Novel Bicyclic Nucleoside Analogues Related to Natural Griseolic Acids

Abstract

Methodologies for the synthesis of novel isomeric nucleosides related to the natural, biologically-active griseolic acids are described. The carbohydrate precursor for the synthesis, 1,4:3,6-dianhydro-d-glucitol, can be prepared easily from d-glucitol.     

Multiple Neurite Formation in Neuroblastoma Cell Lines by Griseolic Acid, a Potent Inhibitor of Cyclic Nucleotide Phosphodiesterases

The morphological change of several neuroblastoma cell lines induced by griseolic acid, a novel and potent inhibitor of cyclic nucleotide phosphodiesterase (PDE), was examined. In the cell lines tested, Neuro-2a (a murine neuroblastoma cell line) showed dose-dependent (1 microM-1 mM) neurite extension. Griseolic acid markedly increased the intracellular cyclic AMP level of Neuro-2a cells, suppressed DNA synthesis (82% at 1 mM), and induced multipolar (multiple-neurite-bearing)-type neuritogenesis. A similar type of neurite outgrowth was induced by 8-bromo-cyclic AMP, which also elevated the intracellular cyclic AMP concentration. In contrast, when Neuro-2a cells were treated with retinoic acid, neurite formation was of the monopolar (single-neurite-bearing) type. Papaverine and theophylline, which have been frequently used as PDE inhibitors, failed to induce these morphological changes up to 1 mM, probably owing to the lesser potency of these compounds as compared with griseolic acid on the inhibition of PDE. Retinoic acid, theophylline, and papaverine were ineffective at elevating the intracellular cyclic AMP level. These results suggest that multipolar-type cell shape change in Neuro-2a cells is correlated with the accumulation of intracellular cyclic AMP and that griseolic acid is a useful compound to induce neuroblastoma cells into terminal differentiation.     

Synthesis and Antitumor Activity of N-Sulfonyl Derivatives of Nucleobases and Sulfonamido Nucleoside Derivatives

Abstract

The introduction of sulfonamido group on the C-2 position of pyrimidine nucleosides was achieved by ring opening of 2,2′- and 2,3′-anhydronucleosides. N-sulfonyl derivatives of nucleobases and sulfonamido derivatives of nucleosides were assayed for in vitro antitumor activity.     

6-Substituted Derivatives of Carbovir: Anti-HIV Activity

Abstract

A series of 6-alkoxy and 6-alkylamino carbovir derivatives were synthesized in order to evaluate prodrug approaches to increased bioavailability of the anti-HIV agent, carbovir. All of the compounds were active against HIV with the N-alkyl derivatives less active than the corresponding O-alkyl derivatives. The adenosine deaminase inhibitor, EHNA, had no effect on the anti-HIV activity of 6-propoxycarbovir, while the adenylic acid deaminase inhibitor, 2′-deoxycoformycin, significantly decreased antiviral activity. These observations suggest that the 6-alkoxycarbovirs are metabolized directly to the monophosphates and are subsequently converted to carbovir monophosphate via adenylic acid deaminase     

Method for the Synthesis of Uric Acid Derivatives

Abstract

A general procedure to obtain tetra-substituted uric acid by stepwise N-alkylation is described. 2,6-Dichloropurine (1) was condensed with 1-propanol by Mitsunobu reaction to give 9-propyl congener (2). Treatment of 2 with ammonia gave adenine derivative (4a), which was converted to the 8-oxoadenine (5b) in 3 steps. Methylation of 5b proceeded site-specifically to give 6-amino-2-chloro-7,8-dihydro-7-methyl-9-propylpurin-8-one (6) as a sole product. Compound 6 was successively treated with NaNO₂ and iodomethane to give 2-chloro-1,6,7,8-tetrahydro-1,7-dimethyl-9-propylpurin-6,8-dione (9) accompanied by the O ⁶-methyl product (8) in 75% and 6.9%, respectively. After nucleophilic substitution of 9 with NaOAc, the product (11) was reacted with iodomethane to give the uric acid (12) and the 2-methoxy product (13) in 46% and 15.5%, respectively. However, the reaction of 11 with the benzylating agents gave only O-benzyl products (14a,b).     

