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Bioorganic & Medicinal Chemistry Letters Jan 20052-(2,6-Diisopropylphenyl)-5-hydroxy-1H-isoindole-1,3-dione (5HPP-33), which was obtained during our previous structural development studies on thalidomide, was revealed... (Comparative Study)
Comparative Study
2-(2,6-Diisopropylphenyl)-5-hydroxy-1H-isoindole-1,3-dione (5HPP-33), which was obtained during our previous structural development studies on thalidomide, was revealed to possess potent tubulin-polymerization-inhibiting activity, comparable to that of the known tubulin-polymerization inhibitors, rhizoxin and colchicine. A major metabolite of thalidomide, 5-hydroxythalidomide, which possesses a hydroxyl group at the position corresponding to that of 5HPP-33, also showed moderate inhibitory activity.
Topics: Colchicine; Indoles; Isoindoles; Lactones; Macrolides; Nerve Tissue Proteins; Thalidomide; Time Factors; Tubulin; Tubulin Modulators
PubMed: 15603947
DOI: 10.1016/j.bmcl.2004.10.072 -
Antimicrobial Agents and Chemotherapy May 2004The microtubule, which is one of the major targets of anthelmintics, anticancer drugs, and fungicides, is composed mainly of alpha- and beta-tubulins. We focused on a...
Screening for microtubule-disrupting antifungal agents by using a mitotic-arrest mutant of Aspergillus nidulans and novel action of phenylalanine derivatives accompanying tubulin loss.
The microtubule, which is one of the major targets of anthelmintics, anticancer drugs, and fungicides, is composed mainly of alpha- and beta-tubulins. We focused on a unique characteristic of an Aspergillus nidulans benA33 mutant to screen for microtubule-disrupting antifungal agents. This mutant, which has a beta-tubulin with a mutation of a single amino acid, undergoes mitotic arrest due to the formation of hyperstable microtubules at 37 degrees C. The heat sensitivity of the mutant is remedied by some antimicrotubule agents. We found that an agar plate assay with the mutant was able to distinguish three types of microtubule inhibitors. The growth recovery zones of the mutant were formed around paper disks containing microtubule inhibitors, including four benzimidazoles, ansamitocin P-3, griseofulvin, and rhizoxin, on the agar plate at 37 degrees C. Nocodazole, thiabendazole, and griseofulvin reversed the mitotic arrest of the mutant and promoted its hyphal growth. Ansamitocin P-3 and rhizoxin showed growth recovery zones around the growth-inhibitory zones. Benomyl and carbendazim also reversed mitotic arrest but produced weaker growth recovery than the aforementioned drugs. Other microtubule inhibitors, such as colchicine, Colcemid, paclitaxel, podophyllotoxin, TN-16, vinblastine, and vincristine, as well as some cytoskeletal inhibitors tested, did not show such activity. In our screening, we newly identified two mycotoxins, citrinin and patulin, two sesquiterpene dialdehydes, polygodial and warburganal, and four phenylalanine derivatives, arphamenine A, L-2,5-dihydrophenylalanine (DHPA), N-tosyl-L-phenylalanine chloromethylketone, and N-carbobenzoxy-L-phenylalanine chloromethyl ketone. In a wild-type strain of A. nidulans, DHPA caused selective losses of microtubules, as determined by fluorescence microscopy, and of both alpha- and beta-tubulins, as determined by Western blot analysis. This screening method involving the benA33 mutant of A. nidulans is useful, convenient, and highly selective. The phenylalanine derivatives tested are of a novel type of microtubule-disrupting antifungal agents, producing an accompanying loss of tubulins, and are different from well-known tubulin inhibitors affecting the assembly of tubulin dimers into microtubules.
Topics: Adenine; Antifungal Agents; Antineoplastic Agents; Aspergillus nidulans; Blotting, Western; Cell Nucleus; Chromosomes, Fungal; Coloring Agents; Drug Evaluation, Preclinical; Electrophoresis, Polyacrylamide Gel; Fungal Proteins; Fungi; Microbial Sensitivity Tests; Microscopy, Fluorescence; Microtubules; Mitosis; Mitotic Index; Nocodazole; Oxazines; Phenylalanine; Tubulin; Xanthenes
PubMed: 15105129
DOI: 10.1128/AAC.48.5.1739-1748.2004 -
Organic Letters Apr 2004[structure: see text] A convergent, stereoselective total synthesis of the macrolide antitumor agent rhizoxin D is described. (+)-DIPCl-promoted asymmetric aldol...
