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The Journal of Organic Chemistry Oct 1998A triply convergent synthetic approach which culminates in the enantioselective syntheses of the C(1)-C(9) and C(12)-C(26) subunits of the macrolide antitumor agent...
A triply convergent synthetic approach which culminates in the enantioselective syntheses of the C(1)-C(9) and C(12)-C(26) subunits of the macrolide antitumor agent rhizoxin is described. The central C(12)-C(20) subunit 4 has been prepared efficiently via diastereoselective enzymatic acetate hydrolysis of 15 with porcine pancreatic lipase, a chelation-controlled Ireland-Claisen rearrangement (10 --> 12) combined with kinetic bromolactonization (12 --> 14), and Mitsunobu inversion (23 --> 26) to introduce the three contiguous C(15)-C(17) stereocenters. Formation of the C(18)-C(19) trisubstituted (E)-olefin was achieved by a stereoselective Horner-Wadsworth-Emmons reaction. The central segment 4 and the oxazole chromophore side chain 3 were coupled using another highly stereoselective Horner-Wadsworth-Emmons reaction. Two different lactone subunits [C(1)-C(9) segment 5 and C(3)-C(10) segment 47] were also prepared, employing a thermodynamically controlled diastereotopic group differentiation tactic for establishing the C(5) stereochemistry.
PubMed: 11672317
DOI: 10.1021/jo980754k -
The Journal of Antibiotics Mar 1986The absolute structure of rhizoxin, a potent antifungal and antitumor antibiotic, was determined by interrelation with compound 2 whose structure was established by...
The absolute structure of rhizoxin, a potent antifungal and antitumor antibiotic, was determined by interrelation with compound 2 whose structure was established by X-ray analysis. Since a 18OH group was introduced at C-3 on a hydrolytic cleavage of C-2, C-3 epoxy group with alkaline H2(18)O, the original epoxy oxygen should be retained at C-2. The stereo-chemistry at C-2 and C-3 positions in rhizoxin was, therefore, determined as 2R,3S.
Topics: Chemical Phenomena; Chemistry; Lactones; Macrolides; Stereoisomerism
PubMed: 3754548
DOI: 10.7164/antibiotics.39.424 -
The Journal of Antibiotics Apr 1984A new 16-membered macrolide designated as rhizoxin was isolated as a toxin produced by Rhizopus chinensis, the causal agent of rice seedling blight . The skeletal...
A new 16-membered macrolide designated as rhizoxin was isolated as a toxin produced by Rhizopus chinensis, the causal agent of rice seedling blight . The skeletal structure was determined by detailed NMR spectroscopic investigation of this compound and of its derivatives. Rhizoxin induced at a concentration of 10 ng/ml abnormal swelling of rice seedling roots, which is one of the characteristic symptoms of this disease. This compound also exhibited potent antifungal activity but little effect against bacteria.
Topics: Anthraquinones; Antifungal Agents; Chemical Phenomena; Chemistry; Drug Evaluation, Preclinical; Fungi; Lactones; Macrolides; Magnetic Resonance Spectroscopy; Molecular Conformation; Rhizopus
PubMed: 6547134
DOI: 10.7164/antibiotics.37.354 -
Biochemical and Biophysical Research... Sep 1992The binding of four potent antimitotic agents, rhizoxin (RZX), phomopsin A (PMS-A), ansamitocin P-3 (ASMP-3), and vinblastine (VLB), to tubulins from RZX-sensitive and... (Comparative Study)
Comparative Study
Binding selectivity of rhizoxin, phomopsin A, vinblastine, and ansamitocin P-3 to fungal tubulins: differential interactions of these antimitotic agents with brain and fungal tubulins.
The binding of four potent antimitotic agents, rhizoxin (RZX), phomopsin A (PMS-A), ansamitocin P-3 (ASMP-3), and vinblastine (VLB), to tubulins from RZX-sensitive and -resistant strains of Aspergillus nidulans, Schizosaccharomyces pombe, and Saccharomyces cerevisiae was investigated. Mycelial extracts to which RZX could bind contained beta-tubulin with Asn as the 100th amino acid residue (Asn-100) in all cases, and those without affinity for RZX contained beta-tubulins with either Ile-100 or Val-100. Though PMS-A shares the same binding site as RZX and ASMP-3 on porcine brain tubulin (Asn-100), only ASMP-3 bound Asn-100 fungal tubulins in a competitive manner with respect to RZX. PMS-A and VLB, which strongly bind to porcine brain tubulin, did not bind to any of the fungal mycelial extracts examined. The results indicate differential interactions of these antimitotic agents with brain and fungal tubulins.
Topics: Animals; Antineoplastic Agents; Aspergillus nidulans; Binding Sites; Binding, Competitive; Brain; Brain Chemistry; Fungi; Lactones; Macrolides; Maytansine; Mycotoxins; Saccharomyces cerevisiae; Schizosaccharomyces; Swine; Tubulin; Vinblastine
PubMed: 1530630
DOI: 10.1016/0006-291x(92)91255-o -
Bioconjugate Chemistry 1993A fluorescent probe (20-demethoxy-20-[3-[[[5-(dimethylamino)naphthalen-1-yl]sulfonyl] amino]propyl]maytansinol 3-isobutyrate, Dan-PDM-3) and a photoaffinity labeling...
