Structure−Activity Relationships of Novel Hematoregulatory Peptides

Abstract

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.

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

“…The ready availability of 2 with Boc and benzyl ester protecting group strategy on solid phase (11) was the basis for the decision to synthesize the first 100 g batch by linear route‐OBn (see Fig. 2) in homogeneous solution.…”

“…(c) Phosphonium salt PyClop (entry 11) gave a very small yield and the formamidinium salts PyClU (entry 12) and PiPClU (entry 13) produced no detectable amounts of the desired product.…”

“…The most critical step in the SPS was the coupling of the N‐protected 2,7‐diaminosuberic acid with lysine. Acceptable yields were achieved by use of prolonged coupling times and repeated cycles (11). While this route was satisfactory for the preparation of small quantities of a variety of analogues required for the elucidation of structure–activity relationships (11), the identification of 2 as a candidate for clinical trials necessitated the synthesis of larger amounts.…”

The Crystal Structure of N,N′-Bis-(1,3-dihydroxy-2-methylprop-2-yl)- pyrazine-2,3-dicarboxamide Semihydrate

“…Of particular interest to the pharmaceuti cal industry are low molecular weight hematoregu latory agents, which offer the same benefits as the larger protein drugs but also have added advantages such as stability and oral bioavailability. During a structure-activity relationship study [3] on a novel hematoregulatory nonapeptide (1, (Pyr-Glu-Asp)2-DAS-(Lys)2) compound 2 comprising pyrazine-2,3-dicarboxylic acid linked to two D-serine residues via amide bonds was discovered [4], This much simplified structure was found to be a highly po tent inducer of a hematopoietic synergistic fac tor (HSF) known to enhance colony formation in a GM-CFC colony forming assay [5]. Direct re placement of the D-Ser residues with 2-amino-2-methyl-1,3-propanediol and 2-amino-2-methyl-1,3-propanediol led to the achiral semi-peptide ana logues 3 and 4 with full biological activity.…”

The Crystal Structure of Dimethyl (2Z, 6Z)-2,7-bis-(benzyloxycarbonylamino) octa-2,6-diendioate: A Useful Precursor for Optically Pure 2,7-Diaminosuberic Acid

“…It has been used as replacement for cys tine in the peptide hormone oxytocin [1 ] and in an analogue of somatostatin [2], The resulting dicarba analogues of these peptides show high biological activity and enhanced metabolic and chemical sta bility owing to the absence of reducible disulfide linkages. Very recently it was found [3] that SK&F 107647 [(Pyr-Glu-Asp)2-DAS-(Lys)2], a nonapeptide containing 2,7-L,L-diaminosuberic acid with hematoregulatory activity, has antiviral and antibac terial activity.…”