Synthesis of a novel hematopoietic peptide, SK&amp;F 107647

Alberts, Doreen; Agner, E; Silvestri, J.; Kwon, Chet; Newlander, Kenneth A.; King, Andrew G.; Pelus, Louis M.; DeMarsh, Peter; Frey, Carrie L.; Petteway, Stephen R.; Huffman, William F.; Bhatnagar, Pradip K.

doi:10.1007/978-94-011-0683-2_118

Cited by 3 publications

(3 citation statements)

References 5 publications

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“…We have shown that 1 and its analogues can induce colony-stimulating activity from stromal cells. In vivo , 1 increases the proliferative rate of CFU-GM cell cycle and modulates effector cell functions. − These properties make 1 and its analogues a remarkable class of compounds that act through host defense modulation. A greater understanding of their mechanism of action and required structural parameters for biological activity may allow us to design novel therapeutic agents.…”

Section: Discussionmentioning

confidence: 99%

“…22 The remaining diamino dicarboxylic acid derivatives were synthesized using methods developed by Scho ¨llkopf et al 23,29 To ensure that both carboxyl groups of the diamino dicarboxylate derivatives reacted, the general method of coupling was modified. 13 Only 0.5 mol equiv of the diamino dicarboxylic acid derivative and 1 mol equiv of the coupling agents were used, and the coupling was allowed to proceed for 48 h. If the coupling was not complete after 48 h, as monitored by qualitative ninhydrin analysis, 20 an additional 1 mol equiv of the coupling reagents was added and coupling was allowed to proceed for an additional 24 h.…”

Section: Chemistrymentioning

confidence: 99%

“…We considered that these difficulties might arise from the facile redox chemistry available to this peptide. To stabilize the oxidized peptide, we replaced the reducible disulfide bond with an isosteric ethylene spacer ) has potent hematoregulatory activity and has been demonstrated to be efficacious in several animal models of infectious diseases and bone marrow transplantation. − In vitro , SK&F 107647 ( 1) stimulates murine and human primary stromal cultures, as well as stromal cell lines to produce colony-stimulating activity (CSA)…”

Section: Introductionmentioning

confidence: 99%

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Structure−Activity Relationships of Novel Hematoregulatory Peptides

et al. 1996

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Hematopoiesis is a lifelong cell renewal process regulated by a family of lineage specific hematopoietic growth factors. Several hematopoietic growth factors such as G-CSF, GM-CSF, and M-CSF have been clinically evaluated for enhancement of host defense in normal and immunocompromised patients and for the treatment of infectious diseases. This paper reports the structure-activity relationships of low molecular weight hematoregulatory peptides based on a nonapeptide (1, SK&F 107647). Like the macromolecular growth factors, these peptides modulate host defense. A molecular target for this class of compounds has not yet been identified. However, the structure-activity relationships established by this study implicate a very specific molecular recognition event that is pivotal for the biological activities of 1 and its analogues.

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Section: Discussionmentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structure−Activity Relationships of Novel Hematoregulatory Peptides

et al. 1996

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Large‐scale synthesis of hematoregulatory nonapeptide SK&F 107647 by fragment coupling

Hiebl¹,

Dp²,

Af³

et al. 1999

The Journal of Peptide Research

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Linear and convergent routes for the large-scale preparation of the hematoregulatory nonapeptide (Glp-Glu-Asp)2-DAS-(Lys)2 (2, SK&F 107647) were investigated. A convergent approach ('3 + 2'-route employing Boc-and benzyl ester protecting groups) was selected for the preparation of multihundred-gram quantities of 2. Key steps were the preparation and the coupling of tripeptide hydrochloride (HCl.H)2-DAS-(Lys(Z)-OBn)2 (6, DAS-2,7-L,L-diaminosuberic acid) and tripeptide Glp-Glu(OBn)-Asp(OBn)-OH (26). Several coupling reagents were investigated in order to reduce the amount of epimerization of this fragment coupling. TDBTU [O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl-1,1,3,3-tetrameth yluronium tetrafluoroborate] was identified as the condensation reagent of choice. Using this synthetic route > 97% pure final product in an overall yield of 35% calculated on di-Boc protected 2,7-L,L-diaminosuberic acid was prepared.

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Treatment of Experimental Gram-Negative and Gram-Positive Bacterial Sepsis with the Hematoregulatory Peptide SK&F 107647

DeMarsh¹,

Wells²,

Lewandowski³

et al. 1996

The Journal of Infectious Diseases

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SK&F 107647, a novel synthetic low-molecular-weight peptide, has demonstrated potent antiinfective activities in murine models of fungal and viral infection. To determine if the hematoregulatory activities of SK&F 107647 could offer protection over conventional antibiotic therapy or as a single agent in animal models of bacterial sepsis, rats were implanted intraperitoneally with a live bacteria-containing fibrin-thrombin clot. Rats pretreated subcutaneously or orally with SK&F 107647 and then infected with either a gram-negative (Escherichia coli) or a gram-positive (Staphylococcus aureus) bacteria-containing clot demonstrated significantly improved survival over control formulation-treated animals. Treated animals showed increased effector cell activation, measured by CD11b expression on neutrophils and monocytes, and up to 1000-fold reduction in the number of E. coli recovered from blood. Thus, the hematoregulatory activities of SK&F 107647 can increase natural host resistance to infections caused by both gram-negative and gram-positive bacteria.

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Synthesis of a novel hematopoietic peptide, SK&F 107647

Cited by 3 publications

References 5 publications

Structure−Activity Relationships of Novel Hematoregulatory Peptides

Structure−Activity Relationships of Novel Hematoregulatory Peptides

Large‐scale synthesis of hematoregulatory nonapeptide SK&F 107647 by fragment coupling

Treatment of Experimental Gram-Negative and Gram-Positive Bacterial Sepsis with the Hematoregulatory Peptide SK&F 107647

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