Synthesis and Biological Evaluation of Pyrimidine Nucleosides Fused with 3′,4′-Tetrahydrofuran Ring

Abstract

Pyrimidine nucleosides fused with 3′,4′-tetrahydrofuran ring were synthesized, starting from 1,2;5,6-di-O-isopropylidene-D-glucose and assayed for antiviral activities. Thymine analogue 1 and its corresponding 2′-deoxy analogue 3 exhibited high cytotoxicity instead of giving antiviral activities.     

1‐Aminobenzocyclobutene‐1‐phosphonic Acid and Related Compounds as Inhibitors of Phenylalanine Ammonia‐Lyase

Five new geminal aminocycloalkanephosphonic acids ( 4 – 8 ) containing both an aromatic ring and a cycloalkane ring were synthesized and evaluated as potential inhibitors of buckwheat phenylalanine ammonia‐lyase (PAL). Within the set of compounds which are related to 2‐aminoindane‐2‐phosphonic acid (AIP, 3 ), a known powerful inhibitor of PAL, racemic 1‐aminobenzocyclobutene‐1‐phosphonic acid ( 4 ), was six times weaker than AIP as an in vitro inhibitor of buckwheat PAL, but six times stronger than AIP as an in vivo inhibitor of phenylalanine‐derived anthocyanin synthesis in buckwheat.     

Synthesis and Conformational Analysis of a Locked Analogue of Carbovir Built on a Bicyclo[3.1.0]-hex-2-enyl Template

Abstract

The synthesis and biological evaluation of a carbovir analogue (5) built on a bicyclo[3.1.0]hex-2-enyl template is described. A conformational analysis using density functional theory at the B3LYP/6-31G* level has been carried out on the rigid pseudosugar template of 5, the cyclopentene moiety of carbovir and the bicyclo[3.1.0]hex-2-yl pseudosugars of two isomeric carbonucleosides (12 and 13) containing exo- and endo-fused cyclopropane rings. The results show that while the planar configuration of the fused cyclopentane ring of compound 5 helps retain weak anti-HIV activity, the ability of the cyclopentene ring of carbovir to easily adopt a planar or puckered conformation with little energy penalty may prove to be a crucial advantage. The bicyclo[3.1.0]hex-2-yl nucleosides 12 and 13 that were inactive against HIV exhibited stiffer resistance to having a planar, fused cyclopentane moiety.     

Ansavaricin J,a New Heterocyclic Ring‐Fused Streptovaricin from Gene stvP5‐Deleted Mutant of Streptomyces spectabilis CCTCC M2017417

A new ring‐fused streptovaricin analogue, named ansavaricin J, was unprecedently isolated from the culture of the genetically modified strains ΔstvP5 which derived from Streptomyces spectabilis CCTCC M2017417. Its structure was elucidated via comprehensive spectroscopic analyses, including 1D‐ and 2D‐NMR tests, and HR‐ESI‐MS data analysis. Notably, ansavaricin J and E represent the only two reported examples of heterocyclic ring‐fused streptovaricins thus far, however, it only showed insignificant antibacterial activities against Staphylococcus aureus.     

Bicyclic γ-amino acids as inhibitors of γ-aminobutyrate aminotransferase

The γ-aminobutyrate (GABA)-degradative enzyme GABA aminotransferase (GABA-AT) is regarded as an attractive target to control GABA levels in the central nervous system: this has important implications in the treatment of several neurological disorders and drug dependencies. We have investigated the ability of newly synthesized compounds to act as GABA-AT inhibitors. These compounds have a unique bicyclic structure: the carbocyclic ring bears the GABA skeleton, while the fused 3-Br-isoxazoline ring contains an electrophilic warhead susceptible of nucleophilic attack by an active site residue of the target enzyme. Out of the four compounds tested, only the one named (+)-3 was found to significantly inhibit mammalian GABA-AT in vitro. Docking studies, performed on the available structures of GABA-AT, support the experimental findings: out of the four tested compounds, only (+)-3 suitably orients the electrophilic 3-Br-isoxazoline warhead towards the active site nucleophilic residue Lys329, thereby explaining the irreversible inhibition of GABA-AT observed experimentally.     

