Lak Shin Jeong

Decreased expression of synapse-related genes and loss of synapses in major depressive disorder

Previous imaging and postmortem studies have reported a lower brain volume and a smaller size and density of neurons in the dorsolateral prefrontal cortex (dlPFC) of subjects with major depressive disorder (MDD). These findings suggest that synapse number and function are decreased in the dlPFC of patients with MDD. However, there has been no direct evidence reported for synapse loss in MDD, and the gene expression alterations underlying these effects have not been identified. Here we use microarray gene profiling and electron microscopic stereology to reveal lower expression of synaptic-function–related genes (CALM2, SYN1, RAB3A, RAB4B and TUBB4) in the dlPFC of subjects with MDD and a corresponding lower number of synapses. We also identify a transcriptional repressor, GATA1, expression of which is higher in MDD and that, when expressed in PFC neurons, is sufficient to decrease the expression of synapse-related genes, cause loss of dendritic spines and dendrites, and produce depressive behavior in rat models of depression.

Improved and alternative synthesis of d- and l-cyclopentenone derivatives, the versatile intermediates for the synthesis of carbocyclic nucleosides

Abstract Improved and alternative syntheses of d - and l -cyclopentenone derivatives were achieved in six steps from d -ribose via ring-closing metathesis (RCM) reaction as a key step. These derivatives serve as very versatile intermediates for the synthesis of carbocyclic nucleosides.

Recent Advances in the Synthesis of the Carbocyclic Nucleosides as Potential Antiviral Agents

Compared with 4′-oxonucleosides, there have been far fewer systematic structure-activity relationship studies on carbocyclic nucleosides as antiviral and antitumour agents. This is mainly because of the synthetic problems in preparing the carbasugars. However, the recent discovery of the ring-closing metathesis (RCM) (a powerful tool for the preparation of 5-membered carbasugar via C-C bond formation) has made it possible to synthesize the key carbasugars to a preparative scale. This review summarizes the asymmetric syntheses of carbasugars and carbocyclic nucleosides, using an RCM reaction as a key step. Furthermore, the review includes valuable information for designing and synthesizing novel carbocyclic nucleosides.

Selective A3 adenosine receptor antagonists derived from nucleosides containing a bicyclo[3.1.0]hexane ring system

We have prepared 50-modified derivatives of adenosine and a corresponding (N)-methanocarba nucleoside series containing a bicyclo[3.1.0]hexane ring system in place of the ribose moiety. The compounds were examined in binding assays at three subtypes of adenosine receptors (ARs) and in functional assays at the A3 AR. The H-bonding ability of a group of 9-riboside derivatives containing a 50-uronamide moiety was reduced by modification of the NH; however these derivatives did not display the desired activity as selective A3 AR antagonists, as occurs with 50-N,N-dimethyluronamides. However, truncated (N)-methanocarba analogues lacking a 40-hydroxymethyl group were highly potent and selective antagonists of the human A3 AR. The compounds were synthesized from D-ribose using a reductive free radical decarboxylation of a 50-carboxy intermediate. A less efficient synthetic approach began with L-ribose, which was similar to the published synthesis of (N)-methanocarba A3AR agonists. Compounds 33b-39b (N6-3-halobenzyl and related arylalkyl derivatives) were potent A3AR antagonists with binding Ki values of 0.7-1.4 nM. In a functional assay of [35S]GTPcS binding, 33b (3-iodobenzyl) completely inhibited stimulation by NECA with a KB of 8.9 nM. Thus, a highly potent and selective series of A3AR antagonists has been described.

