Novel antitumor agents CI-920,PD113,270 and PD113,271. II. Isolation and characterization.

Stampwala, S. S.; Bunge, R. H.; Hurley, Timothy R.; Willmer, N. E.; Brankiewicz, A. J.; Steinman, C. E.; Smitka, Tim A.; French, James C.

doi:10.7164/antibiotics.36.1601

Cited by 104 publications

(38 citation statements)

References 3 publications

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“…As additional controls for effects of PP2A, we evaluated fostriecin and inhibitor-2, other serine-threonine phosphatase inhibitors, on chemotaxis of CD34 ϩ cells. Fostriecin, an antitumor antibiotic, is a highly selective inhibitor of PP2A and inhibits PP2A at 10,000 -40,000 times lower concentrations than that required for inhibition of PP1 in vitro (36,37). Fostriecin, when used at 5 M, inhibited chemotaxis of CD34 ϩ cells toward SDF-1 to a level comparable to that observed with 100 nM OA.…”

Section: Effect Of Pp2a Inhibition On Chemotaxis Of Cd34 ϩ Cells Towamentioning

confidence: 94%

Protein Phosphatase 2A Plays an Important Role in Stromal Cell-Derived Factor-1/CXC Chemokine Ligand 12-Mediated Migration and Adhesion of CD34+ Cells

Basu

Ray

Atkinson

et al. 2007

The Journal of Immunology

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Migration of hemopoietic stem and progenitor cells (HSPC) is required for homing to bone marrow following transplantation. Therefore, it is critical to understand signals underlying directional movement of HSPC. Stromal cell-derived factor-1 (SDF-1)/CXCL12 is a potent chemoattractant for HSPC. In this study, we demonstrate that the serine-threonine protein phosphatase (PP)2A plays an important role in regulation of optimal level and duration of Akt/protein kinase B activation (a molecule important for efficient chemotaxis), in response to SDF-1. Inhibition of PP2A, using various pharmacological inhibitors of PP2A including okadaic acid (OA) as well as using genetic approaches including dominant-negative PP2A-catalytic subunit (PP2A-C) or PP2A-C small interfering RNA, in primary CD34+ cord blood (CB) cells led to reduced chemotaxis. This was associated with impairment in polarization and slower speed of movement in response to SDF-1. Concomitantly, SDF-1-induced Akt phosphorylation was robust and prolonged. Following SDF-1 stimulation, Akt and PP2A-C translocate to plasma membrane with enhanced association of PP2A-C with Akt observed at the plasma membrane. Inhibition of PI3K by low-dose LY294002 partially recovered chemotactic activity of cells pretreated with OA. In addition to chemotaxis, adhesion of CD34+ cells to fibronectin was impaired by OA pretreatment. Our study demonstrates PP2A plays an important role in chemotaxis and adhesion of CD34+ CB cells in response to SDF-1. CD34+ CB cells pretreated with OA showed impaired ability to repopulate NOD-SCID mice in vivo, suggesting physiological relevance of these observations.

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Section: Effect Of Pp2a Inhibition On Chemotaxis Of Cd34 ϩ Cells Towamentioning

confidence: 94%

Protein Phosphatase 2A Plays an Important Role in Stromal Cell-Derived Factor-1/CXC Chemokine Ligand 12-Mediated Migration and Adhesion of CD34+ Cells

Basu

Ray

Atkinson

et al. 2007

The Journal of Immunology

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“…The cytotoxic and antifungal agent 21–23 PD 113,271 ( 3 ) was isolated along with fostriecin ( 1 ) 1,2,18,160 and PD 113,270 ( 2 ). It also inhibits the enzyme topoisomerase II.…”

Section: Pd 113271mentioning

confidence: 99%

Synthetic Strategies Employed for the Construction of Fostriecin and Related Natural Products

2016

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Fostriecin and related natural products present a significant challenge for synthetic chemists due to their structural complexity and chemical sensitivity. This review will chronicle the successful efforts of synthetic chemists in the construction of these biologically active molecules. Key carbon–carbon bond forming reactions will be highlighted, as well as the methods used to install the numerous stereocenters present in this class of compounds.

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“…Fostriecin and the structurally related PD 113,270 and PD 113,271, are three related natural products produced by Streptomyces pulveraceus subsp. fostreus ATCC 31906 [41,45]. Their structures differ from PLMs mainly by the presence of a methyl group at the C-8 position in place of an aminoethyl moiety and a hydroxymethyltrienyl group instead of a cyclohexyldienyl group (Fig.…”

Section: Introductionmentioning

confidence: 99%

Genetic manipulation of the biosynthetic process leading to phoslactomycins, potent protein phosphatase 2A inhibitors

Ghatge

Palaniappan

Choudhuri

et al. 2006

J IND MICROBIOL BIOTECHNOL

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Phoslactomycins (PLMs) represent an unusual structural class of natural products secreted by various streptomycetes, containing an alpha,beta-unsaturated delta-lactone, an amino group, phosphate ester, conjugated diene and a cyclohexane ring. Phosphazomycins, phospholines and leustroducsins contain the same structural moieties, varying only in the acyl substituent at the C-18 hydroxyl position. These compounds possess either antifungal or antitumor activities or both. The antitumor activity of the PLM class of compounds has been attributed to a potent and selective inhibition of protein phosphatase 2A (PP2A). The cysteine-269 residue of PP2Ac-subunit has been shown to be the site of covalent modification by PLMs. In this article, we review previous work on the isolation, structure elucidation and biological activities of PLMs and related compounds and current status of our work on both PLM stability and genetic manipulation of the biosynthetic process. Our work has shown that PLM B is surprisingly stable in solution, with a pH optimum of 6. Preliminary biosynthetic studies utilizing isotopically labeled shikimic acid and cyclohexanecarboxylic acid (CHC) suggested PLM B to be a polyketide-type antibiotic synthesized using CHC as a starter unit. Using a gene (chcA) from a set of CHC-CoA biosynthesis genes from Streptomyces collinus as a probe, a 75 kb region of 29 ORFs encoding PLM biosynthesis was located in the genome of Streptomyces sp. strain HK803. Analysis and subsequent manipulation of plmS2 and plmR2 in the gene cluster has allowed for rational engineering of a strain that produces only one PLM analog, PLM B, at ninefold higher titers than the wild type strain. A strain producing PLM G (the penultimate intermediate in PLMs biosynthesis) has also been generated. Current work is aimed at selective in vitro acylation of PLM G with various carboxylic acids and a precursor-directed biosynthesis in a chcA deletion mutant with the aim of generating novel PLM analogs.

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Novel antitumor agents CI-920,PD113,270 and PD113,271. II. Isolation and characterization.

Cited by 104 publications

References 3 publications

Protein Phosphatase 2A Plays an Important Role in Stromal Cell-Derived Factor-1/CXC Chemokine Ligand 12-Mediated Migration and Adhesion of CD34+ Cells

Protein Phosphatase 2A Plays an Important Role in Stromal Cell-Derived Factor-1/CXC Chemokine Ligand 12-Mediated Migration and Adhesion of CD34+ Cells

Synthetic Strategies Employed for the Construction of Fostriecin and Related Natural Products

Genetic manipulation of the biosynthetic process leading to phoslactomycins, potent protein phosphatase 2A inhibitors

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