α-Hydroxyphosphonate Oligonucleotides: A Promising DNA Type?

Abstract

The synthesis of monomers ( S )-1, ( R )-1 and 2 derived from (5′ S )-, (5′ R )-2′-deoxythymidine-5′-C-phosphonic acids and 2′,5′-dideoxythymidine-5′-C-phosphonic acids was elaborated. The protection of the 5′-hydroxyl by the methoxycarbonyl group was a key step of the synthesis. Prepared monomers were used for the solid-phase assembly of several types oligothymidylate 15-mers ( S )-3, ( S )-4, ( S )-5, ( R )-4 and ( R )-5 containing the chiral 3′-O-P-CH(OH)-5″ internucleotide linkage. Their hybridization properties with dA₁₅ and rA₁₅ were studied as well as their resistance against nuclease cleavage.     

Synthesis and Biological Activity of Some Unsaturated 6-Azauracil Acyclonucleosides

A useful route is described for obtaining Z and E unsaturated alkylating agents 3 and 4. Coupling 6-azauracils 5 and 6 with unsaturated alkylating agent followed by the deprotection with H⁺ resin gave acyclonucleosides 11–14 in good overall yields. Unsaturated acyclonucleosides phosphonates 19 and 20 were prepared using potassium carbonate as base and 4-bromobut-2-enyl diethyl phosphonate 16 as the alkylating agent. The introduction of a propargyl group at the N-3 position of acyclonucleosides 7, 8, 17, 18, 19, and 20 was achieved using potassium carbonate in DMF.     

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.     

A Convenient Synthesis of Acyclic Adenosines with an Unsaturated Side Chain by Modification of 9-(2,3-O-Isopropylidene-D-Ribityl)Adenine

Abstract

In expectation of discovering their antiviral activity, acyclic adenosine derivatives 7, 11, 12, and 16 were designed as analogs of neplanocin A (NPA) and L-eritadenine which are strong inhibitors of S-adenosyl-L-homocysteine hydrolase. The 1′,5′-seco-analog of 4′-deoxymethyl-NPA (DHCA) 7 was synthesized by dideoxygenation of 9-(2,3-O-isopropylidene-D-ribityl)adenine (2). Acyclic DHCA analogs 11 and 16 were obtained by Wittig reaction of the aldehyde 3 with Ph₃P=CHCO₂Et and Ph₃P=CHCN, respectively. Hydrolysis of the ester 11 afforded a vinylog of L-eritadenine 12. The synthesized acyclic nucleosides 7, 10, and 11 were evaluated for antiviral activity, however, none of them showed any significant antiviral activity.     

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 of the Fluoromethyl Derivatives of Carbocyclic Oxetanocin A

Abstract

Treatment of the 2,3-di-O-benzoate 1 with sodium boronhydride mainly afforded the 3-O-benzoate 2 accompanied with isomers 3a,b and fully deprotected product 4. Compound 2 was converted to 5, from which 8 was obtained. The 1-cyclobutanols 8 and 5 were successfully condensed with 6-chloropurine by Mitsunobu reaction to give 9 and 11, respectively. After partial deprotection, the cyclobutyl nucleosides 10 and 15 were subjected to fluorination using DAST to afford the fluoromethyl analogs 12 and 16 from which target compounds 14 and 17 were obtained in good yields, respectively.

     

海南石斛化学成分研究

为了解海南石斛(Dendrobium hainanense Rolfe)的化学成分,采用色谱技术从海南石斛茎叶中分离得到14个化合物,经波谱分析分别鉴定为:2,6-二甲氧基对苯醌(1)、(+)-dehydrovomifoliol(2)、blumenol A(3)、2,7-二羟基-3,4-二甲氧基-9,10-二氢菲(4)、2,7-二羟基-3,4-二甲氧基菲(5)、3,7-二羟基-2,4-二甲氧基菲(6)、3-羟基-2,4,7-三甲氧基-9,10-二氢菲(7)、3-羟基-2,4,7-三甲氧基菲(8)、3,4,7-三羟基-2-甲氧基菲(9)、3,7-二羟基-2,4-二甲氧基-9,10-二氢菲(10)、(+)-lyoniresinol(11)、丁香脂素(12)、denchrysan A(13)和nobilone(14)。这些化合物均为首次从海南石斛中分离得到。活性测试结果表明化合物4~6、8~9、11和14对乙酰胆碱酯酶有抑制活性。     

Synthesis of 1′-Deoxypsicofuranosyl-deoxynucleosides as Potential Anti-HIV Agents

Abstract

Various routes to the targets 1, 2, 3, 1-deoxy-psicofuranosyl nucleoside analogues related to anti-HIV agents, are reported. Two routes afforded their 6′-benzylated derivatives 9, 10 and 15. Only the epoxide 12 and deoxynucleosides 19 and 22 were able to be deprotected leading in the first case to 16 and its ring opening derivative 17 and in the second case to 20 and to the target 3.     

