Novel Mammalian Cell Cycle Inhibitors, Tryprostatins A, B and Other Diketopiperazines Produced by Aspergillus fumigatus. I. Taxonomy, Fermentation, Isolation and Biological Properties.

Cui, Cheng‐Bin; Kakeya, Hideaki; Okada, Gen; Onose, Rie; Osada, Hiroyuki

doi:10.7164/antibiotics.49.527

Cited by 192 publications

(109 citation statements)

References 31 publications

Supporting

Mentioning

104

Contrasting

Order By: Relevance

“…Thus biological evaluation of analogues 1-8 illustrated above indicated that 1 was a weak inhibitor of both topoisomerase II and tubulin polymerization, whereas 2 was only a weak inhibitor of topoisomerase II. The enantiomers (3 and 4) and diastereomers (5)(6)(7)(8) were inactive in both the tubulin polymerization assay and topoisomerase II-mediated DNA relaxation assay. In terms of the stereochemistry of the amino acids present in the diketopiperazine ring, biological evaluation indicated that ligands with the absolute configuration L-Tyr-L-Pro (natural stereochemistry as in 1 and 2) were essential for inhibition of tubulin polymerization and/or topoisomerase II.…”

Section: Effects Of Analogues 1-8 On Tubulin Polymerizationmentioning

confidence: 99%

Synthesis and structure–activity relationship studies on tryprostatin A, an inhibitor of breast cancer resistance protein

Jain

Zhang

Zhou

et al. 2008

Bioorganic & Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

Tryprostatin A is a potent inhibitor of breast cancer resistance protein, consequently a series of structure-activity studies on the cell cycle inhibitory effects of tryprostatin A analogues as potential antitumor antimitotic agents have been carried out. These analogues were assayed for their growth inhibition properties and their ability to perturb the cell cycle in tsFT210 cells. SAR studies resulted in the identification of the essential structural features required for cytotoxic activity. The absolute configuration L-Tyr-L-pro in the diketopiperazine ring along with the presence of the 6-methoxy substituent on the indole moiety of 1 was shown to be essential for dual inhibition of topoisomerase II and tubulin polymerization. Biological evaluation also indicated the presence of the 2-isoprenyl moiety on the indole scaffold of 1 was essential for potent inhibition of cell proliferation. Substitution of the indole N a -H in 1 with various alkyl or aryl groups, incorporation of various L-amino acids into the diketopiperazine ring in place of L-proline, and substitution of the 6-methoxy group in 1 with other functionality provided active analogues. The nature of the substituents present on the indole N a -H or the indole C-2 position influenced the mechanism of action of these analogues. nalogues 68 (IC 50 = 10 μM) and 67 (IC 50 = 19 μM) were 7-fold and 3.5-fold more potent, respectively than 1 (IC 50 = 68 μM) in the inhibition of the growth of tsFT210 cells. Diastereomer-2 of tryprostatin B 8 was a potent inhibitor of the growth of three human carcinoma cell lines: H520 (IC 50 = 11.9 μM), MCF7 (IC 50 = 17.0 μM) and PC3 (IC 50 = 11.1 μM) and was equipotent with etoposide, a clinically used anticancer agent. Isothiocyanate analogue 71 and 6-azido analogue 72 were as potent as 1 in the tsFT210 cell proliferation and may be useful tools in labeling BCRP.

show abstract

Section: Effects Of Analogues 1-8 On Tubulin Polymerizationmentioning

confidence: 99%

Synthesis and structure–activity relationship studies on tryprostatin A, an inhibitor of breast cancer resistance protein

Jain

Zhang

Zhou

et al. 2008

Bioorganic & Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…They were allowed to proceed for 5 min and were terminated by the addition of ethyl acetate. Because enzyme activity was stable at lower than 20 C under the assay conditions in this study, we ran the enzyme reactions at 15 C. The reaction products were extracted with ethyl acetate and analyzed by HPLC and LC/ESI-MS. HPLC analysis was carried out with a Waters ACQUITY UPLC H-Class system (Waters, Milford, MA). The conditions were as follows: column, BEH C18 (2:1 Â 50 mm, 1.7 mm, Waters); flow rate, 0.6 mL/min; solvent A, water containing 0.05% v/v formic acid; solvent B, acetonitrile.…”

