The structures of the novel protein kinase C inhibitors K-252a, b, c and d.

Yasuzawa, Tohru; Iida, Takao; Yoshida, Mayumi; Hirayama, Noriaki; Takahashi, Mitsuru; Shirahata, Kunikatsu; Sano, Hiroshi

doi:10.7164/antibiotics.39.1072

Cited by 126 publications

(90 citation statements)

References 7 publications

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“…D-[U- 13 C] Glucose was directly incorporated into the sugar moiety and indirectly incorporated in aglycon of 2, whereas L-[indole-2- 13 C] tryptophan was directly incorporated in aglycon of 2 to give 13 C labeled indocarbazostatin B, 8 and 9, respectively in these feeding experiments using this mutant. The final assignment of 13 C NMR of indocarbazostatin B in DMSO-d 6 shown in Table 2 …”

Section: The Proposal Biosynthetic Pathway Of Indocarbazostatins In Smentioning

confidence: 99%

“…The new mutant showed high specificity in the productivity of 2 as a major metabolite that is easy to separate. In this paper, we report the precise selection procedure of the producer of indocarbazostatins, identification of K-252c (5) and K-252d (6) [6] in a broth of a mutant producer, control of metabolite production by adding tryptophan, incorporation of putative precursors, D-[U- 13 C 6 ] glucose and L-[indole-2-13 C] tryptophan into 2 using a new mutant strain, Streptomyces sp. MUV-7-8 ( Fig.…”

Section: Introductionmentioning

confidence: 99%

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Biosynthesis of Indocarbazostatin B, Incorporation of D-[U-13C] Glucose and L-[2-13C] Tryptophan

et al. 2005

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High incorporation of D-[U-13 C] glucose and L-[indole-2- 13 C] tryptophan into indocarbazostatin B (2) was observed in a biosynthetic study using a mutant strain, Streptomyces sp. MUV-7-8. The original strain, Streptomyces sp. TA-0403 produced a small amount of indocarbazostatin (1) and indocarbazostatin B (2), which displayed potent biological activities. To facilitate biosynthetic studies, we selected high indocarbazostatin producing mutant strains. The first mutants, Streptomyces sp. MUV-6-83 and MUV-6-17, produced indocarbazostatins C (3) and D (4) as well as 1 and 2. When the production medium was supplemented with D-tryptophan, the MUV-6-17 mutant produced K252c (5), whereas when L-tryptophan was added, it produced K252d (6). On further UV treatment of the mutant strain MUV-6-83, we finally obtained a new mutant producer, Streptomyces sp. MUV-7-8, that produced 2 as a major metabolite with higher productivity. This mutant producer enabled us to do a feeding experiment of the envisioned precursors, glucose and tryptophan.

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Section: The Proposal Biosynthetic Pathway Of Indocarbazostatins In Smentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Biosynthesis of Indocarbazostatin B, Incorporation of D-[U-13C] Glucose and L-[2-13C] Tryptophan

et al. 2005

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“…[16][17][18][19] We show that this is also true for STAT-phosphorylating kinases: K-252a did not evoke STAT …”

Section: Figurementioning

confidence: 92%

“…[16][17][18][19] Both effectors inhibited cytokine-induced growth of M-07e cells as well as cytokine-induced STAT phosphorylation (Figure 4; only IL-3 data shown). The AG-490 results suggest a role for the JAK/STAT pathway in the regulation of TPO-and IL-3-induced growth.…”

Section: Ag-490 and K-252a Inhibit Cytokine-induced Stat Phosphorylationmentioning

confidence: 99%

Effects of thrombopoietin, interleukin-3 and the kinase inhibitor K-252a on growth and polyploidization of the megakaryocytic cell line M-07e

1998

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“…K252b is a member of the K-252a family of naturally occurring indolocarbazole metabolites isolated from the culture broth of Nocardia species (Kase et al, 1986;Yasuzawa et al, 1986).…”

mentioning

confidence: 99%

K‐252b Potentiation of Neurotrophin‐3 Is trkA Specific in Cells Lacking p75^NTR

Maroney¹,

Sanders²,

Neff³

et al. 1997

Journal of Neurochemistry

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K-252b potentiatesthe neurotrophic effects of neurotrophin-3 (NT-3) in primary cultures of rat central cholinergic and peripheral sensory neurons and in a rat pheochromocytoma P012 cell line. The ligand and receptor specificity, and role of the low-affinity neurotrophin receptor (p75NTR) in the potentiation response induced by K-252b, are unknown. To address the issues of ligand and receptor specificity of K-252b potentiation, we have examined neurotrophin-induced DNA synthesis ([ 3H]-thymidine incorporation) in NIH3T3 cells expressing trkA, trkB, or trkC. Neither NT-3 nor K-252b alone could stimulate mitogenic activity in the trkA-overexpressing clone. However, coaddition of K-252b (E0 50 of~-2 nM) with 10-1 00 ng/ml NT-3 led to incorporation of[ 3H]thymidine in trkA expressing cells to a level induced by optimal concentrations of nerve growth factor (NGF). The K252b-and NT-3-induced [3H]thymidineincorporation correlated with an increase in the tyrosine autophosphorylation of the trkA receptor as well as tyrosine phosphorylation of trk-associated phospholipase C-yl and SH2-containing proteins. K-252b did not potentiate submaximal doses of NGF, or maximal doses of brain-derived neurotrophic factor (BDNF) or neurotrophin-4/5 (NT-41 5) in trkA-expressing cells. Furthermore, K-252b did not potentiate DNA synthesis by submaximal doses of BDNF, NT-4/5, or NT-3 in trkB-or trkC-expressing NIH3T3 cells, suggesting that the potentiation profile for K-252b was specific for NT-3 in trkA-expressing cells. We found no expression of p75 NTR in the trk-expressing NIH3T3 cells. This is the first demonstration that K-252b potentiates a trkA-mediated biological nonneuronal response by NT-3 that occurs independent of p75 NTR and appears to be both ligand and receptor specific. Key Words: K-252b-Potentiation-trk-p75 low-affinity nerve growth factor receptor.

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The structures of the novel protein kinase C inhibitors K-252a, b, c and d.

Cited by 126 publications

References 7 publications

Biosynthesis of Indocarbazostatin B, Incorporation of D-[U-13C] Glucose and L-[2-13C] Tryptophan

Biosynthesis of Indocarbazostatin B, Incorporation of D-[U-13C] Glucose and L-[2-13C] Tryptophan

Effects of thrombopoietin, interleukin-3 and the kinase inhibitor K-252a on growth and polyploidization of the megakaryocytic cell line M-07e

K‐252b Potentiation of Neurotrophin‐3 Is trkA Specific in Cells Lacking p75^NTR

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The structures of the novel protein kinase C inhibitors K-252a, b, c and d.

Cited by 126 publications

References 7 publications

Biosynthesis of Indocarbazostatin B, Incorporation of D-[U-13C] Glucose and L-[2-13C] Tryptophan

Biosynthesis of Indocarbazostatin B, Incorporation of D-[U-13C] Glucose and L-[2-13C] Tryptophan

Effects of thrombopoietin, interleukin-3 and the kinase inhibitor K-252a on growth and polyploidization of the megakaryocytic cell line M-07e

K‐252b Potentiation of Neurotrophin‐3 Is trkA Specific in Cells Lacking p75NTR

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K‐252b Potentiation of Neurotrophin‐3 Is trkA Specific in Cells Lacking p75^NTR