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Journal of Drug Targeting 1998Highly lipophilic antitumor agent, palmitoyl rhizoxin (RS-1541), was incorporated into stable lipid emulsions about 100-1000nm in mean diameter consisting of...
Highly lipophilic antitumor agent, palmitoyl rhizoxin (RS-1541), was incorporated into stable lipid emulsions about 100-1000nm in mean diameter consisting of triglyceride ODO and surfactant HCO-60. The pharmacokinetics of RS-1541 were studied after i.v. injection in mice, rats, rabbits, and dogs. Dog showed characteristic pharmacokinetics of RS-1541, compared with other species. RS-1541 was much more rapidly eliminated from plasma with emulsion particles in dogs than in mice, rats, and rabbits. Most amounts of injected RS-1541 were recovered in the liver six hours after administration to dogs, while less than 20% recoveries were observed for mice and rats. To clarify this species variation, opsonization of emulsion particles were evaluated. When emulsions (about 200nm in size) were opsonized by dog plasma, and intravenously injected to rats, total clearance and liver uptake of RS-1541 were increased to 1.8 fold and 2.7 fold of control values, respectively. In contrasts, emulsions opsonized by mouse, rabbit and human plasma did not show such drastic changes in pharmacokinetics of RS-1541 in rats. Furthermore, total clearance of RS-1541 for emulsions opsonized by dog plasma was increased to 1.9 fold of controls after injection to rabbits. These results indicate that opsonizing activities of dog plasma for RS-1541 emulsions are high, compared with other species. This species variation in opsonizing process probably caused the species variation in the pharmacokinetics of RS-1541 incorporated in lipid emulsions.
Topics: Animals; Antibiotics, Antineoplastic; Dogs; Drug Carriers; Emulsions; Injections, Intravenous; Lactones; Liver; Male; Mice; Opsonin Proteins; Rabbits; Rats; Rats, Wistar; Species Specificity; Spleen
PubMed: 9783680
DOI: 10.3109/10611869808997875 -
ELife Sep 2014The rice seedling blight fungus Rhizopus microsporus and its endosymbiont Burkholderia rhizoxinica form an unusual, highly specific alliance to produce the highly potent...
The rice seedling blight fungus Rhizopus microsporus and its endosymbiont Burkholderia rhizoxinica form an unusual, highly specific alliance to produce the highly potent antimitotic phytotoxin rhizoxin. Yet, it has remained a riddle how bacteria invade the fungal cells. Genome mining for potential symbiosis factors and functional analyses revealed that a type 2 secretion system (T2SS) of the bacterial endosymbiont is required for the formation of the endosymbiosis. Comparative proteome analyses show that the T2SS releases chitinolytic enzymes (chitinase, chitosanase) and chitin-binding proteins. The genes responsible for chitinolytic proteins and T2SS components are highly expressed during infection. Through targeted gene knock-outs, sporulation assays and microscopic investigations we found that chitinase is essential for bacteria to enter hyphae. Unprecedented snapshots of the traceless bacterial intrusion were obtained using cryo-electron microscopy. Beyond unveiling the pivotal role of chitinolytic enzymes in the active invasion of a fungus by bacteria, these findings grant unprecedented insight into the fungal cell wall penetration and symbiosis formation.
Topics: Burkholderia; Chitinases; Cryoelectron Microscopy; Electrophoresis, Gel, Two-Dimensional; Host-Pathogen Interactions; Hyphae; Macrolides; Microscopy, Confocal; Microscopy, Electron, Scanning; Mutation; Oryza; Plant Diseases; Proteome; Proteomics; Rhizopus; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Symbiosis
PubMed: 25182414
DOI: 10.7554/eLife.03007 -
Angewandte Chemie (International Ed. in... Aug 2018Ketosynthase (KS) domains of modular type I polyketide synthases (PKSs) typically catalyze the Claisen condensation of acyl and malonyl units to form linear chains. In...
