Data on COA-Cl administration to the APP/PS2 double-transgenic mouse model of Alzheimer׳s disease: Improved hippocampus-dependent learning and unchanged spontaneous physical activity.

We herein present behavioral data regarding whether COA-Cl, a novel adenosine-like nucleic acid analog that promotes angiogenesis and features neuroprotective roles, improves cognitive and behavioral deficits in a murine model for Alzheimer׳s disease (AD). COA-Cl induced significant spatial memory improvement in the amyloid precursor protein/presenilin 2 double-transgenic mouse model of AD (PS2Tg2576 mice). Correspondingly, non-spatial novel object cognition test performance also significantly improved in COA-Cl-treated PS2Tg2576 mice; however, these mice demonstrated no significant changes in physical activity or motor performance.

Design, synthesis, and anti-HIV-1 activity of 1-substituted 3-(3,5-dimethylbenzyl)triazine derivatives.

Background: The reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) is an attractive target for the development of drugs used in the treatment of HIV-1 infection and acquired immune deficiency syndrome (AIDS). We have continued the search for novel anti-HIV-1 agents using the structure-activity relationships of the successful 1,3-disubstituted and 1,3,6-trisubstituted uracil-type HIV-1 RT inhibitors.

Methods: A series of new triazine analogs were synthesized using an established method.

Synthesis and Evaluation of Novel Carbocyclic Oxetanocin A (COA-Cl) Derivatives as Potential Tube Formation Agents.

Six novel carbocyclic oxetanocin A analogs (2-chloro-C.OXT-A; COA-Cl) with various hydroxymethylated or spiro-conjugated cyclobutane rings at the N(9)-position of the 2-chloropurine moiety were synthesized and evaluated using human umbilical vein endothelial cells. All prepared compounds (2a-f) showed good to moderate activity with angiogenic potency.

Design, synthesis, and anti-HIV-1 activity of 1-aromatic methyl-substituted 3-(3,5-dimethylbenzyl)uracil and N-3,5-dimethylbenzyl-substituted urea derivatives.

Background: A new series of 1-aromatic methyl-substituted 3-(3,5-dimethylbenzyl)uracil and N-3,5-dimethylbenzyl-substituted urea derivatives were synthesized and evaluated as non-nucleoside HIV-1 reverse transcriptase inhibitors.

Methods: A series of new 6-azido and 6-amino derivatives of 1-substituted-3-(3,5-dimethylbenzyl)uracils were synthesized using our previously reported method, and three acyclic derivatives were synthesized from urea. The anti-HIV-1 activities of these compounds were determined based on the inhibition of virus-induced cytopathogenicity in MT-4 cells.

Involvement of S1P1 receptor pathway in angiogenic effects of a novel adenosine-like nucleic acid analog COA-Cl in cultured human vascular endothelial cells.

COA-Cl (2Cl-C.OXT-A) is a recently developed adenosine-like nucleic acid analog that promotes angiogenesis via the mitogen-activated protein (MAP) kinases ERK1/2. Endothelial S1P1 receptor plays indispensable roles in developmental angiogenesis.

Synthesis and evaluation of novel 3-(3,5-dimethylbenzyl)uracil analogs as potential anti-HIV-1 agents.

A novel series of uracil derivatives with a 3,5-dimethylbenzyl group at the N(3)-position were synthesized and evaluated as non-nucleoside HIV-1 reverse transcriptase inhibitors. Some of these compounds showed good-to-moderate activity with EC50 values in the submicromolar range. Among them, compound 10c showed significant potency against HIV-1 activity with an EC50 value of 0.

Delayed administration of the nucleic acid analog 2Cl-C.OXT-A attenuates brain damage and enhances functional recovery after ischemic stroke.

2Cl-C.OXT-A (COA-Cl) is a novel nucleic acid analog that enhances angiogenesis through extracellular signal-regulated kinase 1 or 2 (ERK1/2) activation. ERK1/2 is a well-known kinase that regulates cell survival, proliferation and differentiation in the central nervous system.

Anti-human immunodeficiency virus type 1 activity of novel 6-substituted 1-benzyl-3-(3,5-dimethylbenzyl)uracil derivatives.

Nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are important components of current combination therapies for human immunodeficiency virus type 1 (HIV-1) infection. In screening of chemical libraries, we found 6-azido-1-benzyl-3-(3,5-dimethylbenzyl)uracil (AzBBU) and 6-amino-1-benzyl-3-(3,5-dimethylbenzyl)uracil (AmBBU) to be highly active and selective inhibitors of HIV-1 replication in vitro. To determine the resistance profiles of these compounds, we conducted a long-term culture of HIV-1-infected MT-4 cells with escalating concentrations of each compound.

One-handed helical screw direction of homopeptide foldamer exclusively induced by cyclic α-amino acid side-chain chiral centers.

Chiral cyclic α,α-disubstituted amino acids, (3S,4S)- and (3R,4R)-1-amino-3,4-(dialkoxy)cyclopentanecarboxylic acids ((S,S)- and (R,R)-Ac(5)c(dOR); R: methyl, methoxymethyl), were synthesized from dimethyl L-(+)- or D-(-)-tartrate, and their homochiral homoligomers were prepared by solution-phase methods. The preferred secondary structure of the (S,S)-Ac(5)c(dOMe) hexapeptide was a left-handed (M) 3(10) helix, whereas those of the (S,S)-Ac(5)c(dOMe) octa- and decapeptides were left-handed (M) α helices, both in solution and in the crystal state. The octa- and decapeptides can be well dissolved in pure water and are more α helical in water than in 2,2,2-trifluoroethanol solution.

Synthesis of 1-benzyl-3-(3,5-dimethylbenzyl)uracil derivatives with potential anti-HIV activity.

Background: Nine novel uracil analogues were synthesized and evaluated as inhibitors of HIV-1.

Methods: Key structural modifications included replacement of the 6-chloro group of 1-benzyl-6-chloro-3-(3,5-dimethylbenzyl)uracil by other functional groups or N(1)-alkylation of 3-(3,5-dimethylbenzyl)-5-fluorouracil.

Results: These compounds showed only micromolar potency against HIV-1 in MT-4, though two of them; 6-azido-1-benzyl-3-(3,5-dimethylbenzyl) uracil and 6-amino-1-benzyl-3-(3,5-dimethylbenzyl) uracil were highly potent (half maximal effective concentration =0.

A novel nucleic acid analogue shows strong angiogenic activity.

A novel nucleic acid analogue (2Cl-C.OXT-A) significantly stimulated tube formation of human umbilical endothelial cells (HUVEC). Its maximum potency at 100muM was stronger than that of vascular endothelial growth factor (VEGF), a positive control.

Synthesis and anti-HCV activity of 2',5'-deoxy-5'-phenacyladenosine analogs.

Several nucleoside analogs containing a methylene group instead of a 5'-O atom were synthesized to study the effect of the 5'-modification of nucleoside analogs on their anti-HCV activity. Among the analogs, a 5'-phenacyl analog exhibited good anti-HCV activity with an EC(50) of 15.1 muM.

Sumoylation of CoREST modulates its function as a transcriptional repressor.

It is emerging that covalent modifications of many transcription factors and co-factors by the small ubiquitin-like modifier (SUMO) can have a key role in modulating their transcriptional regulation. As SUMO modification is often associated with transcriptional repression, we studied whether it was involved in modulating the repressive activity of CoREST. We showed that CoREST can be modified by SUMO-1 at lysine 294.

Synthesis and evaluation of 5'-modified 2'-deoxyadenosine analogues as anti-hepatitis C virus agents.

In order to study the effect of 5'-modification of 2'-deoxynucleoside on its anti-HCV activity, several analogues were synthesized and evaluated. Among the analogues, a 5'-deoxy-5'-phenacylated analogue exhibited a good anti-HCV activity with an EC(50) of 15.1 microM.

Synthesis of fluorinated nucleosides.

Two practical synthetic approaches to the production of lodenosine [FddA, 9-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)adenine] via 6-chloropurine riboside or 6-chloropurine 3'-deoxyriboside are described. The reaction sequence contains new fluorination methods and new applications of radical reduction. The reagents and reaction conditions of each step have been carefully selected to ensure robustness and safety.

Antiviral activity of 3-(3,5-dimethylbenzyl)uracil derivatives against HIV-1 and HCMV.