The antitumor effect of LJ-529, a novel agonist to A3 adenosine receptor, in both estrogen receptor–positive and estrogen receptor–negative human breast cancers

Agonists to A3 adenosine receptor (A3AR) have been reported to inhibit cell growth and/or induce apoptosis in various tumors. We tested the effect of a novel A3AR agonist generically known as LJ-529 in breast cancer cells. Anchorage-dependent cell growth and in vivo tumor growth were attenuated by LJ-529, independently of its estrogen receptor (ER) α status. In addition, apoptosis was induced as evidenced by the activation of caspase-3 and c–poly(ADP)ribose polymerase. Furthermore, the Wnt signaling pathway was down-regulated and p27kip was induced by LJ-529. In ER-positive cells, the expression of ER was down-regulated by LJ-529, which might have additionally contributed to attenuated cell proliferation. In ER-negative, c-ErbB2-overexpressing SK-BR-3 cells, the expression of c-ErbB2 and its downstream extracellular signal-regulated kinase pathway were down-regulated by LJ-529. However, such effect of LJ-529 acted independently of its receptor because no A3AR was detected by reverse transcription-PCR in all four cell lines tested. In conclusion, our novel findings open the possibility of LJ-529 as an effective therapeutic agent against both ER-positive and ER-negative breast cancers, particularly against the more aggressive ER-negative, c-ErbB2-overexpressing types. [Mol Cancer Ther 2006;5(3):685–92]

Unanticipated retention of configuration in the DAST fluorination of deoxy-4′-thiopyrimidine nucleosides with “up” hydroxyl groups

Abstract Fluorination of 1-(5-O-trityl-3-deoxy-4-thio-β-D-threo-pentofuranosyl)uracil (17) and 1-(5-O-trityl-2-deoxy-4-thio-β-D-threo- pentofuranosyl)uracil (20) with DAST proceeded with exclusive retention of configuration. The structures of the products were confirmed by X-ray analysis.

Stereoselective amination of chiral benzylic ethers using chlorosulfonyl isocyanate: total synthesis of (+)-sertraline.

The stereoselective amination of various chiral benzylic ethers using chlorosulfonyl isocyanate is developed, and the application of this method to the total synthesis of a potent antidepressant, (+)-sertraline, from readily available 1-naphthol is also described.

A short and efficient synthetic approach to hydroxy (E)-stilbenoids via solid-phase cross metathesis

Solid-phase cross metathesis of supported styrenyl ether with styrene derivatives afforded stilbenoids in high yields with complete (E)-selectivity, and this approach could be readily applied for a facile synthesis of a biologically important natural product, resveratrol.

Study of the stability of carbocations by chlorosulfonyl isocyanate reaction with ethers

Abstract The stability order of various alkyl, allyl, and benzyl carbocations was investigated using the novel technique for comparing the stability of carbocations in solution developed by using a simple CSI reaction with various ethers. The p -methoxycinnamyl carbocation was the most stable in our reaction system and the next stable carbocation was the p -methoxybenzyl carbocation. The stability of the other carbocations decreased with methacryl, t -butyl, cinnamyl, acryl, benzyl, 2° and allyl carbocations in that order.

Inactivation of the Cullin (CUL)-RING E3 ligase by the NEDD8-activating enzyme inhibitor MLN4924 triggers protective autophagy in cancer cells.

The multiunit Cullin (CUL)-RING E3 ligase (CRL) controls diverse biological processes by targeting a mass of substrates for ubiquitination and degradation, whereas its dysfunction causes carcinogenesis. Post-translational neddylation of CUL, a process triggered by the NEDD8-activating enzyme E1 subunit 1 (NAE1), is required for CRL activation. Recently, MLN4924 was discovered via a high-throughput screen as a specific NAE1 inhibitor and first-in-class anticancer drug. By blocking CUL neddylation, MLN4924 inactivates CRL and causes the accumulation of CRL substrates that trigger cell cycle arrest, senescence and/or apoptosis to suppress the growth of cancer cells in vitro and in vivo. Recently, we found that MLN4924 also triggers protective autophagy in response to CRL inactivation. MLN4924-induced autophagy is attributed partially to the inhibition of mechanistic target of rapamycin (also known as mammalian target of rapamycin, MTOR) activity by the accumulation of the MTOR inhibitory protein DEPTOR, as well as reactive oxygen species (ROS)-induced stress. Moreover, the blockage of autophagy response enhances apoptosis in MLN4924-treated cells. Together, our findings not only reveal autophagy as a novel cellular response to CRL inactivation by MLN4924, but also provide a piece of proof-of-concept evidence for the combination of MLN4924 with autophagy inhibitors to enhance therapeutic efficacy.