A fluorescent probe (20-demethoxy-20-[3-[[[5-(dimethylamino)naphthalen-1-yl]sulfonyl] amino]propyl]maytansinol 3-isobutyrate, Dan-PDM-3) and a photoaffinity labeling reagent (20-demethoxy-20-[(p-azidobenzoyl)oxy]maytansinol 3-isobutyrate, DABMI) were prepared by derivatization of ansamitocin P-3 (ASMP-3), a maytansinoid. Dan-PDM-3 consists of a tethered dansyl moiety and a maytansinoid moiety. DABMI contains a p-azidobenzoyl group instead of the tethered dansyl moiety of Dan-PDM-3. These compounds were synthesized by reacting 20-demethoxy-20-hydroxymaytansinol-3 isobutyrate (PDM-3) with the corresponding alkyl halide or benzoic acid. Both inhibit tubulin polymerization as potently as ASMP-3 and compete with ASMP-3 for binding to tubulin. The inhibition constants (Ki) of DABMI for the binding to tubulin of rhizoxin and ASMP-3 were 0.54 and 0.36 microM, respectively, which were nearly equal to the dissociation constant (Kd = 0.43 microM) of DABMI measured by the use of [14C]DABMI. The results suggest that Dan-PDM-3 and DABMI interacted with tubulin at the same site as rhizoxin and maytansine. DABMI is irreversibly bound to tubulin upon irradiation. Dan-PDM-3 and DABMI should be useful probes for studying the binding site.
Topics: Affinity Labels; Animals; Antifungal Agents; Azides; Binding, Competitive; Dansyl Compounds; Fluorescent Dyes; Kinetics; Lactones; Macrolides; Maytansine; Microtubules; Protein Binding; Schizosaccharomyces; Swine; Tubulin
PubMed: 8218485
DOI: 10.1021/bc00022a006 -
British Journal of Cancer Feb 1996In a multicentre trial of the EORTC-Early Clinical Trials Group (ECTG) we treated 31 chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC) with... (Clinical Trial)
Clinical Trial
In a multicentre trial of the EORTC-Early Clinical Trials Group (ECTG) we treated 31 chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC) with rhizoxin, a novel tubulin-binding agent. The drug was given as an i.v. bolus injection at 2 mg m-2 once every 3 weeks in an outpatient setting. Prophylactic antiemetics were not routinely given. Of the 29 eligible patients, nine had been treated surgically and three had received radiotherapy. The main toxic effects observed were stomatitis (34% of cycles) and neutropenia (41% of cycles). Neutropenic fever was rare (3% of cycles). Twenty-seven patients were evaluable for response. There were four partial responses (15%), while 13 patients (48%) showed stabilisation of their disease. The median duration of response was 7 months (range 6.0-10.7 months) and median survival from the start of rhizoxin treatment was 6 months (range 2-14.7 months). Rhizoxin as single agent shows activity in patients with advanced NSCLC.
Topics: Adult; Aged; Antibiotics, Antineoplastic; Carcinoma, Non-Small-Cell Lung; Female; Hematopoiesis; Humans; Lactones; Lung Neoplasms; Macrolides; Male; Middle Aged
PubMed: 8562351
DOI: 10.1038/bjc.1996.70 -
ACS Synthetic Biology Oct 2023Bacterial natural products (NPs) are an indispensable source of drugs and biopesticides. Heterologous expression is an essential method for discovering bacterial NPs and...
Bacterial natural products (NPs) are an indispensable source of drugs and biopesticides. Heterologous expression is an essential method for discovering bacterial NPs and the efficient biosynthesis of valuable NPs, but the chassis for Gram-negative bacterial NPs remains inadequate. In this study, we built a mutant Δ::attB by introducing an integrated site () to inactivate the native gladiolin () biosynthetic gene cluster, which stabilizes large foreign gene clusters and reduces the native metabolite profile. The growth and successful heterologous production of high-value NPs such as phylogenetically close -derived antitumor polyketides (PKs) rhizoxins, phylogenetically distant -derived anti-MRSA (methicillin-resistant ) antibiotics WAP-8294As, and -derived antitumor PKs disorazols demonstrate that this strain is a potential chassis for Gram-negative bacterial NPs. We further improved the yields of WAP-8294As through promoter insertions and precursor pathway overexpression based on heterologous expression in this strain. This study provides a robust bacterial chassis for genome mining, efficient production, and molecular engineering of bacterial NPs.
Topics: Biological Products; Burkholderia gladioli; Methicillin-Resistant Staphylococcus aureus; Anti-Bacterial Agents; Biological Control Agents; Polyketides; Multigene Family
PubMed: 37708405
DOI: 10.1021/acssynbio.3c00389 -
Pharmaceutical Research Feb 1996A highly lipophilic antitumor agent, 13-O-palmitoyl-rhizoxin (RS-1541), was incorporated into lipid emulsions of various sizes consisting of triglyceride ODO and...