Design,synthesis, spectral analysis and in vitro microbiological evaluation of 2-phenyl-3-(4,6-diarylpyrimidin-2-yl)thiazolidin-4-ones

A series of novel 2-phenyl-3-(4,6-diarylpyrimidin-2-yl)thiazolidin-4-ones 23-33 were synthesized, and studied for their in vitro antibacterial and antifungal activities against clinically isolated strains. Generally compounds possessing electron donating groups showed good antibacterial activity. Compound 31, which contain both electron withdrawing chloro and electron donating methyl groups showed potent activity against all the tested Gram positive and Gram negative bacterial strains whereas compounds 32 and 33 which contain electron donating methoxy functional group at the para position of the phenyl ring attached to pyrimidine ring showed promising activity against S.aureus, S.typhii and E.coli. Compounds 32 and 33, both containing electron withdrawing groups (-Cl, -F) showed excellent activities against all the tested A. flavus, Mucor, Rhizopus and M.gypsuem fungal strains. while against Mucor, compound 27 which contains an electron donating methyl group at the para position of the phenyl ring attached to pyrimidine ring showed promising activity. Also compound 31, which contains both electron withdrawing chloro and electron donating methyl groups showed potent activity against A. flavus and Rhizopus.     

New conformationally constrained Xxx-Pro bicyclic mimetics

Summary Conformationally constrained peptidomimetics of the Lys-Pro sequence have been obtained using a new polycyclic structure. Bicyclic compounds containing a dioxopiperazine-thiazolidine fused ring have been synthesised starting from N-lysyl-4-ethoxycarbonylthiazolidine-2-carboxylic acid. The carboxyl group in either position 2 or 4 of the thiazolidine ring was reacted with the N-terminal amino group, giving different regioisomers. NMR and computer modelling were used to study the configuration of isomers and the lysine side-chain orientation with respect to the pseudoproline ring.     

Synthesis of 3′-4′-α-Propylene-2′-3′-dideoxynucleosides

Abstract

In order to obtain a high degree of rigidity within the sugar moiety of nucleosides, some bicyclic pyrimidine nucleoside analogues where synthesized starting from cyclopentanone. The C-4′-substituent is fused to the C-3′-position via a propylene to give a [3.3.0]-bicyclic ring system.     

Reactivity Models of 1-N-Vinyluracil and Synthesis of a New Class of Potential Antiviral Agents by the Use of 1,3-Dipolar Cycloaddition Reactions

Abstract

By the use of a convergent approach based on 1,3-dipolar cycloaddition reactions between N-protected formylnitrones generated in situ and 1-N-vinyluracil, a new class of 4′-aza-analogues of 2′,3′-dideoxynucleosides is synthesized. Competitive reaction for the endocyclic bond of uracil also brings to a new isoxazolidine derivative fused with the pyrimidine nucleus.     

Novel Regioselective Formation of S- and N-Hydroxyl-Alkyls of 5-(3-Chlorobenzo[b]Thien-2-yl)-3-Mercapto-4H-1,2,4-Triazole and A Facile Synthesis of Triazolo-Thiazoles and Thiazolo-Triazoles. Role of Catalyst and Microwave

Regioselective alkylation of 5-(3-chlorobenzo[b]thien-2-yl)-4H-1,2,4-triazole (1) with hydroxy alkylating agents 2, 3, 13, and the 2,3-O-isopropylidene-1-O-(p-tolylsulfonyl)-glycerol (10) afforded the corresponding S-alkylated derivatives 6, 7, 11, and 14 under both conventional and microwave irradiation conditions; bentonite as a solid support gave better results, with no change in regioselectivity. A facile intramolecular dehydrative ring closure of 6, 7, 11, and 14 using K₂CO₃ in DMF afforded the corresponding fused triazolo-thiazines and thiazolo-triazole 17–19. The isopropylidenes and acetyl derivatives of the products were prepared.     

