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

The tetrapeptide IV-Acetyl-Ser-Asp-Lys-Pro (AcSDKP), an inhibitor of hacmatopoletic stem cell proliferation, reduces in vivo and in vitro the damage to 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 prepared a set of analogues of AcSDKP. These compounds are derived from the parent peptide by substitution or modification of the N- or of the C-terminus, or substitution of side chains. We report here that almost all investigated analogues retain the antiproliferative activity reducing in vitro the proportion of murine Colony-Forming Units Granulocyte/Macrophage (CFU-GM) in S-phase and inhibiting the entry into cycle of High Proliferative potential Colony-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 retaining antiproliferative activity and devoid of toxicity. The efficacy of AeSDKP analogues in preventing in vitro the primitive haematopoietic cells front entering into cycle makes these molecules new candidates for further in vivo investigations. Copyright (C) 2001 European Peptide Society and John Wiley & Sons, Ltd.