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Biomedical subjects

H K Wang

Publications and source records attributed to H K Wang.

At least 37 records · Page 2Linked to original sources
PubMed1999

Synthesis and cytotoxicity of methyl-4,8-dihydrobenzo[1,2-b:5,4-b']dithiophene-4,8-dione derivatives.

2- and 3-Methyl-4,8-dihydrobenzo[1,2-b:5,4-b']dithiophene-4,8-dione and related derivatives were synthesized and evaluated in vitro by NCI against eight cancer types. Compounds 12-15 showed significant activity against melanoma, NCI-H23 non-small cell lung cancer, and MDA-MB-435 and MDA-N breast cancer cell lines; 2-hydroxymethyl-4,8-dihydrobenzo[1,2-b:5,4-b']dithiophene-4,8-dion e (13) showed the highest activity against melanoma (mean log GI50 = -7.74) and the highest overall potency (mean log GI50 = -6.99).

Antineoplastic Agents↗
PubMed1999

Novel anti-HIV lancilactone C and related triterpenes from Kadsura lancilimba.

Three new triterpene lactones, lancilactones A (1), B (2), and C (3), together with the known kadsulactone A (4), were isolated from the stems and roots of Kadsura lancilimba. Their structures and stereochemistries were determined primarily from mass and NMR spectral data. Compound 3 inhibited HIV replication with an EC50 value of 1.4 microg/mL and a therapeutic index of greater than 71.4.

Anti-HIV Agents↗
PubMed1999

Alcohol metabolism and cardiovascular response in an alcoholic patient homozygous for the ALDH2*2 variant gene allele.

BACKGROUND: Alcohol metabolism is one of the biological determinants that can influence drinking behavior. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the principal enzymes involved in ethanol metabolism. Allelic variation of the ADH and ALDH genes can significantly affect vulnerability for the development of alcoholism. Homozygosity of the variant ALDH2*2 allele previously was believed to fully protect East Asian populations against the development of alcoholism. METHODS: Eighty Han Chinese alcoholics who met DSM-III-R criteria for alcohol dependence and 144 nonalcohol-dependent subjects were recruited and their data combined with data from 340 alcohol-dependent and 545 nonalcohol-dependent subjects described in an earlier report (Chen et al., 1999) to assess risk for alcoholism by logistic regression analysis. Genotypes of ADH2, ADH3, and ALDH2 were determined by polymerase chain reaction and restriction fragment length polymorphism. The ALDH2 genotype was confirmed by direct nucleotide sequencing. Blood ethanol concentration was determined by headspace gas chromatography and acetaldehyde concentration by high-performance liquid chromatography with fluorescence detection of the derivatized product. Cardiovascular hemodynamic parameters were measured by two-dimensional Doppler echocardiography and sphygmomanometry. Extracranial arterial blood flow was measured by Doppler ultrasonography. RESULTS: An alcohol-dependent patient was identified to be ALDH2*2/*2, ADH2*2/*2, and ADH3*1/*2. Following challenge with a moderate oral dose of ethanol (0.5 g/kg of body weight), the patient exhibited peak concentrations for ethanol (55.7 mg/dl) and acetaldehyde (125 microM). During 130 min postingestion, the patient generally displayed similar or even less intense cardiovascular hemodynamic alterations when compared to a previously published study of nonalcoholic individuals with ALDH2*2/*2 who had received a lower dose of ethanol (0.2 g/kg). Logistic regression analysis of the combinatorial genotypes of ADH2 and ALDH2 in 420 alcohol-dependent and 689 nonalcohol-dependent subjects indicated that risk for alcoholism was 100-fold lower for the ADH2*2/*2-ALDH2*2/*2 individuals than the ADH2*1/*1-ALDH2*1/*1 individuals. CONCLUSIONS: The gene status of ALDH2*2/*2 alone can tremendously but not completely (as thought previously) protect against development of alcohol dependence. Individuals carrying the combinatorial genotype of ADH2*2/*2-ALDH2*2/*2 are at the least risk for the disease in East Asians. Physiological tolerance or innate insensitivity to the accumulation of blood acetaldehyde following alcohol ingestion may be crucial for the development of alcoholism in individuals homozygous for ALDH2*2.

