Novel microbial metabolites of the phoslactomycins family induce production of colony-stimulating factors by bone marrow stromal cells. I. Taxonomy, fermentation and biological properties.

Abstract

Three metabolites were isolated from the culture broth of an actinomycete strain identified as Streptomycesplatensis SANK601 91 , that induce the production of colony-stimulating factors (CSFs) by stromal cell line KM-102at ED50concentrations from 40 to 200 ng/ml. The compounds induced quantities of granulocyte CSF (G-CSF) and granulocyte-macrophage CSF (GM-CSF) comparable to those induced by interleukin-1 , a strong CSFinducer. These metabolites were called leustroducsins (A, B and C) and were later found to be structurally related to phoslactomycins. This is the first report of CSFinducing activity by members of the phoslactomycin class. 1503Recent studies have demonstrated the application of colony-stimulating factors (CSFs) in clinical use1}. These substances have been used to recover the peripheral blood leukocytes in leukopenia patients caused by cancer-chemotherapy, radiotherapy and bone marrowtransplantation. WhenCSFs were administered to patients, restorations ofleukocyte counts occurred. However,the in vivo role ofendogenous CSFs is not precisely understood. In particular, little is known about the regulatory mechanism for CSF production or about the relationship between normal blood cell production and endogenous CSFs. It is well knownthat bone marrow stromal cells play an important role in hematopoiesis. Regulation of CSF production by bone marrow stromal cells may be one of the key elements responsible for the control of hematopoiesis in vivo2). Therefore, substances that affect the regulation of CSF production by stromal cells are of potential interest, so we worked to develop screening methods for CSF inducers.In the previous paper3), we described the development of a new screening method for CSF inducers using human bone marrow stromal cell line KM-102. Using this screening method, one strain of actinomycetes, Streptomyces platensis SANK60191, was found to produce novel microbial metabolites that we provisionally namedleustroducsins. Structure determination studies revealed that they are congeners of phoslactomycins. In this paper we report the taxonomy of the producing organism, and also describe the fermentation and biological properties of leustroducsins (LSNs), A, B and C (Fig. 1). The isolation, physicochemical properties and structural elucidation of the metabolites are reported in the accompanying paper4).

Enhancement and Selective Production of Phoslactomycin B, a Protein Phosphatase IIa Inhibitor, through Identification and Engineering of the Corresponding Biosynthetic Gene Cluster

“…Incorporation of [7][8][9][10][11][12][13] C]CHC into PLMs- [7][8][9][10][11][12][13] C]CHC was synthesized from cyclohexanone and K 13 CN via cyclohexanecarbonitrile as described previously (25, 26 The labeled CHC (10 mg) was dissolved in EtOH (1 ml) and added directly to each of 10 flasks containing 70 ml of production medium at 30 h after inoculation. LC-MS analyses (see "Experimental Procedures") of the resulting PLMs allowed an estimation of the level of incorporation of [7- C and [7-13 C]CHC to be separated in the standard manner.…”

“…LC-MS analyses (see "Experimental Procedures") of the resulting PLMs allowed an estimation of the level of incorporation of [7- C and [7-13 C]CHC to be separated in the standard manner. The amount of each 13 C-labeled PLM derived from [7][8][9][10][11][12][13] C]CHC was determined as a percentage of that entire analog pool. The location of the 13 C label was confirmed by 13 C NMR analyses of HPLC purified PLM-B, -E, and -F (see "Experimental Procedures") using previously published 13 C assignments (10).…”

Good Timing in Total Synthesis: The Case of Phoslactomycin A

“…[5] Fostriecin was the first compound of this class of isolated natural products [6] and therefore most intensively studied. [7] Cytostatin [8] and sultriecin [9] have a similar structure and biological profile.…”

Application of a Newly Identified and Characterized 18- O -Acyltransferase in Chemoenzymatic Synthesis of Selected Natural and Nonnatural Bioactive Derivatives of Phoslactomycins

“…1) (6). These compounds (also known as leustroducsins [LSNs], phospholines, and phosphazomycins) have been isolated from various actinomycetes, and their structures are all identical with the exception of the acyl substituent at C-18 (4,5,12,13,20,27,28). Streptomyces sp.…”