PURPOSE
A highly lipophilic antitumor agent, 13-O-palmitoyl-rhizoxin (RS-1541), was incorporated into lipid emulsions of various sizes consisting of triglyceride ODO and surfactant HCO-60. Pharmacokinetics, toxicities, and antitumor activities were evaluated after intravenous administration to mice bearing subcutaneously inoculated M5076 sarcoma cells.
METHODS
The levels of RS-1541 in the plasma and tissues including tumor, were determined by HPLC. The maximum tolerated dose (MTD) was estimated by toxic death and change in body weight. The decrease in tumor diameter was measured for antitumor activity.
RESULTS
There existed large variations in pharmacokinetics of RS-1541, depending on the size of emulsion particles. Compared with a colloidal solution (reference solution), the small (110nm) and medium (230nm) size emulsions showed high concentrations of RS-1541 in the tumor, while the large emulsions (350nm-630nm) exhibited low concentrations. The MTD of RS-1541 was reduced, when incorporated in the emulsions larger than 220nm in size. At MTD, each size of emulsions (70nm-380nm) effectively retarded the tumor growth and increased survival time. The maximum effect was achieved for the 220 nm emulsions.
CONCLUSIONS
When particle size is properly selected, these emulsions could be promising and effective as an injectable carrier for lipophilic antitumor agents in order to enhance the tumor delivery and efficacies while reducing toxicities.
Topics: Animals; Antibiotics, Antineoplastic; Castor Oil; Chemistry, Pharmaceutical; Drug Screening Assays, Antitumor; Drug Synergism; Emulsions; Female; Lactones; Lymphoma, Large B-Cell, Diffuse; Mice; Mice, Inbred Strains; Neoplasm Transplantation; Surface-Active Agents; Triglycerides
PubMed: 8932454
DOI: 10.1023/a:1016063719541 -
Biochemical Pharmacology Jan 1992Phomopsin A is an antimitotic cyclic peptide containing a 13-member ring including an ether linkage. It was isolated from the fungus Phomopsis leptostromiformis as the... (Comparative Study)
Comparative Study
Phomopsin A is an antimitotic cyclic peptide containing a 13-member ring including an ether linkage. It was isolated from the fungus Phomopsis leptostromiformis as the causal agent of lupinosis. Phomopsin A strongly inhibited microtubule assembly (IC50: 2.4 microM). Our study using radiolabeled phomopsin A, prepared biosynthetically by feeding L-[U-14C]isoleucine to the culture of P. leptostromiformis, indicated that at least two binding sites of phomopsin A exist on tubulin on the basis of a Scatchard analysis; i.e. the dissociation constants of a high affinity site (Kd1) and a low affinity site (Kd2) at 37 degrees were determined to be 1 x 10(-8) and 3 x 10(-7) M, respectively. Phomopsin A inhibited the binding of radiolabeled rhizoxin to tubulin with an inhibition constant (Ki) of 0.8 x 10(-8) M. This showed that the high affinity site of phomopsin A is identical to the rhizoxin binding site. The binding of the radiolabeled phomopsin A was also inhibited by rhizoxin and ansamitocin P-3, with an inhibition constant of 10(-7) M, and to a lesser extent by vinblastine. Phomopsin A had no inhibitory effect on colchicine binding to tubulin.
Topics: Animals; Binding Sites; Binding, Competitive; Brain; Colchicine; Kinetics; Lactones; Macrolides; Maytansine; Microtubule Proteins; Mycotoxins; Polymers; Protein Conformation; Structure-Activity Relationship; Swine; Tubulin; Tubulin Modulators; Vinblastine
PubMed: 1739410
DOI: 10.1016/0006-2952(92)90281-m -
Chemico-biological Interactions Dec 1994Dolastatin 10, a cytostatic peptide containing several unique amino acid subunits, was isolated from the marine shell-less mollusk Dolabella auricularia. It inhibits...
Dolastatin 10, a cytostatic peptide containing several unique amino acid subunits, was isolated from the marine shell-less mollusk Dolabella auricularia. It inhibits microtubule assembly at concentrations below 5.0 microM (IC50, 3.0 microM) and causes formation of tubulin aggregates at higher (> 10 microM) concentrations in a somewhat different manner from that caused by vinblastine. Electron microscopical analysis showed irregular aggregates of microtubule proteins in the presence of 10 microM dolastatin 10. Dolastatin 10 inhibited the binding of both radiolabeled rhizoxin and phomopsin A to tubulin with inhibition constants (Ki) of 7 x 10(-8) M and 1 x 10(-7) M, respectively. The results suggest that at least one of the binding sites of dolastatin 10 on tubulin is the rhizoxin binding site.
Topics: Animals; Antineoplastic Agents; Binding Sites; Binding, Competitive; Brain; Depsipeptides; Lactones; Macrolides; Microscopy, Electron; Microtubules; Mollusca; Mycotoxins; Oligopeptides; Polymers; Swine; Tubulin
PubMed: 7923438
DOI: 10.1016/0009-2797(94)90018-3