Adolescent↗
PubMed1998

Anti-AIDS agents. 34. Synthesis and structure-activity relationships of betulin derivatives as anti-HIV agents.

Succinyl and 3'-substituted glutaryl betulin derivatives showed stronger anti-HIV activity and higher therapeutic index (TI) values than their dihydrobetulin counterparts, with ratios of 1.2:1 to 15:1 (cf. 7 and 15, 9 and 17, 10 and 18, 11 and 19, and 12 and 20). For various 3'-substituted glutaryl compounds, the order of anti-HIV effects, from strong to weak inhibition, was 3',3'-dimethyl, 3'-methyl, 3'-ethyl-3'-methyl, followed by 3',3'-tetramethylene glutaryl derivatives (10 > 9 > 11 > 12, 18 > 17 > 19 > 20). The most potent compound, 10, has two 3',3'-dimethylglutaryl groups and displays significant anti-HIV potency with an EC50 value of 0.000 66 microM and a TI of 21 515. Results for compounds (22 and 23) without a C-3 acyl group confirmed the importance of the C-3 acyl group to the anti-HIV effect. With 3',3'-tetramethylene glutaryl derivatives, triacyl 29 showed stronger inhibition than diacyl 12; in contrast, 3',3'-dimethylglutaryl compounds displayed opposite results. 3-Keto compounds (35 and 36) and 2,3-dihydro compounds (39 and 40) had EC50 values in the range of 4.3-10.0 microM, suggesting that A ring modification led to decreased potency. The reduced activity of amide (33 and 34), ester (41), and oxime (42) analogues suggested that the orientation and linkage of the C-3 acyl side chain play crucial roles in the potent anti-HIV activity. Finally, replacing the C-28 acyl group with a bulky non-carboxylic group produced a less potent compound (44). In the study of mechanism of action, our results indicated that fusion is not the primary target for the anti-HIV activity of 10. It appears to inhibit HIV replication at a late stage of the viral life cycle, i.e., after viral protein synthesis.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Recent advances in the discovery and development of flavonoids and their analogues as antitumor and anti-HIV agents.

Antitumor and anti-HIV flavonoids and their analogues will be reviewed with emphasis on those discovered in our laboratory. The active antitumor compounds include the antileukemic tricin (1) and kaempferol-3-O-beta-D-glucopyranoside (2) from Wikstroemia indica, the cytotoxic hinokiflavone (3) from Rhus succedanea, the cytotoxic isoflavone (8) from Amorpha fruticosa, two dihydroxypentamethoxyflavones (9, 10) from Polanisia dodencandra. The development of synthetic 2-phenyl-4-quinolones as potent cytotoxic antimitotic flavonoid analogues and 2-phenylthiochromen-4-ones as potent antitumor flavonoid analogues will be presented. Selected results from other laboratories and antitumor-related biological studies also will be discussed. Flavonoids have also been investigated as potential anti-HIV agents. In our laboratory, acacetin-7-O-beta-D-galactopyranoside (131) from Chrysanthemum morifolium and chrysin (102), as well as apigenin-7-O-beta-D-glucopyranoside (130), from Kummerowia striata, have been found to exhibit anti-HIV activity. In other studies, some flavonoids and related compounds have been investigated as inhibitors of HIV-1 reverse transcriptase, protease, and integrase. The isolation and structural modification of such plant-derived active principles provide a continuing source of potential antitumor and anti-HIV agents.

Animals↗
PubMed1998

Anti-AIDS agents. 30. Anti-HIV activity of oleanolic acid, pomolic acid, and structurally related triterpenoids.

