Synthesis and biological evaluation of analogues of the tetrapeptide N-Acetyl-Ser-Asp-Lys-Pro (AcSDKP), an inhibitor of primitive haematopoietic cellproliferation

The tetrapeptide IV-Acetyl-Ser-Asp-Lys-Pro (AcSDKP), an inhibitor of hacmat opoletic stem cell proliferation, reduces in vivo and in vitro the damage t o the stein cell compartment resulting from treatment with chemotherapeutic agents or ionizing radiations. In order to provide new molecules likely to improve the myeloprotection displayed by this tetrapeptide, we have prepar ed a set of analogues of AcSDKP. These compounds are derived from the paren t peptide by substitution or modification of the N- or of the C-terminus, o r substitution of side chains. We report here that almost all investigated analogues retain the antiproliferative activity reducing in vitro the propo rtion of murine Colony-Forming Units Granulocyte/Macrophage (CFU-GM) in S-p hase and inhibiting the entry into cycle of High Proliferative potential Co lony-Forming Cells (HPP-CFC). This shows that the polar groups of Ser, Asp or Lys are critical for the expression of biological activity, but that the modification of the N- or C-terminus mostly yielded compounds still retain ing antiproliferative activity and devoid of toxicity. The efficacy of AeSD KP analogues in preventing in vitro the primitive haematopoietic cells fron t entering into cycle makes these molecules new candidates for further in v ivo investigations. Copyright (C) 2001 European Peptide Society and John Wi ley & Sons, Ltd.