Ketosynthase (KS) domains of modular type I polyketide synthases (PKSs) typically catalyze the Claisen condensation of acyl and malonyl units to form linear chains. In stark contrast, the KS of the rhizoxin PKS branching module mediates a Michael addition, which sets the basis for a pharmacophoric δ-lactone moiety. The precise role of the KS was evaluated by site-directed mutagenesis, chemical probes, and biotransformations. Biochemical and kinetic analyses helped to dissect branching and lactonization reactions and unequivocally assign the entire sequence to the KS. Probing the range of accepted substrates with diverse synthetic surrogates in vitro, we found that the KS tolerates defined acyl chain lengths to produce five- to seven-membered lactones. These results show that the KS is multifunctional, as it catalyzes β-branching and lactonization. Information on the increased product portfolio of the unusual, TE-independent on-line cyclization is relevant for synthetic biology approaches.
Topics: Bacillus amyloliquefaciens; Burkholderia; Cyclization; Lactones; Macrolides; Models, Molecular; Mutagenesis, Site-Directed; Polyketide Synthases; Protein Domains; Substrate Specificity
PubMed: 29897642
DOI: 10.1002/anie.201804991 -
Angewandte Chemie (International Ed. in... 2009A new "branch" for polyketide synthases was discovered in the biosynthesis of the antimitotic rhizoxin complex in the endofungal bacterium Burkholderia rhizoxinica....
A new "branch" for polyketide synthases was discovered in the biosynthesis of the antimitotic rhizoxin complex in the endofungal bacterium Burkholderia rhizoxinica. Genetic engineering and the structural elucidation of pathway intermediates revealed that a complex polyketide chain is branched at the beta position by an unprecedented conjugate addition of an acetyl building block to an acryloyl precursor (see scheme).
Topics: Antineoplastic Agents; Biocatalysis; Burkholderia; Gene Knockout Techniques; Macrolides; Multigene Family; Polyketide Synthases; Protein Structure, Tertiary
PubMed: 19266509
DOI: 10.1002/anie.200900277 -
Cancer Chemotherapy and Pharmacology 1995RS-1541, an acyl-derivative of rhizoxin (Fig. 1), is a potent antitumor compound. This agent showed cytotoxicity in vitro on some cultured human tumor cells, although it...
RS-1541, an acyl-derivative of rhizoxin (Fig. 1), is a potent antitumor compound. This agent showed cytotoxicity in vitro on some cultured human tumor cells, although it was less potent than rhizoxin. Rhizoxin exhibited antitumor effects by inhibiting the polymerization of tubulin, whereas RS-1541 did not inhibit tubulin polymerization in vitro. However, cell cycle analysis in vivo showed that the two agents had the same mode of action. The cytotoxicity of RS-1541 was enhanced when the initial cell density of the cells was increased. The cytotoxicity was also enhanced when the membrane fraction of St-4 cells, which were the most sensitive to RS-1541 among the cell lines tested, was added to the target cells. When St-4 cells were incubated with [14C]-RS-1541, significant amounts of [14C]-rhizoxin were produced within the cells. Further fractionation of the crude membrane showed that the activity that enhanced the cytotoxicity of RS-1541 (RS-1541-enhancing activity) belonged to the mitochondrial-lysosomal fraction, not to the microsomal fraction. Both the enhancing activity and the activity that converting [14C]-RS-1541 to [14C]-rhizoxin (RS-1541-converting activity) were inhibited by treatment with chloroquine, an inhibitor of lysosomal function. Cholesterol esterase derived from Candida cylindracea had RS-1541-enhancing and -converting activities. These data suggest that RS-1541 exerts its cytotoxic action after being converted to rhizoxin within the cells by a lysosomal enzyme such as cholesterol esterase.
Topics: Antibiotics, Antineoplastic; Biotransformation; Cell Cycle; Humans; Lactones; Lysosomes; Macrolides; Sterol Esterase; Tumor Cells, Cultured
PubMed: 7828270
DOI: 10.1007/BF00689446 -
Organic & Biomolecular Chemistry Dec 2005An enantioselective synthesis of rhizoxin D, isolated from the plant pathogenic fungus Rhizopus chinensis, is described. The overall strategy is based on elaboration of...
An enantioselective synthesis of rhizoxin D, isolated from the plant pathogenic fungus Rhizopus chinensis, is described. The overall strategy is based on elaboration of the delta-lactone-substituted vinyl stannane and the phosphonate-substituted vinyl iodide, followed by their coupling to the core 16-membered macrolide via a sequential intermolecular Horner-Wadsworth-Emmons olefination, leading to (50), and by an intramolecular Stille reaction. The triene oxazole-containing side chain in rhizoxin D is then introduced using the phosphine oxide in an E-selective Horner-Wittig reaction with the macrolide aldehyde.
