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Biomedical subjects

Tak Hang Chan

Publications and source records attributed to Tak Hang Chan.

At least 19 recordsLinked to original sources
PubMed2007

The proteasome as a potential target for novel anticancer drugs and chemosensitizers.

A major challenge in cancer therapy is tumor drug resistance. To overcome it, it is essential to understand the mechanisms and identify the molecules involved, so that they can be specifically targeted in combination therapies. The proteasome is such a validated target: it plays a key role in cancer cell proliferation, inhibition of chemotherapy-induced apoptosis and drug resistance development. Bortezomib (Velcade, PS-341) was the first proteasome inhibitor to receive regulatory approval from the US Food and Drug Administration for the treatment of multiple myeloma. Clinical combination trials have demonstrated a chemo-sensitizing effect of bortezomib on conventional agents in hematological malignancies and some solid tumors such as androgen-independent prostate and ovarian cancer. Although generally well-tolerated, bortezomib still generates toxicity which underscores the need for less toxic proteasome inhibitors. Several naturally occurring products, such as green tea polyphenols and the antibiotic lactacystin, have been shown to be potent proteasome inhibitors. Significantly, green tea polyphenols, as well as several flavonoids such as genistein, curcumin and resveratrol, have also been shown to have chemo-sensitizing properties in prostate, breast, hepatic, and lung tumors. Further studies on natural proteasome inhibitors as chemo-sensitizers could lead to identification of more potent and less toxic compounds that could be used in combination therapies for drug-resistant tumors.

Antineoplastic Agents↗
PubMed2006

Flavonoid dimers as bivalent modulators for pentamidine and sodium stiboglucanate resistance in leishmania.

Drug resistance by overexpression of ATP-binding cassette (ABC) transporters is an impediment in the treatment of leishmaniasis. Flavonoids are known to reverse multidrug resistance (MDR) in Leishmania and mammalian cancers by inhibiting ABC transporters. Here, we found that synthetic flavonoid dimers with three (compound 9c) or four (compound 9d) ethylene glycol units exhibited a significantly higher reversing activity than other shorter or longer ethylene glycol-ligated dimers, with approximately 3-fold sensitization of pentamidine and sodium stibogluconate (SSG) resistance in Leishmania, respectively. This modulatory effect was dosage dependent and not observed in apigenin monomers with the linker, suggesting that the modulatory effect is due to its bivalent nature. The mechanism of reversal activity was due to increased intracellular accumulation of pentamidine and total antimony in Leishmania. Compared to other MDR modulators such as verapamil, reserpine, quinine, quinacrine, and quinidine, compounds 9c and 9d were the only agents that can reverse SSG resistance. In terms of reversing pentamidine resistance, 9c and 9d have activities comparable to those of reserpine and quinacrine. Modulators 9c and 9d exhibited reversal activity on pentamidine resistance among LeMDR1(-/-), LeMDR1(+/+), and LeMDR1-overexpressed mutants, suggesting that these modulators are specific to a non-LeMDR1 pentamidine transporter. The LeMDR1 copy number is inversely related to pentamidine resistance, suggesting that it might be involved in importing pentamidine into the mitochondria. In summary, bivalency could be a useful strategy for the development of more potent ABC transporter modulators and flavonoid dimers represent a promising reversal agent for overcoming pentamidine and SSG resistance in parasite Leishmania.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Flavonoid dimers as bivalent modulators for P-glycoprotein-based multidrug resistance: synthetic apigenin homodimers linked with defined-length poly(ethylene glycol) spacers increase drug retention and enhance chemosensitivity in resistant cancer cells.

Much effort has been spent on searching for better P-glycoprotein- (P-gp-) based multidrug resistance (MDR) modulators. Our approach was to target the binding sites of P-gp using dimers of dietary flavonoids. A series of apigenin-based flavonoid dimers, linked by poly(ethylene glycol) chains of various lengths, have been synthesized. These flavonoid dimers modulate drug chemosensitivity and retention in breast and leukemic MDR cells with the optimal number of ethylene glycol units equal to 2-4. Compound 9d bearing four ethylene glycol units increased drug accumulation in drug-resistant cells and enhanced cytotoxicity of paclitaxel, doxorubicin, daunomycin, vincristine, and vinblastine in drug-resistant breast cancer and leukemia cells in vitro, resulting in reduction of IC50 by 5-50 times. This compound also stimulated P-gp's ATPase activity by 3.3-fold. Its modulating activity was presumably by binding to the substrate binding sites of P-gp and disrupting drug efflux.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Grignard reagents in ionic liquids.

Grignard reagents were generated from magnesium and organic iodides in the ionic liquid n-butylpyridinium tetrafluoroborate, [bpy][BF4], and they showed different reactivity from classical Grignard reagents in organic solvents.