Synthesis and Biological Evaluation of some Acyclic Nucleoside Cyclic Phosphoramidate Derivatives

Abstract

The acyclic nucleosides 2 were treated with 2-chloro-3-methyl-1-oxa-3-aza-2-phosphacyclopentane (3) in the presence of diisopropylethylamine to give the corresponding phosphoramidite derivatives (4). The phosphoramidite intermediates (4) were oxidized with m-chloroperbenzoic acid to the phosphoramidate derivatives (5). Treatment of 5a,b with ZnBr₂ in CH₃NO₂ gave the corresponding acyclic nucleoside cyclic phosphoramidates (6a,b). Attempts to desilylation of 5c by tetrabutylammonium fluoride (TBAF) resulted in opening of the phosphoramidate ring. The newly synthesized compounds were evaluated for antiviral and antitumor cell activity.     

Design,Synthesis, and Molecular Docking of Some Novel Tacrine Based Cyclopentapyranopyridine- and Tetrahydropyranoquinoline-Kojic Acid Derivatives as Anti-Acetylcholinesterase Agents

A novel series of tacrine based cyclopentapyranopyridine- and tetrahydropyranoquinoline-kojic acid derivatives were designed, synthesized, and evaluated as anti-cholinesterase agents. The chemical structures of all target compounds were characterized by ¹H-NMR, ¹³C-NMR, and elemental analyses. The synthesized compounds mostly inhibited acetylcholinesterase enzyme (AChE) with IC₅₀ values of 4.18–48.71 μM rather than butyrylcholinesterase enzyme (BChE) with IC₅₀ values of >100 μM. Among them, cyclopentapyranopyridine-kojic acid derivatives showed slightly better AChE inhibitory activity compared to tetrahydropyranoquinoline-kojic acid. The compound 10-amino-2-(hydroxymethyl)-11-(4-isopropylphenyl)-7,8,9,11-tetrahydro-4H-cyclopenta[b]pyrano[2′,3′ : 5,6]pyrano[3,2-e]pyridin-4-one ( 6f ) bearing 4-isopropylphenyl moiety and cyclopentane ring exhibited the highest anti-AChE activity with IC₅₀ value of 4.18 μM. The kinetic study indicated that the compound 6f acts as a mixed inhibitor and the molecular docking studies also illustrated that the compound 6f binds to both the catalytic site (CS) and peripheral anionic site (PAS) of AChE. The compound 6f showed moderate neuroprotective properties against H₂O₂-induced cytotoxicity in PC12 cells. The theoretical ADME study also predicted good drug-likeness for the compound 6f . Based on these results, the compound 6f seems to be a very promising AChE inhibitor for the treatment of Alzheimer's disease.     

Synthesis of 1-acetyl-3-(2-thienyl)-5-aryl-2-pyrazoline derivatives and evaluation of their anticancer activity

In the present study, 1-acetyl-3-(2-thienyl)-5-aryl-2-pyrazoline derivatives (1–6) were synthesized via the ring closure reaction of 1-(2-thienyl)-3-aryl-2-propen-1-ones with hydrazine hydrate in acetic acid. The chemical structures of the compounds were elucidated by IR, ¹H-NMR, ¹³C-NMR and mass spectral data and elemental analyses. MTT assay, analysis of DNA synthesis and caspase-3 activation assay were carried out to determine anticancer effects of the compounds on A549 and C6 cancer cell lines. They exhibited dose-dependent anticancer activity against A549 and C6 cancer cell lines. Anticancer activity screening results revealed that compounds 1, 2 and 4 were the most potent derivatives among these compounds. But anticancer effects of these compounds may result from different death mechanisms in A549 and C6 cell lines.     