Section: )mentioning

confidence: 99%

“…11,12) A genetic study of a nonribosomal peptide synthetase gene, ftmA, and biochemical studies of two prenyltransferase genes, ftmB and ftmH (also termed ftmPT1 and ftmPT2, respectively), showed that the ftm cluster is associated with the FTM biosynthetic pathway, 4,13,14) but no FTM production was detected in a genome reference strain of A. fumigatus, Af293. 13) Hence, we utilized an FTMproducing strain of A. fumigatus, BM939, 15) to dissect the FTM pathway, and demonstrated the functions of three cytochrome P450s, FtmC, FtmE, and FtmG, in the biosynthetic pathway. 8) In addition, a unique function of -ketoglutarate-dependent dioxygenase FtmF (also termed ftmOx1), which catalyzes endoperoxide bond formation in verruculogen, was recently reported.…”

mentioning

confidence: 99%

A Point Mutation inftmDBlocks the Fumitremorgin Biosynthetic Pathway inAspergillus fumigatusStrain Af293

Kato

Suzuki

Okumura

et al. 2013

Bioscience, Biotechnology, and Biochemistry

Self Cite

View full text Add to dashboard Cite

“…Multicomponent reactions (MCR) have emerged as a powerful tool for delivering the molecular diversity needed in the combinational approaches for the preparation of active compounds [1]. The spirooxindole framework [2], represents an important structural organization present in a number of bioactive natural products, such as coerulescine, horstiline, welwitindolinone A, Spirotryprostatin A, [3] a natural alkaloid isolated from the fermentation broth of Aspergillus fumigates, has been identified as a novel inhibitor of microtubule assembly and the function of muscarinic serotonin receptors [4].The 3-substituted indole nucleus substructure is one of the important heterocycles found in natural products, pharmaceuticals and is important in medicinal chemistry [5]. Its scaffolds are found in a number of biologically active compounds with anticancer,anti-tumour [6], antiinflammatory, hypoglycemic, analgesic and anti-pyretic activities.…”

Section: Introductionmentioning

confidence: 99%

Kinetics of Thermal Decomposition of a Spirooxindole Compound under Non-Isothermal Condition

2016

Can Chem Trans

View full text Add to dashboard Cite

A spirooxindole compound, namely 2′-amino-6′-(1H-indol-3-yl)-2-oxospiro[indole-3,4′-pyran]-3′, 5′-dicarbonitrile (AIOIPD) has been synthesized and characterized by microanalysis, FT-IR, mass spectrum and NMR ( 1 H and 13 C) techniques. The thermal decomposition of the compound was studied by thermogravimetric analysis under dynamic nitrogen atmosphere at different heating rates of 10, 15, 20 and 30 K min -1 . The kinetic parameters were calculated using model fitting (Coats-Redfern, CR) and model-free methods (Friedman, Kissinger-Akahira-Sunose, KAS and Flynn-Wall-Ozawa, FWO). The decomposition process of AIOIPD followed a single step mechanism as evidenced from the data. Existence of compensation effect is noticed for the decomposition of AIOIPD. Invariant kinetic parameters are consistent with the average values obtained by Friedman and KAS inconversional methods.

show abstract

Novel Mammalian Cell Cycle Inhibitors, Tryprostatins A, B and Other Diketopiperazines Produced by Aspergillus fumigatus. I. Taxonomy, Fermentation, Isolation and Biological Properties.

Cited by 192 publications

References 31 publications

Synthesis and structure–activity relationship studies on tryprostatin A, an inhibitor of breast cancer resistance protein

Synthesis and structure–activity relationship studies on tryprostatin A, an inhibitor of breast cancer resistance protein

A Point Mutation inftmDBlocks the Fumitremorgin Biosynthetic Pathway inAspergillus fumigatusStrain Af293

Kinetics of Thermal Decomposition of a Spirooxindole Compound under Non-Isothermal Condition

Contact Info

Product

Resources

About