SYNTHESIS AND ACTIVITY OF PARTIAL RETRO-INVERSO ANALOGS OF THE ANTIMETASTATIC LAMININ-DERIVED PEPTIDE, YIGSR-NH2

This paper describes the synthesis and biological evaluation of six pa rtial retro-inverso peptidomimetic analogs of YIGSR-NH2, a synthetic p eptide from the beta 1 chain of laminin, which has antimetastatic acti vity. The intent was to improve the antimetastatic potency of YIGSR-NH 2 by limiting the in vivo enzymatic degradation through the incorporat ion of fraudulent peptide bonds. We have prepared the following retro- inverso peptides, Tyr-Ile-Gly-Ser-gArg-CHO (1), Tyr-gIle-mGly-Ser-Arg- NH2 (2), Tyr-gIle-mGly-Ser-gArg-CHO (3), gTyr-D-rIle-mGly-Ser-Arg-NH2 (4), Tyr-Ile-Gly-gSer-D-rArg-CHO (5) and Tyr-gIle-rGly-D-rSer-D-rArg-C HO (6). In vitro assays for B16F10 melanoma cell adhesion showed no si gnificant activity for these six peptides. Peptides 1-3, 5 and 6 were further tested, in vivo, for their ability to inhibit tumor metastases to the lung in mice injected in the tail vein with B16F10 melanoma ce lls. All five of the retro-inverso peptides tested showed statisticall y significant inhibition of metastasis, but the most active peptides w ere 5 and 6, which showed 57 and 69% inhibition of metastasis, respect ively. (C) Munksgaard 1997.