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1.  Synthesis of 4’-Ethynyl-2’-deoxy-4’-thioribonucleosides and Discovery of a Highly Potent and Less Toxic NRTI 
ACS medicinal chemistry letters  2011;2(9):692-697.
The synthesis of 4’-ethynyl-2’-deoxy-4’-thioribonucleosides was carried out utilizing an electrophilic glycosidation in which 4-ethynyl-4-thiofuranoid glycal 16 served as a glycosyl donor. Electrophilic glycosidation between 16 and the silylated nucleobases (N4-acetylcytosine, N6-benzoyladenine and N2-acetyl-O6-diphenylcarbamoylguanine) was carried out in the presence of N-iodosuccinimide (NIS) leading to the exclusive formation of the desired β-anomers 29, 33 and 36. Anti-HIV studies demonstrated that these 4’-thio nucleosides were less cytotoxic to T-lymphocyte (i.e. MT-4 cells) than the corresponding 4’-ethynyl derivatives of 2’-deoxycytidine (44), 2’-deoxyadenosine (45) and 2’-deoxyguanosine (46). Comparison of the selectivity indices (SI) was made between 4’-thionucleosides (32, 41 and 43) and the corresponding 4’-oxygen analogues 44–46 by using the reported CC50 and EC50 values. In the case of cytosine and adenine nucleosides, comparable SI values were obtained: 32 (545) and 45 (458); 41 (>230) and 45 (1,630). In contrast, 4’-ethynyl-2’-deoxy-4’-thioguanosine 43 was found to possess a SI value of >18,200, which is twenty times better than that of 46 (933).
doi:10.1021/ml2001054
PMCID: PMC3686520  PMID: 23795238
4’-thionucleosides; glycal; electrophilic glycosidation; anti-HIV-1 activity; nucleoside reverse transcriptase inhibitors
2.  Prefrontal cortex and hybrid learning during iterative competitive games 
Behavioral changes driven by reinforcement and punishment are referred to as simple or model-free reinforcement learning. Animals can also change their behaviors by observing events that are neither appetitive nor aversive, when these events provide new information about payoffs available from alternative actions. This is an example of model-based reinforcement learning, and can be accomplished by incorporating hypothetical reward signals into the value functions for specific actions. Recent neuroimaging and single-neuron recording studies showed that the prefrontal cortex and the striatum are involved not only in reinforcement and punishment, but also in model-based reinforcement learning. We found evidence for both types of learning, and hence hybrid learning, in monkeys during simulated competitive games. In addition, in both the dorsolateral prefrontal cortex and orbitofrontal cortex, individual neurons heterogeneously encoded signals related to actual and hypothetical outcomes from specific actions, suggesting that both areas might contribute to hybrid learning.
doi:10.1111/j.1749-6632.2011.06223.x
PMCID: PMC3302724  PMID: 22145879
belief learning; decision making; game theory; reinforcement learning; reward
3.  Synthesis of 4′-Ethynyl-2′-deoxy-4′-thioribonucleosides and Discovery of a Highly Potent and Less Toxic NRTI 
ACS Medicinal Chemistry Letters  2011;2(9):692-697.
The synthesis of 4′-ethynyl-2′-deoxy-4′-thioribonucleosides was carried out utilizing an electrophilic glycosidation in which 4-ethynyl-4-thiofuranoid glycal 16 served as a glycosyl donor. Electrophilic glycosidation between 16 and the silylated nucleobases (N4-acetylcytosine, N6-benzoyladenine, and N2-acetyl-O6-diphenylcarbamoylguanine) was carried out in the presence of N-iodosuccinimide (NIS), leading to the exclusive formation of the desired β-anomers 29, 33, and 36. Anti-HIV studies demonstrated that these 4′-thio nucleosides were less cytotoxic to T-lymphocyte (i.e., MT-4 cells) than the corresponding 4′-ethynyl derivatives of 2′-deoxycytidine (44), 2′-deoxyadenosine (45), and 2′-deoxyguanosine (46). Comparison of the selectivity indices (SI) was made between 4′-thionucleosides (32, 41, and 43) and the corresponding 4′-oxygen analogues 44-46 by using the reported CC50 and EC50 values. In the case of cytosine and adenine nucleosides, comparable SI values were obtained as follows: 32 (545) and 44 (458); 41 (>230) and 45 (1630). In contrast, 4′-ethynyl-2′-deoxy-4′-thioguanosine 43 was found to possess a SI value of >18200, which is 20 times better than that of 46 (933).
doi:10.1021/ml2001054
PMCID: PMC3686520  PMID: 23795238
4′-Thionucleosides; glycal; electrophilic glycosidation; anti-HIV-1 activity; nucleoside reverse transcriptase inhibitors
4.  Qualitative difference between “bulb” membranes and other vacuolar membranes 
Plant Signaling & Behavior  2011;6(12):1914-1917.
