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Biomedical subjects

C H Wong

Publications and source records attributed to C H Wong.

At least 37 records · Page 2Linked to original sources
PubMed2001

Design, synthesis, and biological evaluation of HIV/FIV protease inhibitors incorporating a conformationally constrained macrocycle with a small P3' residue.

A series of norstatine-based HIV/FIV protease inhibitors incorporating a 15-membered macrocycle as a mimic of the tripeptide (Ala-Val-Phe), a motif with a small P3' residue elective against the FIV protease and the drug-resistant HIV proteases, has been synthesized. It was found that the macrocycle is important to the overall activity of the inhibitors. Certain inhibitors were developed expressing low nanomolar inhibitory activity against the HIV/FIV proteases and they are also effective against some drug-resistant as well as TL3-resistant HIV proteases.

Amino Acid Motifs↗
PubMed2001

Enzymes for chemical synthesis.

New catalytic synthetic methods in organic chemistry that satisfy increasingly stringent environmental constraints are in great demand by the pharmaceutical and chemical industries. In addition, novel catalytic procedures are necessary to produce the emerging classes of organic compounds that are becoming the targets of molecular and biomedical research. Enzyme-catalysed chemical transformations are now widely recognized as practical alternatives to traditional (non-biological) organic synthesis, and as convenient solutions to certain intractable synthetic problems.

Carbon↗
PubMed2001

Structure-activity studies of FIV and HIV protease inhibitors containing allophenylnorstatine.

The interaction of P1 and P3 side chains with the combining S1 and S3 hydrophobic subsites of HIV and FIV proteases has been explored using asymmetric competitive inhibitors. The inhibitors evaluated contained (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid (allophenylnorstatine) as the hydroxymethylcarbonyl isostere, (R)-5,5-dimethyl-1, 3-thiazolidine-4-carbonyl as P1', Val as P2 and P2' residues, and a variety of amino acids at the P3 and P3' positions. All inhibitors showed competitive inhibition of both enzymes with higher potency against the HIV protease in vitro. Within this series, 31 (VLE776) is the most effective inhibitor against FIV protease, and it contains Phe at P3, but no P3' residue. VLE776 also exhibited potent antiviral activities against the drug-resistant HIV mutants (G48V and V82F) and the TL3-resistant HIV mutants. Explanation of the inhibition activities was described. In addition, a new strategy was described for development of bifunctional inhibitors, which combine the protease inhibitor and another enzyme inhibitor in one molecule.

Aspartic Acid Endopeptidases↗
PubMed2001

A dual strategic approach to mega-aortic aneurysms.

Staged resection of mega-aortas with Borst's two-stage elephant trunk (ETK) is the gold standard but has a higher mortality and morbidity compared to single-segment repair. We report the first case of combined surgical and covered-stent approach in Europe. Location and dilatation of the proximal landing zone accounts for the majority of failures in covered-stenting but an ETK is stable, easy to localise and gives an excellent seal. In high-risk cases where surgical resection is not offered, stenting is an option. The lack of a thoracotomy is an advantage in often-frail patients recovering from stage-I and shortens ITU-stay. Therefore, a combined approach is an acceptable alternative in selected individuals.

Aged↗
PubMed2001

The use of left heart bypass in adult and recurrent coarctation repair.

OBJECTIVES: Paraplegia following coarctation repair occurs in 0.4% of infants. However, for older children, adults and re-operations, the incidence can be as high as 2.6%. Yet there is no consensus on the need for spinal cord protection or the optimal method. This paper reports our experience with left heart bypass (LHB) in adult and re-do coarctation. METHODS: Between 1997 and 2000, nine patients underwent elective resection of coarctation (three re-dos, two balloons) with a mean age of 17.9 years (range, 8-44) and weight of 52 kg (range, 17.3-109). The mean trans-coarctation gradient was 29.6 mmHg (range, 20-45). Patients were placed on LHB using a centrifugal pump with full heparinization through a fourth-space thoracotomy. Patients were cooled to 31-34 degrees C for additional spinal cord protection. Repair was carried out with an inter-positional graft (5/9), a Gore-Tex patch (2/9) or end-to-end anastomosis (2/9). The mean cross-clamp and bypass times were 36.4 (range, 19-65) and 40.3 min (range, 22-70), respectively. RESULTS: No patient developed transient or permanent paraplegia. The mean peak creatinine was 80 micromol/l (range, 51-123). CONCLUSIONS: LHB is simple, easy and safe to implement, and is the only technique capable of maintaining independent upper and lower body perfusion pressure. Potentially, it provides the best spinal cord protection, and extends the margin of safety and time to execute an accurate repair.

Adolescent↗
PubMed2001

Hexosaminidase inhibitors as new drug candidates for the therapy of osteoarthritis.