Oleanolic acid (1) was identified as an anti-HIV principle from several plants, including Rosa woodsii (leaves), Prosopis glandulosa (leaves and twigs), Phoradendron juniperinum (whole plant), Syzygium claviflorum (leaves), Hyptis capitata (whole plant), and Ternstromia gymnanthera (aerial part). It inhibited HIV-1 replication in acutely infected H9 cells with an EC50 value of 1.7 microg/mL, and inhibited H9 cell growth with an IC50 value of 21.8 microg/mL [therapeutic index (T. I.) 12.8]. Pomolic acid, isolated from R. woodsii and H. capitata, was also identified as an anti-HIV agent (EC50 1.4 microg/mL, T. I. 16.6). Although ursolic acid did show anti-HIV activity (EC50 2.0 microg/mL), it was slightly toxic (IC50 6.5 microg/mL, T. I. 3.3). A new triterpene (11) was also isolated from the CHCl3-soluble fraction of R. woodsii, though it showed no anti-HIV activity. The structure of 11 was determined to be 1beta-hydroxy-2-oxopomolic acid by spectral examination. Based on these results, we examined the anti-HIV activity of oleanolic acid- or pomolic acid-related triterpenes isolated from several plants. In addition, we previously demonstrated that derivatives of betulinic acid, isolated from the leaves of S. claviflorum as an anti-HIV principle, exhibited extremely potent anti-HIV activity. Accordingly, we prepared derivatives of oleanolic acid and evaluated their anti-HIV activity. Among the oleanolic acid derivatives, 18 demonstrated most potent anti-HIV activity, with an EC50 value of 0. 0005 microg/mL and a T. I. value of 22 400.

Anti-HIV Agents↗
PubMed1998

Report of invasive Rhodococcus equi infections in Taiwan, with an emphasis on the emergence of multidrug-resistant strains.

From November 1995 to October 1997, seven patients with invasive infections due to Rhodococcus equi were treated in Taiwan. Four patients had pulmonary lesions, and one each of the remaining three patients had a recurrent Port-A-Cath (Kabi-Pharmacia, North Ryde, New South Wales, Australia)-related bacteremia, a primary bacteremia, and a brain abscess. Three patients had underlying hematologic malignancies, and one each of the remaining four patients had diabetes mellitus, Waldenström's macroglobulinemia, long-term use of steroids, and AIDS. The 13 isolates of R. equi recovered from these patients were identified by using API Coryne System (bioMérieux, Marcy l'Etoile, France), VITEK GPI card (bioMérieux Vitek, Hazelwood, MO), supplemental biochemical tests, and cellular fatty acid chromatograms. Susceptibilities of these isolates to 16 antimicrobial agents, with use of the agar dilution method, varied; among them, amikacin and trimethoprim-sulfamethoxazole were the most active agents. Different random amplified polymorphic DNA (RAPD) patterns of isolates from different patients documented the lack of epidemiological relatedness of the causative organisms of these infections. This study confirms the emergence of multidrug-resistant R. equi infection in Taiwan and documents the relapsing or reactivating nature of this infection.

Actinomycetales Infections↗
PubMed1998

Tuberculous peritonitis: analysis of 35 cases.

Thirty five patients with tuberculous peritonitis were studied retrospectively. Tuberculous peritonitis was defined as the isolation of Mycobacterium tuberculosis from ascites or dialysate, and/or caseating granuloma/acid-fast bacilli from peritoneal biopsy specimens from patients with pulmonary tuberculosis or a response to treatment for tuberculosis. Among the patients studied, nine with cirrhosis of the liver; seven with diabetes mellitus and six with end-stage renal disease, of whom four had undergone continuous ambulatory peritoneal dialysis. The most frequent signs of tuberculous peritonitis included ascites, fever and anemia. Ascites was found in 31 patients (89%). Abnormal findings on chest radiographs were found in 26 patients (74%), of whom 22 patients (63%) had pleural effusion and five had miliary lung lesions. Seven out of 35 patients were found to have positive culture of sputum or pleural effusion for M. tuberculosis. Two patients were found to have concomitant tuberculous peritonitis and enteritis. Multiple organ involvement was found in eight patients. Eleven patients (31%) died: eight were older than 60 years; six had cirrhosis of the liver and nine were diagnosed post-mortemly. In Taiwan, tuberculous peritonitis should be considered in patients with abnormality of chest radiography and nonresolving peritonitis.

Adolescent↗
PubMed1998

Zemaphyte Phytopharm plc.

Zemaphyte, a Chinese herbal extract, is under development by Phytopharm as a potential therapy for severe atopic eczema.

