title: Substance P analogs containing alpha,alpha-dialkylated amino acids with potent anticancer activity.
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.
authors.affiliation: Dabur Research Foundation, 22 Site IV, Sahibabad, Ghaziabad 201010, India. drsudhanand@yahoo.co.in
authors.forename: Sudhanand
authors.initials: S
authors.lastname: Prasad
authors.forename: Archna
authors.initials: A
authors.lastname: Mathur
authors.forename: Manu
authors.initials: M
authors.lastname: Jaggi
authors.forename: Anu T
authors.initials: AT
authors.lastname: Singh
authors.forename: Rama
authors.initials: R
authors.lastname: Mukherjee
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D016503:Drug Delivery Systems; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013373:Substance P / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010455:Peptides; D013373:Substance P