Simulations of the c-subunit of ATP-synthase reveal helix rearrangements

Abstract

The c-subunit of the enzyme, ATP synthase couples the proton movement through the a-subunit with its own rotation and subsequent rotation of the F1 ring to drive ATP synthesis. Here, we perform μs time-scale coarse-grained molecular dynamics simulations of the c-subunit to characterize its structure and dynamics. Two different helix-helix interfaces, albeit with similar interfacial characteristics, are sampled in the simulations. The helix-2 of the c-subunit monomer rotates around the axis of helix-1 bringing about a change in the interface. Previous models have also proposed such a change in the helix interface but postulated that helix-2 swivels around its own axis. Such large-scale changes in helix packing motifs have not been observed before. The helix-swirling persists even in the c-subunit ring but the dynamics is much slower. The cooperative behavior in the ring appears to stabilize a conformation less-populated in the monomer. Analyzing the stability of the c-subunit ring, it was found that six lipid molecules are necessary to fill the central cavity of the ring. These lipid molecules were not aligned with the surrounding bilayer but protruded towards the periplasmic side. The characterization of the monomer and ring presented in this work sheds light into the structural dynamics of the c-subunit and its functional relevance.     

A Convenient Approach to N-3 Alkylation of 9-Substituted Guanines

Abstract

Aryl or tert-butyl substituent in the 6 position of 3,9-dihydro-3-[(2-hydroxy-ethoxy)methyl]-9-oxo-6-R-5H-imidazo[1,2-α]purine 1 directs the benzylation reaction partly into N-4 position to give 3. Cleavage of the third ring of 3 gives 3-benzylacycloguanosine 5, a first 3-aralkilo-9-substituted guanine.     

Synthesis of Certain Acyclic Nucleoside Analogs of 1,2,4-Triazolo[3,4-f][1,2,4]triazine and Pyrimido[5,4-d]pyrimidine

Abstract

Synthesis of 2-penten-1-yl (8a) and ganciclovir analog (8b) of 1,2,4-triazolo[3,4-f][1,2,4]triazine was accomplished by the ring annulation of the corresponding hydrazides (6a and 6b), which in turn was obtained by the dehydrative coupling of 4 with 5a or 5b. Base catalysed ring expansion of N9-alkylpurine-6-carbonitriles (10a 10c 10e) provided the acyclic analogs of 4-aminopyrimido-[5,4-d]pyrimidines (13a 13d 13e). Debenzylation of 13e afforded the ganciclovir analog (13f) of 4-amino-8-(β-D-ribofuranosylamino)-pyrimido[5,4-d]pyrimidine. However, compound 10b did not undergo the expected rearrangement but resulted in the formation of the methyl formimidate derivative (12).     

New species and a new combination in Myrtaceae from northeastern South America

Three new species of Myrtaceae (Calyptranthes bracteata, Eugenia gonglycocarpa, andMyrcia rupta) from northeastern South America are described and illustrated, and a new combination (Eugenia tetramera) is proposed. The closed-calyx and the completely or partially fused cotyledons ofMyrcia rupta, unusual features for the genus, are discussed and compared with related species inMyrcia andMarlierea.     

Synthesis and Antimicrobial Evaluation of Novel Pyrazolones and Pyrazolone Nucleosides

The synthesis of a novel series of 4-arylhydrazono-5-methyl-1,2-dihydropyrazol-3-ones 4a–h, and their N ²-alkyl and acyclo, glucopyranosyl, and ribofuranosyl derivatives is described. K₂CO₃ catalyzed alkylation of 4a–h with allyl bromide, propargyl bromide, 4-bromobutyl acetate, 2-acetoxyethoxymethyl bromide, and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide proceeded selectively at the N ²-position of the pyrazolinone ring. Glycosylation of 4a with 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose under Vorbruggen glycosylation conditions gave the corresponding N ²-4-arylhydrazonopyrazolone ribofuranoside 9a in good yield. Conventional deprotection of the acetyl protected nucleosides furnished the corresponding 4-arylhydrazonopyrazolone nucleosides in good yields. Selected numbers of the newly synthesized compounds were screened for antimicrobial activity. Compounds 4b, 12a, and 14d showed moderate activities against Aspergillus flavus, Penicillium sp., and Escherichia coli.     