Journal Article↗
PubMed1997

Antitumor agents--CLXXIII. Synthesis and evaluation of camptothecin-4 beta-amino-4'-O-demethyl epipodophyllotoxin conjugates as inhibitors of mammalian DNA topoisomerases and as cytotoxic agents.

Two conjugates composed of a camptothecin and a 4'-O-demethyl epipodophyllotoxin derivative joined by an imine linkage were prepared and evaluated as inhibitors of mammalian DNA topoisomerases I and II. Target compounds stimulated cleavable complex formation with both types of enzyme in vitro although activities were reduced at least twofold relative to the activity of unconjugated constituents. The behavior of the most active conjugate as an inhibitor of cell growth closely resembled both topoisomerase I- and II- inhibitory components in that the compound displayed a combined spectrum of activity against various drug-resistant KB sublines. Cytotoxic activity and selectivity were largely retained through conjugation, the exception being a lower than expected activity against a pleiotrophic multidrug-resistant subline. The induced levels and the properties of cellular protein-associated DNA complexes were consistent with topoisomerase involvement and with the in vitro cleavage assay results. Based on the present findings, conjugation afforded cleavable complex-forming topoisomerase inhibitors which display dual target specificity and a broad spectrum of cytotoxic activity against drug-resistant cells.

Animals↗
PubMed1996

Pretransplant injection of allograft recipients with donor blood or lymphocytes permits allograft tolerance without the presence of persistent donor microchimerism.

Donor-recipient microchimerism has recently been suggested to play a critical role in the induction and maintenance of allograft tolerance. In this study we sought evidence for this hypothesis using the LEW-to-ACI cardiac allograft as a model system. Donor-specific tolerance to cardiac allografts was induced by intravenous or intraportal injection of graft recipients with donor peripheral blood, T cells, or B cells 7 days before transplantation. All the graft recipients injected with donor antigens accepted donor heart grafts indefinitely when compared with control recipients that rejected donor allografts in 12 days. Long-term graft survivors rejected third-party BN heart allografts in 14 days without an adverse effect on the survival of the first LEW heart allografts, demonstrating the specificity of the tolerance. Tissue lysates prepared from heart, kidney, liver, bone marrow, thymus, lymph nodes, and spleen of tolerant (>120 days) graft recipients were analyzed for the presence of donor DNA using LEW T cell receptor C beta gene-specific primers for polymerase chain reaction that detects donor DNA at > or = 1:10,000 dilution. Donor DNA was detected in 77% of tolerant graft recipients. Chimeric recipients showed variations in the levels and presence of donor DNA in different tissues. The status of donor microchimerism, with respect to its presence and tissue distribution, was dependent upon the donor cell type and route of injection used for the induction of tolerance. Intraportal injection of the graft recipients with donor peripheral blood resulted in the highest degree of chimerism, whereas intravenous injection with donor B cells did not induce detectable microchimerism in this group of recipients. These data clearly demonstrate that the presence of microchimerism is common following administration of donor cells, but that its presence is not an absolute requirement for the long-term survival of allografts.

Animals↗
PubMed1996

Antitumor agents. 166. Synthesis and biological evaluation of 5,6,7,8-substituted-2-phenylthiochromen-4-ones.

As a continuation of our structure--activity relationship study of substituted 2-phenyl-4-quinolones and flavonoids as antitumor and antiviral agents, a series of 5,6,7,8-substituted-2-phenylthiochromen-4-ones has been synthesized by condensation of substituted thiophenols and ethyl benzoylacetates. Target compounds were evaluated for biological activity. Among them, compounds 7, 10, 12, and 13 displayed significant growth inhibitory action against a panel of tumor cell lines including human ileocecal carcinoma (HCT-8), murine leukemia (P-388), human melanoma (RPMI), and human central nervous system tumor (TE671) cells. Compounds 10, 12, and 19 displayed DNA topoisomerase I inhibitory activity in vitro and compound 11 was an in vitro, inhibitor of DNA topoisomerase II. Compound 11 was most active (ED50 value, 0.65 microM) against HIV in acutely infected H9 lymphocytes and had a therapeutic index of about 5.

