Abstract
Six analogs (peptides 1–6) of the potent substance P (SP) derivative known as ‘Antagonist D’ were synthesized by substituting constrained amino acids Aib or Acp (cycloleucine, 1‐amino cyclopentane carboxylic acid) at different positions in the Antagonist D sequence: D‐Arg^1^‐Pro^2^‐Lys^3^‐Pro^4^‐D‐Phe^5^‐Gln^6^‐D‐Trp^7^‐Phe^8^‐D‐Trp^9^‐Leu^10^‐Leu^11^‐NH~2~. In the preliminary in vitro antiproliferative screening of the analogs on different human cancer cell lines by 3–(4,5–dimethylthiazol–2–yl)–2,5–diphenyltetrazolium bromide (MTT) assay, peptide 1 was found to be the most active. Further, peptide 1 was butanoylated (analog 5) or octanoylated (analog 6) at the N‐terminus. SP analogs 1, 5, and 6 were evaluated in vivo in a xenograft model of human primary colon tumor (PTC) cell line in athymic nude mice and were found to cause tumor regression. This study investigates if the use of the constrained amino acids Aib and Acp in the designed SP analogs can retain the in vitro and in vivo anticancer activities, which could be useful in cancer therapy and drug targeting. Further, the strategy of incorporation of Aib or Acp in biologically active peptides can be exploited in determining the receptor‐bound conformation and in transforming these bioactive peptides into pharmacologically useful drugs. Copyright © 2007 European Peptide Society and John Wiley & Sons, Ltd.