Nucleobase Modified Peptide Nucleic Acid

Abstract

The Pd⁰/Cu^I catalyzed cross-coupling of terminal alkynes onto peptide nucleic acid monomers or submonomers bearing iodinated nucleobases has been utilized as a route to base-modified oligomers. Both 5-iodouracil and 5-iodocytosine derivatives undergo the cross-coupling to give the expected products in moderate to good yields. However, depending on the particular substrates and reaction conditions, the cross-coupling may be followed by a ring closing reaction to give the fluorescent furano- and pyrrolo-fused uracil and cytosine derivatives, respectively.     

Synergistic Taste Effects of Some New Ribonucleotide Derivatives

Taste effects of six newly synthesized ribonucleotide derivatives, i.e., disodium salts of 2-methyl-5′-inosinic acid · 6H₂O, 2-ethyl-5′-inosinic acid · 1.5H₂O, 2-N-methyl-5′-guanylic acid · 5.5H₂O, 2-N-dimethyl-5′-guanylic acid · 2.5H₂O, 2-methylthio-5′-inosinic acid · 6H₂O and 2-ethylthio-5′-inosinic acid · 2H₂O, were studied. Stimulus thresholds (detection thresholds) of these derivatives ranged from about 0.02 to 0.006 g/100ml. Flavor-enhancing activities of them were 2.3 to 8.0 times larger than that of disodium 5′-inosinate · 7.5H₂O IMP) in the synergistic effect with monosodium glutamate. Furthermore, the quality of taste of all the derivatives was recognized to be the same kind to that of IMP.     

Synthesis and PreliminaryIn Vitro Evaluation of Antimycobacterial Activity of New Pyrrolo[1,2-a]quinoxaline-carboxylic Acid Hydrazide Derivatives

New pyrrolo[1,2-a]quinoxaline-2- or -4-carboxylic acid hydrazide derivatives were synthesized from nitroaniline or 1,2-phenylenediamine, and evaluated in vitro for their antimycobacterial activity as part of a TAACF TB screening program. Two compounds 7c and 13 showed an interesting activity at 6.25?μg/mL against Mycobacterium tuberculosis H₃₇Rv, with a 94 and 100 percentage inhibition, respectively.     

Xanchryones I−N,Six Unusual Phloroglucinol-Amino Acid Hybrids from the Leaves of Xanthostemon chrysanthus

Six new phloroglucinol derivatives, xanchryones I−N ( 1 – 6 ), were isolated from the leaves of Xanthostemon chrysanthus. Compounds 1 – 6 are unusual phloroglucinol-amino acid hybrids constructed through C₂−N and O−C₁′ bonds forming a peculiar oxazole ring. The structures and absolute configurations of compounds 1 – 6 were determined by MS, NMR, and single-crystal X-ray diffraction. Moreover, the anti-inflammatory and antibacterial activities of these compounds were evaluated.     

Acyloin Rearrangement of 6-Dehydro Derivatives of Grayanotoxin-II

The 5/7 membered ring system of 6-dehydro derivatives (2, 3, 5 and 6) of grayanotoxin-II (1) was converted to a 6/6 membered ring system (8a and 8b) in consequence of an acyloin rearrangement in alkaline media. The configurations of C₃ and C₆ of the products (8a and 8b) were determined.     

Effects of Ascorbate on the Oxidation of Derivatives of Hydroxycinnamic Acid and the Mechanism of Oxidation of Sinapic Acid by Cell Wall-Bound Peroxidases

A cell wall fraction isolated from epicotyls of Vigna angularis,which contained both ionically and covalently bound peroxidases,rapidly oxidized p-coumaric, caffeic and ferulic acids and slowlyoxidized sinapic acid. The oxidation of sinapic acid was greatlyenhanced in the presence of p-coumaric, caffeic or ferulic acid.Ascorbate (20 µM) inhibited the oxidation of ferulic acidby about 70% and completely inhibited the oxidation of p-coumaricand ferulic acids. The cell wall fraction was capable of bindingferulic and sinapic acids but not caffeic acid. p-Coumaric acidbound only slightly to cell walls. The oxidation of p-coumaricand ferulic acids by KCl-washed cell walls was inhibited byabout 60% and 10%, respectively, by 20 µM ascorbate, butthe oxidation of caffeic acid was completely inhibited by ascorbateat less than 20 µM. The oxidation of derivatives of hydroxycinnamicacid by peroxidases released from cell walls by washing with1 M KCl was completely inhibited by ascorbate. These resultssuggest that the inhibition by ascorbate depends on the substituentgroup of the phenyl ring of the derivatives of hydroxycinnamicacid when the oxidation reaction is catalyzed by cell wall-boundperoxidases and that the oxidation of sinapic acid is mediatedby phenoxyl radicals of derivatives of hydroxycinnamic acidother than sinapic acid. (Received December 2, 1993; Accepted March 3, 1994)     