Borates↗
PubMed2006

Ionic-liquid-supported synthesis: a novel liquid-phase strategy for organic synthesis.

Soluble ionic liquids have recently been used as supports for catalyst/reagent immobilization and synthesis in homogeneous solution phase. The wide range of ionic liquid supports available makes their use as supports compatible with most common chemistries. The solubility properties of these ionic liquid supports can be tuned by the variation of cations and anions to make them phase separate from less polar organic solvents and aqueous media. The ionic-liquid-supported species can therefore be purified from the reaction mixture by simple washings. Ionic-liquid-supported catalysts and reagents have been prepared and used, and they are easily recovered and reused. Parallel and combinatorial libraries of small molecules have been synthesized. Ionic-liquid-supported synthesis (ILSS) has been applied to the preparation of oligopeptides and oligosaccharides. The comparison of ILSS with solid-phase synthesis, soluble-polymer-supported synthesis, and fluorous phase synthesis has been highlighted where applicable.

Carbohydrate Conformation↗
PubMed2005

Electrospray mass spectral fragmentation study of N,N'-disubstituted imidazolium ionic liquids.

The tandem positive electrospray mass spectrometry (ESMS(n)) fragmentation of ionic liquids incorporating the 1-methyl-imidazolium ring substituted on N(II) with an alkyl chain functionalized with an alcohol, carboxylic acid, or an iodobenzyl or iodobenzoyl ester is presented for the first time. The influence of chain length and function is studied. Esterified structures led to intense CID fragments lacking the imidazolium ring allowing full characterization of the ester moiety. Fragment ion compositions for this interesting and newly important class of compounds are established through accurate mass data and deuterium labeling. The presence of the cationic ring system produces intense even electron molecular cations in electrospray that undergo multiple stages of CID to yield fragments which often are radical cations. Unusual losses of methyl and hydrogen radicals are frequently noted.

Journal Article↗
PubMed2005

Formation and reactions of alkylzinc reagents in room-temperature ionic liquids.

[reaction: see text] The presence of a suitable amount of bromide or chloride ions was found to be critical in forming the alkylzinc reagents from alkyl iodides and zinc metal in the room-temperature ionic liquid, N-butylpyridinium tetrafluoroborate. Beta-hydride transfer in the reactions of butylzinc reagents with aldehydes can also be reduced by a bromide ion.

Indicators and Reagents↗
PubMed2005

Synthetic peracetate tea polyphenols as potent proteasome inhibitors and apoptosis inducers in human cancer cells.

It has been suggested that proteasome activity is essential for tumor cell proliferation and drug resistance development. We have previously shown that natural and synthetic ester bond-containing tea polyphenols are selective inhibitors of the chymotrypsin-like activity of the proteasome. The most abundant catechin in green tea is (-)-epigallocatechin-3-gallate [(-)-EGCG], which has been found by many laboratories to exhibit the most potent anticancer activity. We have reported that (-)-EGCG is also the most effective proteasome inhibitor among all the natural green tea catechins tested. Unfortunately, (-)-EGCG is very unstable in neutral and alkaline conditions. In an attempt to increase the stability and thus the efficacy, we synthesized several (-)-EGCG analogs with acetyl protected -OH groups as prodrugs. Here we report, for the first time, that these acetylated synthetic tea analogs are much more potent than natural (-)-EGCG in inhibiting the proteasome in cultured tumor cells. Consistently, these protected analogs showed much higher potency than (-)-EGCG to inhibit proliferation and transforming activity and to induce apoptosis in human leukemic, prostate, breast, and simian virus 40-transformed cells. Additionally, these protected analogs had greatly reduced effects on human normal and non-transformed cells. Therefore, these peracetate protected tea polyphenols are more efficacious than (-)-EGCG and possess great potential to be developed into novel anticancer drugs. Identification of the cytosolic metabolite(s) of peracetate-protected polyphenols in cultured tumor cells and examination of their in vivo tumor growth-inhibitory activity are currently underway in our laboratory.

Antineoplastic Agents↗
PubMed2005

Structure-activity study of epi-gallocatechin gallate (EGCG) analogs as proteasome inhibitors.

The structure-activity relationship of a number of synthetic green tea polyphenol analogs involving modifications of A ring and B ring of epi-gallocatechin gallate (EGCG) as proteasome inhibitors has been examined. It was found that in B ring, a decrease in the number of OH groups led to decreased potency. Introduction of a hydrophobic benzyl group into the 8 position of A ring did not significantly affect the proteasome-inhibitory potency.

Catechin↗
PubMed2005

Multiple losses of neutral C14H14 in the tandem mass spectrometry of several perbenzyl ether intermediates in the synthesis of green tea constituents.