[structure: see text] A convergent, stereoselective total synthesis of the macrolide antitumor agent rhizoxin D is described. (+)-DIPCl-promoted asymmetric aldol reaction, Evans-Tishchenko 1,3-diol synthesis, modified Julia coupling, and Horner-Wadsworth-Emmons reactions are featured.
Topics: Antineoplastic Agents; Lactones; Macrolides; Molecular Conformation; Stereoisomerism
PubMed: 15101763
DOI: 10.1021/ol049701h -
Biology of Reproduction Jun 2004Two-cell bovine embryos become arrested in development when exposed to a physiologically relevant heat shock. One of the major ultrastructural modifications caused by...
Two-cell bovine embryos become arrested in development when exposed to a physiologically relevant heat shock. One of the major ultrastructural modifications caused by heat shock is translocation of organelles toward the center of the blastomere. The objective of the present study was to determine if heat- shock-induced movement of organelles is a result of cytoskeletal rearrangement. Two-cell bovine embryos were cultured at 38.5 degrees C (homeothermic temperature of the cow), 41.0 degrees C (physiologically relevant heat shock), or 43.0 degrees C (severe heat shock) for 6 h in the presence of either vehicle, latrunculin B (a microfilament depolymerizer), rhizoxin (a microtubule depolymerizer), or paclitaxel (a microtubule stabilizer). Heat shock caused a rearrangement of actin-containing filaments as detected by staining with phalloidin. Moreover, latrunculin B reduced the heat-shock-induced movement of organelles at 41.0 degrees C but not at 43.0 degrees C. In contrast, movement of organelles caused by heat shock was inhibited by rhizoxin at both temperatures. Furthermore, rhizoxin, but not latrunculin B, reduced the swelling of mitochondria caused by heat shock. Paclitaxel, while causing major changes in ultrastructure, did not prevent the movement of organelles or mitochondrial swelling. It is concluded that heat shock disrupts microtubule and microfilaments in the two-cell bovine embryo and that these changes are responsible for movement of organelles away from the periphery. In addition, intact microtubules are a requirement for heat-shock-induced swelling of mitochondria. Differences in response to rhizoxin and paclitaxel are interpreted to mean that deformation of microtubules can occur through a mechanism independent of microtubule depolymerization.
Topics: Actin Cytoskeleton; Animals; Bridged Bicyclo Compounds, Heterocyclic; Cattle; Cell Nucleus; Cleavage Stage, Ovum; Cytoplasm; Female; Heat-Shock Response; Lactones; Macrolides; Microscopy, Electron; Microtubules; Mitochondrial Swelling; Movement; Paclitaxel; Thiazoles; Thiazolidines
PubMed: 14960486
DOI: 10.1095/biolreprod.103.024901 -
The Journal of Biological Chemistry Apr 2004The African trypanosome Trypanosoma brucei transcribes the active variant surface glycoprotein (VSG) gene from one of about 20 VSG expression sites (ESs). In order to...
The African trypanosome Trypanosoma brucei transcribes the active variant surface glycoprotein (VSG) gene from one of about 20 VSG expression sites (ESs). In order to study ES control, we made reporter lines with a green fluorescent protein gene inserted behind the promoter of different ESs. We attempted to disrupt the silencing machinery, and we used fluorescence-activated cell sorter analysis for the rapid and sensitive detection of ES up-regulation. We find that a range of treatments that either block nuclear DNA synthesis, like aphidicolin, or modify DNA-like cisplatin and 1-methyl-3-nitro-1-nitrosoguanidine results in up-regulation of silent ESs. Aphidicolin treatment was the most effective, with almost 80% of the cells expressing green fluorescent protein from a silent ES. All of these treatments blocked the cells in S phase. In contrast, a range of toxic chemicals had little or no effect on expression. These included berenil and pentamidine, which selectively cleave the mitochondrial kinetoplast DNA, the metabolic inhibitors suramin and difluoromethylornithine, and the mitotic inhibitor rhizoxin. Up-regulation also affected other RNA polymerase I (pol I) transcription units, as procyclin genes were also up-regulated after cells were treated with either aphidicolin or DNA-modifying agents. Strikingly, this up-regulation of silent pol I transcription units was bloodstream form-specific and was not observed in insect form T. brucei. We postulate that the redistribution of a limiting bloodstream form-specific factor involved in both silencing and DNA repair results in the derepression of normally silenced pol I transcription units after DNA damage.
