A novel oxiranylchromenone derivative, MHY336, induces apoptosis and cell cycle arrest via a p53- and p21-dependent pathway in HCT116 human colon cancer cells.

In this study, we compared cytotoxicity, cell cycle distribution, and apoptosis on MHY336 treatment in three human colorectal carcinoma HCT116 cells: p53+/+ (p53­wt), p53-/- (p53-null), and p21-/- (p21-null), as well as investigated the roles of p53 and p21 in cell death. Using these three isogenic variants, the roles of p53 and p21 in the cellular response to treatment with MHY336, a novel topoisomerase IIα inhibitor, were investigated. Our results showed that MHY336 treatment increased the expression of p53 over time in cells with wild-type p53 status. This elevated levels of p53 is associated with increased DNA fragmentation, and cleavage of poly(ADP-ribose) polymerase, consistent with increased sensitivity of these cells to apoptotic stimuli. However, p53-null and p21-null cells were more resistant to the antiproliferative and apoptotic effects of MHY336 than p53-wt cells. The same result was achieved by knocking down p53 and p21 with siRNA in p53-wt cells, indicating that p53 and p21 play a crucial role in MHY336-induced cell cycle arrest and apoptosis. Taken together, these results suggest that MHY336 could be a potential candidate to be used in chemoprevention and/or treatment of colon cancer.

Adaptive redundant speech transmission over wireless multimedia sensor networks based on estimation of perceived speech quality.

An adaptive redundant speech transmission (ARST) approach to improve the perceived speech quality (PSQ) of speech streaming applications over wireless multimedia sensor networks (WMSNs) is proposed in this paper. The proposed approach estimates the PSQ as well as the packet loss rate (PLR) from the received speech data. Subsequently, it decides whether the transmission of redundant speech data (RSD) is required in order to assist a speech decoder to reconstruct lost speech signals for high PLRs. According to the decision, the proposed ARST approach controls the RSD transmission, then it optimizes the bitrate of speech coding to encode the current speech data (CSD) and RSD bitstream in order to maintain the speech quality under packet loss conditions. The effectiveness of the proposed ARST approach is then demonstrated using the adaptive multirate-narrowband (AMR-NB) speech codec and ITU-T Recommendation P.563 as a scalable speech codec and the PSQ estimation, respectively. It is shown from the experiments that a speech streaming application employing the proposed ARST approach significantly improves speech quality under packet loss conditions in WMSNs.

Design, synthesis and anticancer activity of novel dihydrobenzofuro[4,5-b][1,8]naphthyridin-6-one derivatives.

On the basis of the chemical structures of psorospermin with a xanthone template and acronycine derivatives with an acridone template, rac-1 and rac-2 constructed on an 1,2-dihydrobenzofuro[4,5-b][1,8]naphthyridin-6(11H)-one scaffold were designed and synthesized as potential anticancer agents. Their anticancer activities were evaluated against five human cancer cell lines. Rac-2 showed similar anticancer activity to doxorubicin and rac-1 exhibited even higher anticancer activity against LNCaP (IC(50)=0.14 µM), DU145 (IC(50)=0.15 µM), PC3 (IC(50)=0.30 µM) and MCF-7 (IC(50)=0.26 µM) cancer lines than doxorubicin and rac-2. Also, rac-1 revealed very potent anticancer activity (IC(50)=0.15 µM) against MCF-7/ADR cell (doxorubicin-resistant breast cancer cell) lines and induced G2/M phase arrest of the cell cycle in MCF-7/ADR cells.

Synthesis of enantiomerically pure D- and L-bicyclo[3.1.0]hexenyl carbanucleosides and their antiviral evaluation.

Based upon the fact that L-nucleosides have been generally known to be less cytotoxic than D-counterparts, L-bicyclo[3.1.0]hexenyl carbanucleoside derivatives with a fixed north conformation were designed and synthesized by employing a novel synthetic strategy starting from (R)-epichlorohydrin in order to search for new anti-HIV agents with high potency and less cytotoxicity. A tandem alkylation, γ-lactonization, a chemoselective reduction of ester in the presence of γ-lactone functional group, a RCM reaction, and a Mitsunobu coupling reaction were used as key reactions. D-Counterpart nucleosides were also prepared according to the same synthetic method. Among the synthesized carbanucleosides, D-thymine nucleoside, D-2 and L-thymine nucleoside, L-2 exhibited excellent anti-HIV-1 and -2 activities, in MT-4 cells, which were higher than those of ddI, an anti-AIDS drug. Whereas D-2 exhibited high cytotoxicity in MT-4 cell lines, L-2 did not show any discernible cytotoxicity in all cell lines tested, reflecting that L-2 may be a good candidate for an anti-AIDS drug. L-2 also showed weak anti-HSV-2 activity without cytotoxicity. However, none of the synthesized nucleosides exhibited antiviral activities against RNA viruses including coxsakie, influenza, corona and polio viruses, maybe due to their 2',3'-dideoxy structure. Potent antiviral effects of D-2 and L-2 indicate that nucleosides belonging to a class of D4Ns can be an excellent candidate for anti-DNA virus agents. This research strongly supports L-nucleosides of a class of D4Ns to be a very promising candidate for antiviral agents due to its low cytotoxicity and a good antiviral activity.

