Tyropeptins A and B, New Proteasome Inhibitors Produced by Kitasatospora sp. MK993-dF2. II. Structure Determination and Synthesis.

Momose, Isao; Sekizawa, Ryuichi; Hirosawa, Sehei; Ikeda, Daishiro; Naganawa, Hiroshi; Iinuma, Hisae; Takeuchi, Tomio

doi:10.7164/antibiotics.54.1004

Cited by 34 publications

(22 citation statements)

References 22 publications

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“…MK993-dF2. [7][8][9][10] In an effort to enhance its inhibitory potency, a structural model of tyropeptin A bound to the site responsible for chymotrypsin-like activity of the mammalian 20S proteasome was constructed. Based on these modeling experiments, several derivatives were synthesized.…”

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confidence: 99%

Increased ABCB1 Expression in TP-110-Resistant RPMI-8226 Cells

Iijima

Momose

Ikeda

2010

Bioscience, Biotechnology, and Biochemistry

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, a novel proteasome inhibitor, has been found to possess potent growth inhibition in human multiple myeloma cells. To enhance its therapeutic effects, we established TP-110-resistant RPMI-8226 (RPMI-8226/ TP-110) cells and elucidated their resistance mechanisms. The IC 50 value for TP-110 cytotoxicity in the RPMI-8226/TP-110 cells was about 10-fold higher than that of the parental sensitive cells. The RPMI-8226/TP-110 cells exhibited distinct drug resistance to other proteasome inhibitors. Furthermore, they showed high cross-resistance to the cytotoxic effects of doxorubicin, etoposide, taxol, and vincristine. P-glycoprotein (MDR1), encoded by ABCB1, was elevated in the RPMI-8226/TP-110 cells, and the MDR1 inhibitor verapamil overcame their resistance to TP-110. The results of DNA microarray and RT-PCR suggested that the expression of ABCB1 is significantly elevated in RPMI-8226/TP-110 cells. This indicates that resistance in RPMI-8226/TP-110 cells is involved in the expression of P-glycoprotein, a drug-efflux pump.

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confidence: 99%

Increased ABCB1 Expression in TP-110-Resistant RPMI-8226 Cells

Iijima

Momose

Ikeda

2010

Bioscience, Biotechnology, and Biochemistry

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“…Tyropeptin A derivatives modified at the N-terminal moiety of tyropeptin A were synthesized as shown in Scheme 1. The Boc group of 1 10) was removed with TFA, and the resulting free amine was coupled to a variety of acids (R-CH 2 COOH). Resulting 2 was hydrogenolyzed with palladium on charcoal to give 3.…”

Section: Resultsmentioning

confidence: 99%

“…We had previously synthesized tyropeptin A in order to determine the structures, 10) and various tyropeptin A derivatives were synthesized by a similar procedure. The synthetic routes to the tyropeptin A derivatives modified in the N-terminal group are shown in Schemes 1 and 2, while the preparation procedures for the O-methyl derivatives of tyropeptin A and TP-104 are illustrated in Schemes 3 and 4.…”

Section: Methodsmentioning

confidence: 99%

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Synthesis and Activity of Tyropeptin A Derivatives as Potent and Selective Inhibitors of Mammalian 20S Proteasome

Momose

Umezawa

Hirosawa

et al. 2005

Bioscience, Biotechnology, and Biochemistry

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Tyropeptin A, a potent proteasome inhibitor, was isolated from the culture broth of Kitasatospora sp. MK993-dF2. We synthesized the derivatives of tyropeptin A to enhance its inhibitory potency. Among the synthesized derivatives, the most potent compound, TP-104, exhibited a 20-fold inhibitory potency enhancement for chymotrypsin-like activity of 20S proteasome compared to tyropeptin A. Additionally, TP-110 specifically inhibited the chymotrypsin-like activity, but did not inhibit the post-glutamyl-peptide hydrolyzing (PGPH) and the trypsin-like activities of 20S proteasome. In vitro TP-110 strongly inhibited the growth of various cell lines.

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“…1). 10) Tyropeptin A inhibits chymotrypsin-like and trypsin-like activities of the proteasome in vitro. However, it is unclear whether tyropeptin A can permeate through cell membranes and inhibit the proteasome activity in intact cells.…”

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confidence: 99%