Topics: Animals; Antiprotozoal Agents; Aphidicolin; Blood; DNA Damage; Diminazene; Enzyme Inhibitors; Gene Silencing; Genes, Reporter; Green Fluorescent Proteins; Luminescent Proteins; Membrane Glycoproteins; Pentamidine; Protozoan Proteins; RNA Polymerase I; S Phase; Suramin; Transcription, Genetic; Trypanocidal Agents; Trypanosoma brucei brucei; Up-Regulation; Variant Surface Glycoproteins, Trypanosoma
PubMed: 14726511
DOI: 10.1074/jbc.M312307200 -
Molecular and Cellular Biochemistry Nov 2003Studies on vinca domain binding drugs were done in great details by a number of workers as it is recognized as a potential target for anticancer drug development. Their... (Review)
Review
Studies on vinca domain binding drugs were done in great details by a number of workers as it is recognized as a potential target for anticancer drug development. Their structures, properties, mode of action, success and failures as potential anticancer drug have been discussed in short details in this review. Among these drugs rhizoxin and maytansine are competitive inhibitors, and bind at the vinblastine binding site of tubulin where as others are non-competitive inhibitors. Besides binding, these drugs also differ in the extent of GTP hydrolysis, GTP exchange and in the stabilization of colchicine binding site. The toxicity level of these drugs towards the host cells and the extent of efflux of drugs by the P-glycoprotein mediated pump are also discussed.
Topics: Animals; Antineoplastic Agents; Binding Sites; Humans; Microtubules; Protein Structure, Tertiary; Tubulin; Tubulin Modulators; Vinca Alkaloids
PubMed: 14619954
DOI: 10.1023/a:1026045100219 -
The Journal of Organic Chemistry May 2003The convergent, highly enantioselective synthesis of rhizoxin D, a natural product possessing potent antitumor and antifungal bioactivity, is described. The C(1)-C(9)...
The convergent, highly enantioselective synthesis of rhizoxin D, a natural product possessing potent antitumor and antifungal bioactivity, is described. The C(1)-C(9) fragment of the molecule was synthesized utilizing a threefold pseudosymmetric intermediate ultimately derived from gamma-butyrolactone. The central core of rhizoxin D was prepared via a chiral resolution/asymmetric aldol protocol. Several methods for the generation of the polyene fragment were explored, and the side-chain was ultimately prepared from serine in six steps. The unification of the left and right wings of the molecule was achieved using a one-step olefination protocol, and the macrocyclization was carried out using a Horner-Emmons olefination at the C(2)-C(3) olefin.
Topics: Alkenes; Antineoplastic Agents; Catalysis; Cyclization; Indicators and Reagents; Lactones; Macrolides; Molecular Structure; Stereoisomerism
PubMed: 12762720
DOI: 10.1021/jo034011x -
European Journal of Pharmacology Jan 2003Our previous study revealed that rhizoxin...