Electrospray and matrix-assisted laser desorption/ionization (MALDI) tandem mass spectrometry (MS/MS) experiments were used to investigate an unusual fragmentation in collision-induced dissociation (CID) of sodiated and potassiated perbenzyl ether intermediates obtained in the total synthesis of gallate ester constituents of green tea. Prominent fragments correspond to multiple sequential losses of neutral C14H14 that were not observed in the protonated and ammoniated species, that instead present fragment ion series in which members are separated by C7H6. High-resolution MALDI quadrupole time-of-flight (Q-TOF) and electrospray-Fourier transform mass spectrometry (FTMS) were used to confirm elemental compositions of these and related ions.

Esters↗
PubMed2005

Evaluation of proteasome-inhibitory and apoptosis-inducing potencies of novel (-)-EGCG analogs and their prodrugs.

The anti-cancer and cancer-preventive effects of green tea and its main constituent (-)-epigallocatechin gallate [(-)-EGCG] are well documented by a variety of studies, including epidemiological, cell culture, animal, and clinical studies. While (-)-EGCG remains the most potent polyphenol in green tea, it is very unstable in neutral or alkaline conditions (i.e. physiologic pH). In an effort to discover more stable polyphenol proteasome inhibitors, we synthesized several novel (-)-EGCG analogs with -OH groups eliminated from the B- and/or D-rings. In addition, we also synthesized their putative prodrugs with -OH groups protected by peracetate that can be removed by cellular cytosolic esterases. We first examined the structure-activity relationship of these unprotected and protected compounds to their proteasome-inhibitory potentials. We found that decreasing -OH groups from either the B- or D-ring leads to diminished proteasome-inhibitory activity in vitro. However, in cultured tumor cells only the protected analogs were capable of potently inhibiting the proteasome activity. Furthermore, these protected analogs induced apoptotic cell death in a tumor cell-specific manner. The superior efficacy of the protected (-)-EGCG analogs indicates the formation of an entirely new compound(s) in intact tumor cells. These data suggest that the B-ring/D-ring peracetate-protected EGCG analogs have great potential to be developed into novel anti-cancer and cancer-preventive agents.

Anticarcinogenic Agents↗
PubMed2004

A potential prodrug for a green tea polyphenol proteasome inhibitor: evaluation of the peracetate ester of (-)-epigallocatechin gallate [(-)-EGCG].

Green tea has been shown to have many biological effects, including effects on metabolism, angiogenesis, oxidation, and cell proliferation. Unfortunately, the most abundant green tea polyphenol (-)-epigallocatechin gallate or (-)-EGCG is very unstable in neutral or alkaline medium. This instability leads to a low bioavailability. In an attempt to enhance the stability of (-)-EGCG, we introduced peracetate protection groups on the reactive hydroxyls of (-)-EGCG (noted in text as 1). HPLC analysis shows that the protected (-)-EGCG analog is six times more stable than natural (-)-EGCG under slightly alkaline conditions. A series of bioassays show that 1 has no inhibitory activity against a purified 20S proteasome in vitro, but exhibits increased proteasome-inhibitory activity in intact leukemic cells over natural (-)-EGCG, indicating an intercellular conversion. Inhibition of cellular proteasome activity by 1 is associated with induction of cell death. Therefore, our results indicate that the protected analog 1 may function as a prodrug of the green tea polyphenol proteasome inhibitor (-)-EGCG.

Catechin↗
PubMed2004

Experimental and theoretical studies of the propargyl-allenylindium system.

The transient organoindium intermediates formed in the reaction of propargyl bromide with indium in aqueous media and tetrahydrofuran were investigated by NMR spectroscopy and found to be allenylindium(I) and allenylindium(III) dibromide. The influence of solvent and methyl substitution on the propargyl-allenylindium system was also studied. The experimental observations were supported by theoretical calculations using the B3LYP/6-311+G* method.

Journal Article↗
PubMed2004

Green tea and tea polyphenols in cancer prevention.

The cancer-preventive effects of green tea and its main constituent (-)-epigallocatechin gallate [(-)-EGCG] are widely supported by results from epidemiological, cell culture, animal and clinical studies in the recent decade. In vitro cell culture studies show that tea polyphenols potently induce apoptotic cell death and cell cycle arrest in tumor cells but not in their normal cell counterparts. Green tea polyphenols affect several signal transduction pathways, including growth factor-mediated, the mitogen-activated protein kinase (MAPK)-dependent, and ubiquitin/proteasome degradation pathways. Epidemiological studies have suggested that the consumption of green tea lowers the risk of cancer. Various animal studies have revealed that treatment by green tea inhibits tumor incidence and multiplicity in different organ sites such as skin, lung, liver, stomach, mammary gland and colon. Phase I and II clinical trials were carried out recently to explore the anticancer effects of green tea in patients with cancer. At this time, more mechanistic research, animal studies, and clinical trials are necessary to further evaluate the role of green tea in cancer prevention.

Anticarcinogenic Agents↗