“Bulb” is a mobile and complex structure appearing in vacuolar membrane of plant cell. We recently reported new fluorescent marker lines for bulbs and bulb-less mutants. We tried multicolor visualization of vacuolar membrane to show distinct segregation of bulb-positive protein (γTIP or AtVAM3) and bulb-negative protein (AtRab75). Unexpectedly, GFP-AtRab75 resulted to localize in bulb under the condition of co-expression with TagRFP-AtVAM3. The signal intensities of GFP-AtRab75 and TagRFP-AtVAM3 were quantified and compared. The result indicates that TagRFP-AtVAM3 is concentrated in bulb than GFP-AtRab75.
doi:10.4161/psb.6.12.18061
PMCID: PMC3337177  PMID: 22105033
AtRab75; AtVam3; plant growth; Rab-GTPase; SNARE; vacuolar membranes; “bulb”
5.  Distributed coding of actual and hypothetical outcomes in the orbital and dorsolateral prefrontal cortex 
Neuron  2011;70(4):731-741.
SUMMARY
Knowledge about hypothetical outcomes from unchosen actions is beneficial only when such outcomes can be correctly attributed to specific actions. Here, we show that during a simulated rock-paper-scissors game, rhesus monkeys can adjust their choice behaviors according to both actual and hypothetical outcomes from their chosen and unchosen actions, respectively. In addition, neurons in both dorsolateral prefrontal cortex and orbitofrontal cortex encoded the signals related to actual and hypothetical outcomes immediately after they were revealed to the animal. Moreover, compared to the neurons in the orbitofrontal cortex, those in the dorsolateral prefrontal cortex were more likely to change their activity according to the hypothetical outcomes from specific actions. Conjunctive and parallel coding of multiple actions and their outcomes in the prefrontal cortex might enhance the efficiency of reinforcement learning and also contribute to their context-dependent memory.
doi:10.1016/j.neuron.2011.03.026
PMCID: PMC3104017  PMID: 21609828
6.  Indomethacin Analogues that Enhance Doxorubicin Cytotoxicity in Multidrug Resistant Cells without Cox Inhibitory Activity 
ACS Medicinal Chemistry Letters  2011;2(5):353-357.
Conformationally restricted indomethacin analogues were designed and prepared from the corresponding 2-substituted indoles, which were synthesized by a one-pot isomerization/enamide-ene metathesis as the key reaction. Conformational analysis by calculations, NMR studies, and X-ray crystallography suggested that these analogues were conformationally restricted in the s-cis or the s-trans form due to the 2-substituent as expected. Their biological activities on cyclooxygenase-1 (COX-1) inhibition, cyclooxygenase-2 (COX-2) inhibition, and modulation of MRP-1-mediated multidrug resistance (MDR) are described. Some of these indomethacin analogues enhanced doxorubicin cytotoxicity, although they do not have any COX inhibitory activity, which suggests that the MDR-modulating effect of an NSAID can be unassociated with its COX-inhibitory activity. This may be an entry into the combination chemotherapy of doxorubicin with a MDR modulator.
doi:10.1021/ml100292y
PMCID: PMC4017980  PMID: 24900317
Cancer; conformation analysis; cytotoxicity; drug design; nitrogen heterocycles
7.  Development of Full-Length cDNAs from Chinese Cabbage (Brassica rapa Subsp. pekinensis) and Identification of Marker Genes for Defence Response 
Arabidopsis belongs to the Brassicaceae family and plays an important role as a model plant for which researchers have developed fine-tuned genome resources. Genome sequencing projects have been initiated for other members of the Brassicaceae family. Among these projects, research on Chinese cabbage (Brassica rapa subsp. pekinensis) started early because of strong interest in this species. Here, we report the development of a library of Chinese cabbage full-length cDNA clones, the RIKEN BRC B. rapa full-length cDNA (BBRAF) resource, to accelerate research on Brassica species. We sequenced 10 000 BBRAF clones and confirmed 5476 independent clones. Most of these cDNAs showed high homology to Arabidopsis genes, but we also obtained more than 200 cDNA clones that lacked any sequence homology to Arabidopsis genes. We also successfully identified several possible candidate marker genes for plant defence responses from our analysis of the expression of the Brassica counterparts of Arabidopsis marker genes in response to salicylic acid and jasmonic acid. We compared gene expression of these markers in several Chinese cabbage cultivars. Our BBRAF cDNA resource will be publicly available from the RIKEN Bioresource Center and will help researchers to transfer Arabidopsis-related knowledge to Brassica crops.
doi:10.1093/dnares/dsr018
PMCID: PMC3158467  PMID: 21745830
Arabidopsis; Brassica rapa; full-length cDNA; jasmonic acid; salicylic acid

Results 1-7 (7)