Alcohols as Replacements of the Central Amide in β-Turns, Synthesis of Pro-Aib Hydroxyethylene Isostere and Analysis in Model β-Turn Peptides

Pro-Aib hydroxyethylene isosteres (S,R)- and (S,S)-7 were synthesized by cascade addition of 2-methyl-1-propenylmagnesium bromide to Boc-Pro-OMe in the presence of CuCN, followed by ketone reduction and olefin oxidation. By protecting the amine and hydroxyl groups in an oxazolidinone ring, hydroxyethylene isosteres 7 were successfully incorporated into Boc-Phe-Pro- ψ -[CH-(OH)-CH₂]-Aib-NHBn(α -Me) (S,R)-and (S,S)-11, which were characterized by ¹H NMR and IR spectroscopy. Examination of the NOESY spectra and the influence of solvent changes on the chemical shifts of the amide and carbamate proton signals for (S,R)-and (S,S)-11 indicated that both hydroxyethylene isosteres could adopt compact turn structures. The alcohol appears to act as a hydrogen donor in a seven-membered ring intramolecular hydrogen bond. In addition, analysis of the respective peptide (S,S)-16, in which the hydroxyl group was masked as a methyl ether, showed that the turn conformation was disrupted, and indicated the importance of the alcohol as a hydrogen-bond donor for turn stability. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Design,synthesis, characterization and in vitro antimicrobial evaluation of 4,6-diaryl-4,5-dihydro-2-phenyl-2H-indazol-3-ols

New 4,6-diaryl-4,5-dihydro-2-phenyl-2H-indazol-3-ols 25-32 were designed, synthesized and in vitro microbially evaluated using clinically isolated bacterial strains viz Staphylococcus aureus, β-Heamolytic streptococcus, Vibreo cholerae, Salmonella typhii, Shigella felxneri and fungal strains viz Aspergillus flavus, Mucor, Rhizopus and Microsporum gypsuem. Results of this study showed that the nature of the substituents on the phenyl rings viz., methyl, methoxy, chloro, nitro as well as the bromo functions at the meta and para positions of the aryl moieties determined the nature and extent of the activity of the fused indazolonol compounds 25-32.     

Chemical constituents from the fungus Monascus purpureus and their antifungal activity

One new cyclohex-2-enone derivative, purpureusone (1), together with seven known compounds (2–8) were isolated from the n-BuOH-soluble fraction of the 95% EtOH extract of the red yeast rice fermented with the yellow mutant of the fungus Monascus purpureus BCRC 38038. Their structures were characterized by direct interpretation of their spectroscopic methods, including 1D NMR (¹H, ¹³C NMR, DEPT), 2D NMR (COSY, NOESY, HSQC and HMBC), and HRESIMS. Purpureusone (1) contains a cyclohex-2-enone skeleton connected with one γ-lactone ring, one octanoyl, and 2-oxopentyl side chains. Some isolates were evaluated for their antifungal effect against Candida albicans and Saccharomyces cerevisiae using a TLC bioautographic method. Compound 1 showed antifungal inhibitory activity in vitro.     

Protective Group-Free Syntheses of (±)-Frontalin, (±)-endo-Brevicomin, (±)-exo-Brevicomin,and (±)-3,4-Dehydro-exo-brevicomin: Racemic Pheromones with a 6,8-Dioxabicyclo[3.2.1]octane Ring

Protective group-free syntheses of four racemic pheromones with a 6,8-dioxabicyclo[3.2.1]octane ring were achieved in five or six steps from commercially available (±)-3-butyn-2-ol (6) and 2-alkenyl halides or 2-alken-1-ol by employing Lewis acid-catalyzed acetalization of δ, ε-epoxy ketones as the key reaction. (±)-Frontalin (1) was prepared in a 25% overall yield in five steps from methallyl chloride (5a), (±)-endo-brevicomin (2) was prepared in a 23% overall yield in five steps from (E)-2-pentenyl bromide (5b), and (±)-exo-brevicomin (3) and (±)-3,4-dehydro-exo-brevicomin (4) were both prepared in a 4% overall yield in six steps based on (Z)-2-penten-1-ol (12).     

Occurrence of a resveratrol trimer diglucoside derivative with a fused heptacyclic skeleton in Shorea uliginosa

Uliginoside H (1) is a new resveratrol trimer diglucoside derivative with fused heptacycles. It was discovered from the acetone extract of the stem bark of Shorea uliginosa (Dipterocarpaceae). Spectroscopic analysis, such as NMR experiments, was used to elucidate the structure, and the absolute configuration was determined using circular dichroism data. Notably, 1 has a fused ring system composed of a dihydrobenzofuran ring, a hexahydrocyclopenta[c]chromene ring, and a cyclohex-2-enone ring, each with eight asymmetric carbons. Thus, a plausible biosynthetic pathway for 1 was proposed.