Tryprostatins A and B, Novel Mammalian Cell Cycle Inhibitors Produced by Aspergdlus fumigatus .

Cui, Cheng‐Bin; Kakeya, Hideaki; Okada, Gen; Onose, Rie; Ubukata, Makoto; Takahashi, Ikuo; Isono, Kiyoshi; Osada, Hiroyuki

doi:10.7164/antibiotics.48.1382

Cited by 142 publications

(64 citation statements)

References 6 publications

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“…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%

“…If one examines the structures of tryprostatins (1-7) and compares them with that of the active analogue 8, one can generate the following conclusion: the L-Tyr unit in the diketopiperazine ring was essential for potent tumor cell growth inhibition since none of the other tryprostatins (3)(4)(5)(6), which contained the D-Tyr unit, exhibited activity. Biological evaluation of analogue 8 also indicated that the inhibition of the growth of human cancer cells by analogue 8 was not due to the inhibition of topoisomerase II or tubulin polymerization since analogue 8 was inactive against these two molecular targets.…”

Section: Effects Of Analogues 1-8 On Tubulin Polymerizationmentioning

confidence: 99%

“…Methylene chloride (2 L) was added to the residue and the suspension which resulted was filtered to remove unwanted salts. After removal of the CH 2 Cl 2 , the crude product was purified by flash chromatography (silica gel, 2% EtOAc in hexane) to give 77% of the desired 6 …”

Section: (5r2s)-36-diethoxy-5-[6-methoxy-2-(triethylsilyl)-3-indolymentioning

confidence: 99%

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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

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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.

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Section: Effects Of Analogues 1-8 On Tubulin Polymerizationmentioning

confidence: 99%

Section: Effects Of Analogues 1-8 On Tubulin Polymerizationmentioning

confidence: 99%

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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

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“…from the Philippines [39]. An enantiospecific total synthesis of tryprostatin A (9), which is a cytotoxic diketopiperazine from Aspergillus fumigatus strain BM939 [40], employed a new regiospecific bromination procedure [41] [42]. The marine sediment origin of A. fumigatus produced tryprostatin B (10) [43].…”

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confidence: 99%

Diketopiperazines from Marine Organisms

Huang

Zhou

Tian

et al. 2010

Chemistry & Biodiversity

143

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Diketopiperazines (DKPs), which are cyclic dipeptides, have been detected in a variety of natural resources. Recently, the interest in these compounds increased significantly because of their remarkable bioactivity. This review deals with the chemical structures, biosynthetic pathways, and biological activities of DKPs from marine microorganisms, sponges, sea stars, tunicates (ascidians), and red algae. The literature has been covered up to December 2008, and a total 124 DKPs from 104 publications have been discussed and reviewed. Some of these compounds have been found to possess various bioactivities including cytotoxicity, and antibacterial, antifungal, antifouling, plant-growth regulatory, and other activities.

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“…4) were unambiguously identified as a series of simple and re-arranged DKPs based on their molecular formulae as established by HRESIMS analysis, and comparison of their characteristic 1 H and 13 C NMR spectral data with their previously reported data. 8,[19][20][21][22] In the current study, although fumitremorgin C 4 and tryprostatin B 5 (Fig. 4) were obtained as an inseparable mixture, they were unambiguously identified using extensive 2D NMR spectral analysis as well as their HRESIMS quasimolecular ions observed at m/z 380.1969 [M+H] + and m/z 352.2020 [M+H] + for fumitremorgin C 4 and tryprostatin B 5, respectively.…”

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confidence: 99%

Antibacterial activity of diketopiperazines isolated from a marine fungus using t-butoxycarbonyl group as a simple tool for purification

Elgendy

Rateb

2015

Bioorganic & Medicinal Chemistry Letters

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Tryprostatins A and B, Novel Mammalian Cell Cycle Inhibitors Produced by Aspergdlus fumigatus .

Cited by 142 publications

References 6 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

Diketopiperazines from Marine Organisms

Antibacterial activity of diketopiperazines isolated from a marine fungus using t-butoxycarbonyl group as a simple tool for purification

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