A novel epoxypropoxy flavonoid derivative and topoisomerase II inhibitor, MHY336, induces apoptosis in prostate cancer cells.

Here, we reported the synthesis of a novel topoisomerase II inhibitor, MHY336, which that has strong topoisomerase-mediated anticancer activity but fewer side effects than other topoisomerase II inhibitors. The catalytic activity of MHY336 on the topoisomerase II enzyme was the same as that of the etoposide. In a cell-free system, MHY336 exhibited a potent activity on scavenging of reactive oxygen species against 3-morpholinosydnonimine hydrochloride (SIN-1)-induced oxidative stress. An in vitro cell-based assay demonstrated that MHY336 significantly inhibited the proliferation of three prostate cancer cell lines, LNCaP, PC-3, and DU145 cells. Notably, the cytotoxicity of MHY336 was more potent in LNCaP cells (IC(50)=1.39 µM) than in DU145 (IC(50)=2.94 µM) and PC3 cells (IC(50)=3.72 µM). Furthermore, MHY336 treatment induced similar levels of cytotoxicity compared to doxorubicin treatment (IC(50)=1.55 µM) in LNCap cells. Also, MHY336 significantly down-regulated topoisomerase II alpha expression and up-regulated p53 expression in LNCaP cells (wild-type p53), whereas it up-regulated the topoisomerase II alpha protein in both DU145 and PC3 cells (p53 mutated or deleted). MHY336 induced G2/M or S phase arrest in LNCaP cells through a well-documented topoisomerase II-dependent mechanism. Further studies using Annexin V-FITC binding assay, DAPI staining, and Western blot analyses illustrated that MHY336 markedly induced apoptotic cell death via the mitochondria-mediated intrinsic pathway in LNCaP cells. These results suggest that MHY336 is an attractive chemotherapeutic agent because of its topoisomerase II-mediated anti-tumour activity in human prostate cancer.

Isolated cerebrospinal fluid leakage due to a spinal stab wound in a child.

Spinal stab wounds are relatively rare, especially in children. Moreover, as the pediatric spine anatomy differs from that of an adult, physicians managing stab wounds in this area should keep some special considerations in mind. This study reports an interesting case of spinal cerebrospinal fluid leakage without significant spinal injury in a 32-month-old child.

Efficient and practical synthesis of L-hamamelose.

An efficient synthetic route of L-hamamelose was successfully accomplished starting from D-ribose. L-Hamamelose was synthesized in 42% overall yield with six reaction steps via a stereoselective Grignard reaction, a stereoselective crossed aldol reaction and a controlled oxidative cleavage of the double bond of a vinyl diol compound. During the oxidative cleavage of the double bond of the vinyl diol compound with osmium tetroxide and NaIO(4), an over-oxidative cleavage of alpha-hydroxyl aldehyde generated from ring opening of the first cleaved product, formyl lactol, did not occur, probably due to the stability of the lactol form. A plausible mechanism for the stereoselective crossed aldol reaction was suggested. The final target compound, L-hamamelose can play a very important role as a chiral building block in synthesizing a wide variety of enantiopure compounds.

Synthesis of pyrimidine analog of fluoroneplanocin A as potential anti-HCV agent.

N-hydroxycytosine nucleoside 3 was synthesized as potential anti-HCV agent, starting from D-ribose using an iodine-fluorine exchange reaction by a help of BuLi, a RCM reaction, a stereoselective reduction and a Mitsunobu reaction as the key steps.

Synthesis of novel cyclopropyl nucleoside analogues as potential antiherpetic agent.

Synthesis of novel cyclopropyl pyrimidine and purine nucleoside derivatives was successfully achieved using one pot reactions including an alkylation, an oxirane-ring opening reaction and a lactonization and a hydroboration-oxidation as the key steps in order to find new antiherpetic agent.

Synthesis and antiviral evaluation of conformationally fixed bicyclohexanyl nucleosides with ethenyl group at C3'-position.

Conformationally fixed bicyclo[3.1.0]hexanyl nucleosides 1 and 2 with C3'-ethenyl group were successfully synthesized and evaluated against various viruses. Carbenoid intramolecular cycloaddition and diastereoselective Grignard reaction were employed as the key reaction steps.

Synthesis and biological evaluation of 5''-iodoneplanocin A and its analogues.

5''-Iodoneplanocin A was enantiopurely synthesized as potential antiviral and antitumor agents starting from D-ribose using an addition-iodination-elimination reaction, a RCM reaction and an oxidative rearrangement.

Asymmetric synthesis of apio fluoroneplanocin A analogs as potential AdoHcy hydrolase inhibitor.

Apio fluoroneplanocin A (apio F-NPA, 3) and its uracil analogue 4 have been designed and asymmetrically synthesized starting from D-ribose. Introduction of fluoro group into vinylic position of 5 was accomplished successfully over 5 steps employing key reactions such as iodination according to an addition-elimination reaction mechanism, stereo- and regioselective reduction of alpha,beta-unsaturated ketone, and electrophilic fluorination. This methodology can be adapted to the synthesis of fluoro compounds extensively.