Study of reactivity of cyanoacetohydrazonoethyl-N-ethyl-N-methyl benzenesulfonamide: preparation of novel anticancer and antimicrobial active heterocyclic benzenesulfonamide derivatives and their molecular docking against dihydrofolate reductase

Abstract

This article describes the synthesis of some novel heterocyclic sulfonamides having biologically active thiophene 3, 4, 5, 6, coumarin 8, benzocoumarin 9, thiazole 7, piperidine 10, pyrrolidine 11, pyrazole 14 and pyridine 12, 13. Starting with 4-(1-(2-(2-cyanoacetyl)hydrazono)ethyl)-N-ethyl-N-methylbenzenesulfonamide (2), which was prepared from condensation of acetophenone derivative 1 with 2-cyanoacetohydrazide. The structures of the newly synthesized compounds were confirmed by elemental analysis, IR, ¹H NMR, ¹³C NMR, ¹⁹F NMR and MS spectral data. All the newly synthesized heterocyclic sulfonamides were evaluated as in-vitro anti-breast cancer cell line (MCF7) and as in-vitro antimicrobial agents. Compounds 8, 5 and 11 were more active than MTX reference drug and compounds 12, 7, 4, 14, 5 and 8 were highly potent against Klebsiella pneumonia. Molecular operating environment performed virtual screening using molecular docking studies of the synthesized compounds. The results indicated that some prepared compounds are suitable inhibitor against dihydrofolate reductase (DHFR) enzyme (PDBSD:4DFR) with further modification.     

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.     

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.     

Theoretical mechanistic study of the reaction of the methylidyne radical with methylacetylene

A detailed doublet potential energy surface for the reaction of CH with CH₃CCH is investigated at the B3LYP/6-311G(d,p) and G3B3 (single-point) levels. Various possible reaction pathways are probed. It is shown that the reaction is initiated by the addition of CH to the terminal C atom of CH₃CCH, forming CH₃CCHCH 1 (1a,1b). Starting from 1 (1a,1b), the most feasible pathway is the ring closure of 1a to CH₃–cCCHCH 2 followed by dissociation to P ₃ (CH₃–cCCCH+H), or a 2,3 H shift in 1a to form CH₃CHCCH 3 followed by C–H bond cleavage to form P ₅ (CH₂CHCCH+H), or a 1,2 H-shift in 1 (1a, 1b) to form CH₃CCCH₂ 4 followed by C–H bond fission to form P ₆ (CH₂CCCH₂+H). Much less competitively, 1 (1a,1b) can undergo 3,4 H shift to form CH₂CHCHCH 5. Subsequently, 5 can undergo either C–H bond cleavage to form P ₅ (CH₂CHCCH+H) or C–C bond cleavage to generate P ₇ (C₂H₂+C₂H₃). Our calculated results may represent the first mechanistic study of the CH + CH₃CCH reaction, and may thus lead to a deeper understanding of the title reaction.     

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.     

Synthesis of Acyclovir and HBG Analogues Having Nicotinonitrile and Its 2-methyloxy 1,2,3-triazole

Reaction of pyridin-2(1H)-one 1 with 4-bromobutylacetate (2), (2-acetoxyethoxy)methyl bromide (3) gave the corresponding nicotinonitrile O-acyclonucleosides, 4 and 5, respectively. Deacetylation of 4 and 5 gave the corresponding deprotected acyclonucleosides 6 and 7, respectively. Treatment of pyridin-2(1H)-one 1 with 1,3-dichloropropan-2-ol (8), epichlorohydrin (10) and allyl bromide (12) gave the corresponding nicotinonitrile O-acyclonucleosides 9, 11, and 13, respectively. Furthermore, reaction of pyridin-2(1H)-one 1 with the propargyl bromide (14) gave the corresponding 2-O-propargyl derivative 15, which was reacted via [3+2] cycloaddition with 4-azidobutyl acetate (16) and [(2-acetoxyethoxy)methyl]azide (17) to give the corresponding 1,2,3-triazole derivatives 18 and 19, respectively. The structures of the new synthesized compounds were characterized by using IR, ¹H, ¹³C NMR spectra, and microanalysis. Selected members of these compounds were screened for antibacterial activity.     

Synthesis and Antimicrobial Activity of Some S-β-D-Glucosides of 4-Mercaptopyrimidine

5-Acetyl-2-aryl-6-methyl-4-(2,3,4,6-tetra- O -acetyl-β-D-glucopyranosylmercapto)pyramidines 3a–c were obtained by the reaction of 5-acetyl-2-aryl-6-methyl-pyrimidine thiol 1a–c with 2,3,4,6-tetra- O -acetyl-α-D-glucopyranosyl bromide (2) in aq. KOH/acetone. The reaction of 1a–c with peracetylated galactose 5 and peracetylated ribose 8 under MW irradiation gave 5-acetyl-2-aryl-6-methyl-4-(2,3,4,6-tetra- O -acetyl-β-D-galactopyranosylmercapto)pyrimidine 6a–c and 5-acetyl-2-aryl-6-methyl-4-(2,3,5-tri- O -acetyl-β-D-ribofuranosylmercapto)pyrimidines 9a–c. The deprotection of 3a–c, 6a–c, and 9a–c in the presence of methanol and TEA/H₂O yielded the deprotected products 4a–c, 7a–c, and 10a–c. The structures of the compounds were confirmed by using IR, ¹H, ¹³C spectra and microanalysis. Selected members of these compounds were screened for antimicrobial activity.     

Synthesis of Optically Pure (R)-4a-Methyl-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone and Its Transformation into (+)-7-Hydroxycostal

A novel synthesis of the enone 12 starting from (+)-dihydrocarvone (3) and its transformation into (+)-7-hydroxycostal (1) are described. The ketone 10, obtained from 4 through a four-step sequence was converted to 12 by acid-catalyzed elimination and subsequent regioselective hydrogenation. Alternatively, the methoxyhydroperoxide 13 generated by the ozonolysis of 4 was subjected to the Criegee rearrangement, providing a mixture of 10 and 14, which on acid treatment, gave 11. Transformation of 12 into 19 was accomplished via a five-step reaction sequence. The reaction of 19 with the lithium alkoxide of 2-lithio-2-propenol afforded (+)-7-hydroxycostol (2), whose oxidation with manganese dioxide gave rise to (+)-7-hydroxycostal (1).     

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。     

<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 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.