IC₅₀ values of 4.66 and 2.16?µM, respectively, compared with sorafenib reference drug (IC₅₀?=?1.28?µM). Molecular modelling studies for compounds 6b, 7, and 8b were conducted to exhibit the binding mode towards EGFR kinase, which showed similar interaction with erlotinib.     

Eriogonum (Polygonaceae) novelties from Baja California,Mexico

Five new entities ofEriogonum are described from Baja California and Baja California Sur, Mexico, including one species,E. preclarum, and four varieties of other species:E. fasciculatum var.emphereium,E. wrightii var.oresbium,E. elongatum var.areorivum, andE. grande var.testudinum. Three combinations are proposed:E. wrightii var.dentatum,E. elongatum var.vollmeri, andE. repens.