BACKGROUND: Articular cartilage from patients with osteoarthritis is characterized by a decreased concentration and reduced size of glycosaminoglycans. Degeneration of the cartilage matrix is a multifactorial process, which is due in part to accelerated glycosaminoglycan catabolism. Recently, we have demonstrated that hexosaminidase represents the dominant glycosaminoglycan-degrading glycosidase released by chondrocytes into the extracellular compartment and is the dominant glycosidase in synovial fluid from patients with osteoarthritis. Inhibition of hexosaminidase activity may represent a novel approach to the prevention of cartilage matrix glycosaminoglycan degradation and a potentially new strategy to treat osteoarthritis. RESULTS: We have synthesized and investigated a series of iminocyclitols designed as transition-state analog inhibitors of human hexosaminidase, and demonstrated that the five-membered iminocyclitol 4 expresses the strongest inhibitory activity with K(i)=24 nM. Inhibition of hexosaminidase activity in human cultured articular chondrocytes and human chondrosarcoma cells with iminocyclitol 4 resulted in accumulation of hyaluronic acid and sulfated glycosaminoglycans in the cell-associated fraction. Similarly, incubation of human cartilage tissue with iminocyclitol 4 resulted in an accumulation of glycosaminoglycans in the pericellular compartment. CONCLUSIONS: Inhibition of hexosaminidase activity represents a new strategy for preventing or even reversing cartilage degradation in patients with osteoarthritis.

Cartilage, Articular↗
PubMed2001

Combinatorial library of five-membered iminocyclitol and the inhibitory activities against glyco-enzymes.

BACKGROUND: Oligosaccharide processing enzymes are important classes of catalysts involved in synthesizing specific oligosaccharide structures on proteins and sphingolipids. Development of specific inhibitors of such enzymes is of current interest as these inhibitors may be used to control cellular functions. Five-membered iminocyclitols have been shown to be potent inhibitors of such enzymes. Since a rational design and synthesis of inhibitors is often extremely difficult due to the limited information regarding the structure of the active site, we carried out a combinatorial library approach. RESULTS: To create diversity, we decided to use an aldehyde group of a protected iminocyclitol for reductive amination and the Strecker reaction. After transformation of the nitrile group introduced by the Strecker reaction into an amine and amide and complete deprotection, a small library of five-membered iminocyclitols consisting of 27 compounds was synthesized. A series of compounds obtained by reductive amination was first screened as potential inhibitors of glycosidases and glycosyltransferases. Among them, compounds carrying a C(10)-alkyl group showed marked enhancement of inhibitory activity against alpha-mannosidase at 10 microM concentration when compared with its parent compound and deoxymannojirimycin. Furthermore, compounds having the phenylethyl group showed an extremely strong inhibitory effect against alpha-galactosaminidase at a K(i) value of 29.4 nM. Compounds with an aminomethyl and amide group at the C-1' position of these two molecules showed a decrease in inhibitory activities. CONCLUSIONS: A combinatorial approach based on five-membered iminocyclitols with a galacto-configuration was exploited. The potential usefulness of the library as a source of inhibitors of glycoenzymes is clearly shown in this study.

Amino Sugars↗
PubMed2001

Outcome of the acute abdomen in patients with previous spinal cord injury.

BACKGROUND: Patients with spinal cord injury (SCI) have always posed difficulties for the diagnosis of an acute abdomen. The aim of the present study was to define this problem retrospectively at Princess Alexandra Hospital and to assess the results of treatment for these patients. METHODS: A retrospective review was conducted of 133 SCI patients admitted with an acute abdomen in the 16 years prior to this analysis at the Spinal Injuries Unit (SIU) of Princess Alexandra Hospital. There were 21 patients who conformed to the study criteria. All the patients had sustained traumatic SCI at or above the level of T11, more than 1 month prior to admission. RESULTS: There were 13 male and eight female patients. The time lapse between SCI and the onset of an acute abdomen ranged from 1.5 months to 27 years. The age range was 26-79 years. The majority of patients had C6 injuries (six patients). There were 18 patients with injury levels above T6 and three patients with injuries below this level. The time taken to diagnose the cause of the acute abdomen ranged between I day and 3 months. Investigations were found to be useful in making the diagnoses in 61.9% of cases. There were 14 patients who had surgical interventions. Five patients had surgical complications and there were two deaths in the study. The length of follow up was 1-132 months. The mortality in the study was 9.5%. CONCLUSION: An aggressive approach to the diagnosis and treatment of the acute abdomen in SCI patients with suspicious symptoms is recommended. A high index of suspicion should be maintained in those patients with pre-existing SCI who present with abdominal trauma.

Abdomen, Acute↗
PubMed2001

Modulations of spinal serotonin activity affect the development of morphine tolerance.