Studies on griseolic acid derivatives. III. Synthesis and biological activities of the adducts of griseolic acid and their base exchanged derivatives

Addition reactions across the double bond of griseolic acid were investigated. Dihydrogriseolic acid was obtained by a reduction of the adduct having halogen at 4' position. The ring juncture of the two five membered rings of the dihydro derivatives was all "cis" configuration. An acetolysis of the protected dihydro derivative gave corresponding 1'-acetoxy sugar. A glycosidation of this sugar derivative with silylated bases gave base exchanged derivatives of the dihydrogriseolic acid. The influence of the base moiety and the double bond to the PDE inhibitory activity was investigated. As a result, we found that this type of compounds had a weaker inhibitory activity than the corresponding compounds which had an original double bond or a dihydro bond that made the ring juncture of the two five membered ring "trans".     

Synthesis and Antiviral Activity of Hydrazides and Substituted Benzalhydrazides of Betulinic Acid and Its Derivatives

New nitrogen-containing derivatives of betulinic and betulonic acids, hydrazides and N"-benzalhydrazides, were synthesized. Their antiviral activities toward viruses of influenza A virus, herpes simplex type I virus, enterovirus ECHO6, and HIV-1 were studied in vitro. Betulinic acid 3-oxime was found to have the highest activity against the influenza virus. Betulonic acid, betulinic acid 4-chlorobenzalhydrazide, betulonic acid 3-oxime benzalhydrazide, and betulinic acid hydrazide inhibited the replication of herpes simplex type I virus. Betulinic acid hydrazide also showed antiviral activity toward HIV-1. All the derivatives of betulinic acid under study displayed a low antiviral activity toward enterovirus ECHO6.     

Short Synthesis and Antiviral Activity of Acyclic Phosphonic Acid Nucleoside Analogues

An efficient route for synthesizing novel allylic and cyclopropanoid phosphonic acid nucleoside analogues is described. The condensation of the bromine derivatives 6 and 18 with nucleoside bases (A, U, T, C, G) under standard nucleophilic substitution and deprotection conditions, afforded the target phosphonic acid nucleoside analogues. These compounds were evaluated for their antiviral properties against various viruses. Cyclopropanoid phosphonic adenine nucleoside analogue 23 showed significant anti-HIV activity.     

Synthesis of 6-Sulfur Analogues of Oxanosine and Closely Related Derivatives Thereof

Abstract

Novel β-D-ribofuranosides having a 5-substituted imidazo [4,5-d] [1,3]thiazine ring, including the S⁶-congener 3 of oxanosine 2, were synthesized for screening their anticancer and antiviral activities.     

Synthesis of Thymine Derivatives of 4-Hydroxyvaline

Abstract

A synthetic route to thymine derivatives of (2S,3R)- and (2S,3S)-4-hydroxyvaline has been developed starting from commercially available L-aspartic acid.     

Hydrolase-Mediated Resolutions with Carbonic Acid Derivatives

It is shown that in the presence of crude PPL (Sigma type II) carbonic acid diesters ent-2 can be hydrolyzed enantioselectively. In contrast to hydrolysis of carboxylic esters working under pH-stat conditions is not necessary anymore. Vice versa, the enantioselective acylation of glycidol with carbonic acid derivatives, e.g. carbonic acid anhydrides, proceeds less selectively.