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RP-1776, a novel cyclic peptide, was isolated from the culture broth of Streptomyces sp. KYI 1784. RP-1776 selectively inhibited the binding of PDGFBB to the extracellular domain of the PDGF /^receptor with an IC50 value of 11±6/im. Detailed binding experiments suggested that RP-1776 directly interacts with PDGF BB. RP-1776 inhibited the phosphorylation of the PDGFj3-receptor induced by PDGFBB. These results suggested that RP-1776 antagonizes the signaling of PDGFBB probably through the inhibition of PDGFBB binding to the PDGF^-receptor. Platelet-derived growth factor (PDGF) is a potent mitogen and chemotactic molecule for various cells, released from activated platelets. h2) PDGFis also expressed in embryonal tissues, and has neurotrophic activity for neuronal cells in rat brain, suggesting involvement of

Six structurally related antitumor antibiotics named GEX1 compounds were isolated from a culture broth of Streptomyces sp. GEX1A was identified as a known herbicide, herboxidiene, structurally interested by the tetrahydropyran moiety and the side chain including a conjugated diene. GEX1Q1-Q5 were determined as novel compounds related to herboxidiene. All GEX1 lines in vitro, but were not active against both Gram-positive and-negative bacteria. Though GEX1A/herboxidiene exhibited antitumor activity in murine tumor-planted mouse models, both GEX1Q3 and GEX1Q5 did not. In the course of a screening for new antitumor antibiotics, we isolated six structurally related compounds from a culture broth of Streptomyces sp. Among them, GEX1Q1, GEX1Q2, GEX1Q3, GEX1Q4 and GEX1Q5 are novel compounds. The major product, GEX1A was identified as a known herbicide, herboxidiene1). In this paper, the taxonomy of the producing strain, fermentation, isolation, and antitumor properties of GEX1 compounds are described. The structure determination of GEX1Q1-Q5 will be reported in elsewhere. Materials and Methods Microorganism The producing strain GEX1 compounds was isolated from a soil sample collected in Yamanashi prefecture, Japan. The strain has been deposited at the International

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MK and PTN are involved both in the inflammatory and reparative processes after partial hepatectomy, and as a whole are beneficial for liver regeneration.

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In the course of screening for inhibitors of the lymphocyte kinase, Lck (p56^fc), aiming at novel immunosuppressants, we isolated a novel alkaloid, lymphostin (LK6-A), from the culture broth of Streptomyces sp. KYI1783. Lymphostin was produced in a fermentation mediumsupplemented with a highly porous polymer resin, which prevented the degradation of this compound in the culture broth. Lymphostin inhibited the kinase activity of Lck with an IC50 value of 0.05jUM, and exhibited potent inhibitory activity against the mixed lymphocyte reaction (MLR) with an IC50 value of 0.009um.

RES-701-2, -3 and -4, novel cyclic peptide endothelin antagonists, were isolated from the culture broths of Streptomyces sp. RE-701 and RE-896. RES-70Is selectively inhibited the ET-1 binding to endothelin type B receptor (ETB receptor) with IC50 values ranging from 5 to 20nM. Taxonomyof the producing strains, fermentation, isolation and biochemical properties of RES-70I s are described. Endothelins(ETs), which consist of 21 amino acid residues, are a family of potent vasoactive peptides termed endothelin -1, -2, and -3 (ET-1, ET-2 and ET-3)1}. ETs induce numerous biological responses in both vascular and non-vascular tissues by binding to at least two distinct receptor subtypes, ETAand ETB. The ETA receptor shows a high affinity for ET-1 and mediates vasoconstriction, whereas the ETBreceptor is nonselective for isopeptides and mediates vasoconstriction as well as vasodilatation2'3).In the course of screening of endothelin antagonists, wehave recently isolated a novel cyclic peptide RES-701-1 from the fermentation broth of Streptomyces sp. RE-7014'5).RES-701-1 selectively inhibited ET-1 binding to ETB receptor and blocked ETB receptor-mediated responces6). In the present investigation, we have found that many strains of Streptomyces produce RES-701-1-related compounds and isolated three novel compounds, designated RES-701-2, RES-701-3 and RES-701-4 from the culture broths. In this paper, we describe taxonomy of the producing strains, fermentation, isolation and biological properties of RES-701-2, -3 and -4. Studies on structural determination are described in the succeeding paper. (3-[125I]iodotyrosyl13)Endothelin-l was purchased from Du Pont-New England Nuclear. Other radioligands used for binding assays were purchased from Du Pont-New England Nuclear and Amersham. Endothelin-1 (ET-1) was purchased Materials and Methods Materials