8 research outputs found
Synthesis and structural characterization of glucopyranosylamide films on gold
Self-assembled monolayers (SAMs) of glucose derivatives on gold have been prepared from α- and β-glucopyranosylamide derivatives. The glucosyl conjugates were synthesized stereoselectively via the in situ generation of glucosyl isoxazolines followed by treatment with thiopyridyl esters. The resulting film structures were characterized by atomic force microscopy, reflection Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy. The experimental data indicated that α- or β-linked glucopyranosylamide derivatives with free hydroxyl groups attach to gold via the thiol linker. Both derivatives form monolayer films with high packing densities-comparable to those typically observed for alkanethiol monolayers on gold. Acetate analogues of these conjugates do not form SAMs on gold; they form multilayered films under identical deposition conditions. © 2007 American Chemical Society
Identifying a resistance determinant for the antimitotic natural products disorazole C<inf>1</inf> and A<inf>1</inf>
Disorazoles are macrocyclic polyketides first isolated from the fermentation broth of the myxobacterium Sorangium cellulosum. Both the major fermentation product disorazole A1 and its much rarer companion disorazole C1 exhibit potent cytotoxic activity against many human tumor cells. Furthermore, the disorazoles appear to bind tubulin uniquely among known antimitotic agents, promoting apoptosis or premature senescence. It is uncertain what conveys tumor cell sensitivity to these complex natural products. Therefore, we generated and characterized human tumor cells resistant to disorazole C1. Resistant cells proved exceedingly difficult to generate and required single step mutagenesis with chronic stepwise exposure to increasing concentrations of disorazole C1. Compared with wild-type HeLa cells, disorazole C1-resistant HeLa/DZR cells were 34- and 8-fold resistant to disorazole C1 and disorazole A1 growth inhibition, respectively. HeLa/DZR cells were also remarkably cross-resistant to vinblastine (280-fold), paclitaxel (2400-fold), and doxorubicin (47-fold) but not cisplatin, suggesting a multidrug-resistant phenotype. Supporting this hypothesis, MCF7/MDR cells were 10-fold cross-resistant to disorazole C 1. HeLa/DZR disorazole resistance was not durable in the absence of chronic compound exposure. Verapamil reversed HeLa/DZR resistance to disorazole C1 and disorazole A1. Moreover, HeLa/DZR cells expressed elevated levels of the drug resistance ATP-binding cassette ABCB1 transporter. Loss of ABCB1 by incubation with short interfering RNA restored sensitivity to the disorazoles. Thus, the multidrug resistance transporter ABCB1 can affect the cytotoxicity of both disorazole C1 and A1. Disorazole C1, however, retained activity against cells resistant against the clinically used microtubule-stabilizing agent epothilone B. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
Inhibition of Histone Deacetylase Expands the Renal Progenitor Cell Population
One of the first hallmarks of kidney regeneration is the reactivation of genes normally required during organogenesis. Identification of chemicals with the potential to enhance this reactivation could therapeutically promote kidney regeneration. Here, we found that 4-(phenylthio)butanoic acid (PTBA) expanded the expression domains of molecular markers of kidney organogenesis in zebrafish. PTBA exhibits structural and functional similarity to the histone deacetylase (HDAC) inhibitors 4-phenylbutanoic acid and trichostatin A; treatment with these HDAC inhibitors also expanded the renal progenitor cell population. Analyses in vitro and in vivo confirmed that PTBA functions as an inhibitor of HDAC activity. Furthermore, PTBA-mediated renal progenitor cell expansion required retinoic acid signaling. In summary, these results support a mechanistic link among renal progenitor cells, HDAC, and the retinoid pathway. Whether PTBA holds promise as a therapeutic agent to promote renal regeneration requires further study
Microtubule Binding and Disruption and Induction of Premature Senescence by Disorazole C1S⃞
Disorazoles comprise a family of 29 macrocyclic polyketides isolated from
the fermentation broth of the myxobacterium Sorangium cellulosum. The
major fermentation product, disorazole A1, was found previously to
irreversibly bind to tubulin and to have potent cytotoxic activity against
tumor cells, possibly because of its highly electrophilic epoxide moiety. To
test this hypothesis, we synthesized the epoxide-free disorazole C1
and found it retained potent antiproliferative activity against tumor cells,
causing prominent G2/M phase arrest and inhibition of in vitro
tubulin polymerization. Furthermore, disorazole C1 produced
disorganized microtubules at interphase, misaligned chromosomes during
mitosis, apoptosis, and premature senescence in the surviving cell
populations. Using a tubulin polymerization assay, we found disorazole
C1 inhibited purified bovine tubulin polymerization, with an
IC50 of 11.8 ± 0.4 μM, and inhibited
[3H]vinblastine binding noncompetitively, with a
Ki of 4.5 ± 0.6 μM. We also found noncompetitive
inhibition of [3H]dolastatin 10 binding by disorazole
C1, with a Ki of 10.6 ± 1.5 μM,
indicating that disorazole C1 bound tubulin uniquely among known
antimitotic agents. Disorazole C1 could be a valuable chemical
probe for studying the process of mitotic spindle disruption and its
relationship to premature senescence
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