To test whether modulations of spinal serotonin (5-HT) levels would affect the development of morphine tolerance, we treated rats with either intrathecal 5-HT or 5,7-dihydroxytryptamine (5,7-DHT; a 5-HT neurotoxin) in addition to systemic infusion with morphine (2 mg x kg(-1) x h(-1)). Continuous infusion of 5-HT (10 microg x 6 microL(-1) x h(-1)) into the lumbar subarachnoid space of rats for 9 h accelerated the development of morphine tolerance. The area under the curve for the tail-flick latency test was 454.1 +/- 35.1 in the Sham Control group vs 327.6 +/- 41.0 in the 5-HT-Infused group. mu-opioid receptor binding in the lumbar spinal cord showed a decrease in the Bmax (maximal binding -46.5%), but not the binding affinity (Kd), in 5-HT-infused rats. However, intrathecal injection of 5,7-DHT (50 microg), which resulted in a 48% reduction in 5-HT and 51% reduction in 5-hydroxyindoleacetic acid concentrations, led to an attenuation of morphine tolerance (the area under the curve was 613.0 +/- 24.7 in the 5,7-DHT-Lesioned group). The binding study indicated that the affinity of lumbar micro-opioid receptors decreased 196% in 5-HT-depleted rats, whereas there was no effect on apparent binding. The infusion of 5-HT (10 microg x 6 microL(-1) x h(-1)) was not analgesic and the 5,7-DHT-induced lesion did not affect acute morphine-induced analgesia. We conclude that activity of spinal 5-HT-containing neurons plays a crucial role during the development of morphine tolerance.

5,7-Dihydroxytryptamine↗
PubMed2001

Viral evolution in response to the broad-based retroviral protease inhibitor TL-3.

TL-3 is a protease inhibitor developed using the feline immunodeficiency virus protease as a model. It has been shown to efficiently inhibit replication of human, simian, and feline immunodeficiency viruses and therefore has broad-based activity. We now demonstrate that TL-3 efficiently inhibits the replication of 6 of 12 isolates with confirmed resistance mutations to known protease inhibitors. To dissect the spectrum of molecular changes in protease and viral properties associated with resistance to TL-3, a panel of chronological in vitro escape variants was generated. We have virologically and biochemically characterized mutants with one (V82A), three (M46I/F53L/V82A), or six (L24I/M46I/F53L/L63P/V77I/V82A) changes in the protease and structurally modeled the protease mutant containing six changes. Virus containing six changes was found to be 17-fold more resistant to TL-3 in cell culture than was wild-type virus but maintained similar in vitro replication kinetics compared to the wild-type virus. Analyses of enzyme activity of protease variants with one, three, and six changes indicated that these enzymes, compared to wild-type protease, retained 40, 47, and 61% activity, respectively. These results suggest that deficient protease enzymatic activity is sufficient for function, and the observed protease restoration might imply a selective advantage, at least in vitro, for increased protease activity.

Amino Acid Sequence↗
PubMed2001

Uncommon hand tumours.

This paper presented clinical examples of some rare or uncommon presentations of tumours of the hand, including glomus tumour, intraosseous dermoid, fibrolipoma of the radial nerve, blastomycotic cyst and synovial sarcoma. Each lesion is illustrated by review of case histories, radiological and pathological features.

Adult↗
PubMed2000

Chemo-enzymatic total synthesis of 3-epiaustraline, australine, and 7-epialexine.

Sequential enzymatic aldol reaction and bis-reductive amination leads to the total syntheses of tetrahydroxylated pyrrolizidine alkaloids, 3-epiaustaline (14), australine (1), and 7-epialexine (11). This approach allows for their rapid construction without the need for protecting group manipulation of the hydroxyl functionality. In addition, an improved procedure for the asymmetric epoxidation of divinyl carbinol (3) was described, and the product was used in a concise synthesis of the required triol 7 and ent-7.

Epoxy Compounds↗
PubMed2000

Regeneration of PAPS for the enzymatic synthesis of sulfated oligosaccharides.

This paper describes the study of 3'-phosphoadenosine-5'-phosphosulfate (PAPS) regeneration from 3'-phosphoadenosine-5'-phosphate (PAP) for use in practical syntheses of carbohydrate sulfates which are catalyzed by sulfotransferases. Among the regeneration systems, the one with recombinant aryl sulfotransferase proved to be the most practical. This regeneration system was coupled with a sulfotransferase-catalyzed reaction, using a recombinant Nod factor sulfotransferase, for the synthesis of various oligosaccharide sulfates that were further glycosylated using glycosyltransferases.

Arylsulfotransferase↗
PubMed2000

Nucleotide-evoked ion transport and [Ca(2+)](i) changes in normal and hyperhidrotic human sweat gland cells.

Apical and basolateral application of ATP and UTP evoked [Ca(2+)](i) and short circuit current (Isc) increases in normal and hyperhidrotic human eccrine sweat gland cells grown into functionally polarised epithelia on permeable supports. Basolateral application to hyperhidrotic cells exhibited a markedly greater increase in Isc than in normal cells. Hyperhidrotic cells also demonstrated differences from the normal in [Ca(2+)](i) and Isc responses to ATP when pre-treated with thapsigargin. The data demonstrate the presence of apical and basolateral receptors that allow nucleotides to increase [Ca(2+)](i) and Isc. The results suggest that changes from the normal in transepithelial ion transport contribute to the characteristic excessive fluid production of hyperhidrotic sweat glands.

Adenosine Triphosphate↗