Antiviral activity of 1,3-disubstituted uracil derivatives was evaluated against HIV-1 and HCMV. It appears that the nitrogen of the 1-cyanomethyl group is important for anti-HIV-1 activity, suggesting interaction with the amino acid residues of HIV-1 reverse transcriptase. 1-Arylmethyl derivatives also exhibited good anti-HIV-1 activity; and that of the 2- and 4-picolyl derivatives was particularly excellent.

Suppression of subgenomic hepatitis C virus replication by 5'-O-masked analogues of 6-chloropurine-2'-deoxyriboside.

A series of nucleoside analogues whose 5'-hydroxyl groups are masked by various protective groups were synthesized and evaluated to develop novel anti- hepatitis C virus (HCV) agents. Among the several analogues that showed anti-HCV potency, a 5'-O-benzoyl-2'-deoxyribonucleoside analogue exhibited high anti-HCV activity with an EC(50) of 6.1 microM.

Anti-angiogenic activities of nucleosides and nucleotides and their structure-activity relationship.

The effects of nucleosides and nucleotides on the tube formation of human umbilical vein endothelial cells (HUVEC) were compared. Twenty eight compounds including endogenous species were examined and many of them were revealed to have inhibitory potency. The potency was strengthened significantly when the sugar moiety of ribonucleosides was modified.

5'-O-masked 2'-deoxyadenosine analogues as lead compounds for hepatitis C virus (HCV) therapeutic agents.

On the basis of our previous study on antiviral agents against the severe acute respiratory syndrome (SARS) coronavirus, a series of nucleoside analogues whose 5'-hydroxyl groups are masked by various protective groups such as carboxylate, sulfonate, and ether were synthesized and evaluated to develop novel anti-hepatitis C virus (HCV) agents. Among these, several 5'-O-masked analogues of 6-chloropurine-2'-deoxyriboside (e.g.

Controlling 3(10)-helix and alpha-helix of short peptides in the solid state.

L-Leu hexapeptide containing alpha-aminoisobutyric acid (Aib) forms a right-handed (P) 3(10)-helix, whereas that containing cyclic alpha,alpha-disubstituted amino acid Ac(5)c(dOM) assumes a right-handed (P) alpha-helix in the solid state.

Synthesis and biological evaluation of nucleoside analogues having 6-chloropurine as anti-SARS-CoV agents.

Nucleoside analogues that have 6-chloropurine as the nucleobase were synthesized and evaluated for anti-SARS-CoV activity by plaque reduction and yield reduction assays in order to develop novel anti-SARS-CoV agents. Among these analogues, two compounds, namely, 1 and 11, exhibited promising anti-SARS-CoV activity that was comparable to those of mizoribine and ribavirin, which are known anti-SARS-CoV agents. Moreover, we observed several SAR trends such as the antiviral effects of the 6-chloropurine moiety, unprotected 5'-hydroxyl group and benzoylated 5'-hydroxyl group.

Anti-SARS-CoV activity of nucleoside analogs having 6-chloropurine as a nucleobase.

Nucleoside analogs that have 6-chloropurine as a nucleobase were synthesized and evaluated to develop novel anti-SARS-CoV agents. Two compounds among them showed promising activity that was comparable to mizoribine and ribavirin. Moreover, one of the compounds showed a structurally unique property.

Synthesis of purin-2-yl carboxylate from O6-methylguanosine.

O6-methylguanosine derivative was treated with sodium nitrite or isoamylnitrite in the presence of the carboxylic acid to give the purin-2-yl carboxylate (2), an unusual product bearing a carboxylic group at 2-position of purine moiety.

Telomere shortening in human HL60 cells by treatment with deoxyguanosine analogs.

Telomerase is a cellular endogenous reverse transcriptase thought to play an important role in the maintenance of telomere length. We investigated the effects of 3'-azido-2',3'-dideoxyguanosine (AZddG) and carbocyclic oxetanocin G (C.OXT-G), of which the triphosphate derivatives AZddGTP and C.

Synthesis and antiviral activity of 1-substituted 3-(3,5-dimethylbenzyl)uracil against HIV-1.

1,3-disubstituted uracils were obtained from uracil by the stepwise alkylation at N-1 and N-3 position with alkyl halide/alkali or alcohol under Mitsunobu conditions. The antiviral activity against HIV-1 of these compounds was examined to find that 1-cyanomethyl-3-(3,5-dimethylbenzyl)uracil and 1-phenyl-3-(3,5-dimethyl-benzyl)uracil showed powerful inhibition.