Antineoplastic Agents↗
PubMed1996

Antitumor 2,3-dihydro-2-(aryl)-4(1H)-quinazolinone derivatives. Interactions with tubulin.

A series of derivatives of 2,3-dihydro-2-(aryl)-4(1H)-quinazolinone (DHQZ) with known antitumor activity was re-evaluated in the National Cancer Institute cancer cell line screen. Analysis by the COMPARE algorithm suggested that their cytotoxicity derived from interactions with tubulin. Significant inhibition of tubulin assembly and of the binding of radiolabeled colchicine to tubulin was demonstrated with several of the compounds, particularly NSC 145669, 175635, and 175636. The DHQZ derivatives are structurally analogous to a number of antimitotic agents, flavonols and derivatives of 2-styrylquinazolin-4(3H)-one and of 2-phenyl-4-quinolone. Structure-activity analogies between these agents, the combretastatins, and the colchicinoids were analyzed and summarized.

Animals↗
PubMed1996

Femtomolar sensitivity using a channel-etched thin film waveguide fluoroimmunosensor.

A dual channel, evanescent fluoroimmunoassay format is used to detect femtomolar analyte concentrations (i.e. less than 1 part per trillion [w/w]) on an etched channel siliconoxynitride thin film integrated optical waveguide. Two assays are used to demonstrate the dose-response behaviour of the sensor: (1) a direct assay of a fluorescently-labeled protein ligand binding to an immobilized protein receptor, and (2) an indirect sandwich assay of a non-fluorescent protein ligand binding to an immobilized protein receptor, as detected by the binding of a fluorescently-labeled secondary receptor protein. A red-emitting cyanine dye (Cy-5), which minimized background fluorescence and scatter losses of the waveguide, was used in both assays. To our knowledge, this is the first report of femtomolar sensitivity in an immunosensing instrument.

Biosensing Techniques↗
PubMed1996

Identification of ent-16 beta, 17-dihydroxykauran-19-oic acid as an anti-HIV principle and isolation of the new diterpenoids annosquamosins A and B from Annona squamosa.

Phytochemical analysis of the fruits of Annona squamosa yielded 12 known kaurane derivatives (1-11, 13) and two new kaurane diterpenoids, which have been named annosquamosin A (16 beta-hydroxy-17-acetoxy-ent-kauran-19-al) (12) and annosquamosin B (19-nor-ent-kaurane-4 alpha,16 beta,-17-triol) (14). The structures of the new compounds were established by spectral analyses and chemical evidence. Among these 14 compounds, 16 beta, 17-dihydroxy-ent-kauran-19-oic acid (2) showed significant activity against HIV replication in H9 lymphocyte cells with an EC50 value of 0.8 microgram/mL (therapeutic index > 5).

Antiviral Agents↗
PubMed1995

4-4-20 anti-fluorescyl IgG Fab' recognition of membrane bound hapten: direct evidence for the role of protein and interfacial structure.

The surface forces apparatus was used to identify the molecular forces that control the interactions of monoclonal 4-4-20 antifluorescyl IgG Fab' fragments with fluorescein-presenting supported planar bilayers. At long range, the electrostatic force between oriented Fab' and fluorescein monolayers was controlled by the composition of the protein exterior surrounding the antigen-combining site rather than by the overall protein charge. The measured positive electrostatic potential of the Fab' monolayer at pH > pI(Fab') was consistent with the structure of the exposed Fab' surface in which a ring of positive charge at the mouth of the antigen-combining site dominates the local electrostatic surface properties. Substantial differences in the electrostatic forces measured with denatured Fab' further demonstrated that the measured electrostatic surface properties and the consequent long-range interaction forces are controlled by the protein surface composition. At short range, the strength of the Fab'-mediated adhesion was modulated not only by the length of the fluorescein tether but also by membrane hydration. Steric hydration barriers at the membrane surface reduced the adhesion strength in proportion to their range of influence. These results provide direct evidence that long-range protein interactions with immobilized ligands are controlled by both the protein and the membrane surface compositions, while short-range, specific binding is modulated by both the protein structure and the membrane interfacial properties.

Antibodies, Monoclonal↗