Our previous study revealed that rhizoxin ([1S-[1R*,3R*,5S*,8R*(1R*,2S*,3E,5E,7E),10R*,11S*,13S*,14E,16S*,17S*]]-10-hydroxy-8-[2-methoxy-1,3,7-trimethyl-8-(2-methyl-4-oxazolyl)-3,5,7-octatrienyl]-11,16-dimethyl-4,7,12,18-tetraoxatetracyclo[15.3.1.03,5.011,13]heneicos-14-ene-6,19-dione) has a potent inhibitory effect on in vivo angiogenesis. However, little is known regarding the mechanism by which rhizoxin exhibits antiangiogenic activity. In this study, we examined its effects on the functions of endothelial cells associated with neovascular formation in vivo, using cultured vascular endothelial cells. Rhizoxin concentration-dependently inhibited the proliferation of bovine carotid artery endothelial cells, human umbilical vein endothelial cells and human dermal microvascular endothelial cells, the IC(50) values being 7, 5 and 0.4 nM, respectively. In addition, it reduced the extracellular plasminogen activator level in bovine vascular endothelial cells in the low nM range, and suppressed the migration of human dermal microvascular endothelial cells in the pM range. Furthermore, it blocked the tubular morphogenesis of human umbilical vein endothelial cells and human dermal microvascular endothelial cells on Matrigel in a concentration-dependent manner; the IC(50) values being 40 and 130 pM, respectively. These results suggest that rhizoxin exhibits antiangiogenic activity through the combined inhibition of some functions of endothelial cells responsible for induction of in vivo angiogenesis.
Topics: Angiogenesis Inhibitors; Animals; Antifungal Agents; Cattle; Cell Movement; Endothelium, Vascular; Humans; Lactones; Macrolides; Plasminogen Activators
PubMed: 12524138
DOI: 10.1016/s0014-2999(02)02853-4 -
The Journal of Organic Chemistry Nov 2002Rhizoxin D (2) was synthesized from four subunits, A, B, C, and D representing C3-C9, C10-C13, C14-C19, and C20-C27, respectively. Subunit A was prepared by cyclization...
Rhizoxin D (2) was synthesized from four subunits, A, B, C, and D representing C3-C9, C10-C13, C14-C19, and C20-C27, respectively. Subunit A was prepared by cyclization of iodo acetal 21, which set the configuration at C5 of 2 through a stereoselective addition of the radical derived from dehalogenation of 21 at the beta carbon of the (Z)-alpha,beta-unsaturated ester. Aldehyde 29 was obtained from phenylthioacetal 24 and condensed with phosphorane 30, representing subunit B, in a Wittig reaction that gave the (E,E)-dienoate 31. This ester was converted to aldehyde 33 in preparation for coupling with subunit C. The latter in the form of methyl ketone 55 was obtained in six steps from propargyl alcohol. An aldol reaction of 33 with the enolate of 55 prepared with (+)-DIPCl gave the desired beta-hydroxy ketone 56 bearing a (13S)-configuration in a 17-20:1 ratio with its (13R)-diastereomer. After reduction to anti diol 57 and selective protection as TIPS ether 58, the C15 hydroxyl was esterified to give phosphonate 59. An intramolecular Wadsworth-Emmons reaction of aldehyde 62, derived from delta-lactone 60, furnished macrolactone 63, which was coupled in a Stille reaction with stannane 68 to give 2 after cleavage of the TIPS ether.
Topics: Antineoplastic Agents; Lactones; Molecular Structure; Rhizopus
PubMed: 12398499
DOI: 10.1021/jo020537q -
Investigational New Drugs Aug 2002The aim of this study was to determine the antitumor activity of irofulven when administered in combination with a variety of antimitotic agents. Irofulven in...
The aim of this study was to determine the antitumor activity of irofulven when administered in combination with a variety of antimitotic agents. Irofulven in combination with either paclitaxel or docetaxel demonstrated synergistic activity in both the in vitro and in vivo studies. The majority of xenograft bearing animals that received suboptimal (< MTD) doses of irofulven and a taxane demonstrated complete cures. In contrast, in vitro studies produced either an additive or an antagonistic effect when irofulven was combined with other antimitotic agents such as vinca alkaloids, rhizoxin, s-trityl cysteine, or allocolchicine. Xenograft studies of irofulven and vinca alkaloids reflected in vitro results, as the tumor response in combination treated animals was less than the response in irofulven (monotherapy) treated animals. These results indicate that the therapeutic activity of irofulven is enhanced when combined with taxanes, and warrant further evaluation of these combinations.
Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Bridged-Ring Compounds; Cell Survival; Colchicine; Cysteine; Drug Synergism; Female; Lactones; Macrolides; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Sesquiterpenes; Taxoids; Tubulin; Tumor Cells, Cultured; Vinca Alkaloids
PubMed: 12201490
DOI: 10.1023/a:1016201807796