Topics: Antineoplastic Agents; Lactones; Macrolides; Molecular Structure
PubMed: 16327903
DOI: 10.1039/b507570j -
Frontiers in Microbiology 2022Heterologous expression is an indispensable approach to exploiting natural products from phylogenetically diverse microbial communities. In this study, we constructed a...
Heterologous expression is an indispensable approach to exploiting natural products from phylogenetically diverse microbial communities. In this study, we constructed a heterologous expression system based on strain E264 by deleting efflux pump genes and screening constitutive strong promoters. The biosynthetic gene cluster (BGC) of disorazol from So ce12 was expressed successfully with this host, and the yield of its product, disorazol F, rather than A, was improved to 38.3 mg/L by promoter substitution and insertion. In addition to the disorazol gene cluster, the BGC of rhizoxin from was also expressed efficiently, whereas no specific peak was detected when shuangdaolide BGC from sp. B59 was transformed into the host. This system provides another option to explore natural products from different phylogenetic taxa.
PubMed: 36466684
DOI: 10.3389/fmicb.2022.1073243 -
Cancer Chemotherapy and Biological... 1997
Review
Topics: Animals; Antineoplastic Agents; Dacarbazine; Humans; Lactones; Macrolides; Neovascularization, Pathologic; Suramin; Temozolomide; Thymidylate Synthase; Tirapazamine; Triazines; Uracil
PubMed: 9551214
DOI: No ID Found -
British Journal of Cancer Nov 1995Rhizoxin is a tubulin-binding anti-neoplastic agent which is active in a range of murine tumour models. The recommended schedule, of intravenous (i.v.) bolus... (Clinical Trial)
Clinical Trial
Rhizoxin is a tubulin-binding anti-neoplastic agent which is active in a range of murine tumour models. The recommended schedule, of intravenous (i.v.) bolus administration at a dose of 2 mg m-2 every 3 weeks, has been assessed in three phase II trials of ovarian, renal and colorectal cancer. In general terms the drug was fairly well tolerated, but the response rate was disappointing: 0/18, colorectal cancer; 0/18, renal cancer; 1 partial response (PR)/17, ovarian cancer.
Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Colorectal Neoplasms; Female; Humans; Kidney Neoplasms; Lactones; Macrolides; Middle Aged; Ovarian Neoplasms; Treatment Outcome
PubMed: 7577480
DOI: 10.1038/bjc.1995.498 -
Gan To Kagaku Ryoho. Cancer &... Mar 1988Effort looking for new antitumor antibiotics useful for the treatment of curing cancer resulted to the discovery of a number of new compounds with newer action mechanism... (Review)
Review
Effort looking for new antitumor antibiotics useful for the treatment of curing cancer resulted to the discovery of a number of new compounds with newer action mechanism as well as newer structural feature. The antibiotics which have been discovered since 1984 are discussed under classifications of action mechanism and structural feature, as well. The first group, which belong to a novel class of antibiotics containing a bicyclodiynene carbon skeleton in the molecules exhibited the most strong anti-tumor activity comparing with the antitumor antibiotics so far discovered. The action mechanism of this was explained by the diradical formation of diynene-cyclization, which led to the scission of double strand DNA. Amongst, esperamicin A seems of great interest in view of the therapeutic development. Moreover, elsamicin A, a member of chatarin antibiotics, and FR-900482 compound, an antibiotic having a polycyclic alkalodal skeleton are under development for the new chemotherapeutic agents. Rhizoxin, the metabolite of Rhizopus chinensis is also a promising candidate as anticancer agent. Its action mechanism was classified as an inhibitor of mitosis by binding to the microtibline proteins. Rhizoxin A shows no cross resistance with vincristine. MX2 (KRN 8602), the morpholino derivative of 13-deoxo-10-hydroxy-carminomycin, shows anticancer activity against tumor cells resistant to P388/ADM as well as low cardial toxicity. Miscellaneous compounds whose action mechanism are unknown are described.
Topics: Animals; Antibiotics, Antineoplastic; Humans; Lethal Dose 50; Neoplasms; Neoplasms, Experimental; Structure-Activity Relationship
PubMed: 3279909
DOI: No ID Found