Substance P analogs containing α,α‐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.

The Role of Neurokinin-1 Receptor in the Microenvironment of Inflammation and Cancer

“…These results suggest that the in vivo activity of NK-1 and NK-2 antagonists may be a result of a cytostatic effect rather than a cytotoxic effect [173, 182]. Moreover, it has been reported that SP antagonists exert an antitumor action in a xenograft model of a human primary colon tumor cell line [183]. These findings are consistent with previous evidences showing that the inhibition of TAC1 expression by small interfering RNA in breast cancer cells shows a lack of tumorigenic phenotype and an inhibition of bone marrow metastasis in nude mice [39], while overexpression of NK-1 receptor leads to a transforming phenotype [184].…”

New aspects concerning ulcerative colitis and colonic carcinoma: Analysis of levels of neuropeptides, neurotrophins, and TNFalpha/TNFreceptor in plasma and mucosa in parallel with histological evaluation of the intestine

“…49 SP analogs have been found to cause tumor regression in a xenograft model of human primary colon tumor cell line. 50 For the treatment of locally advanced colorectal cancer, it is discussed that treatment with TNF␣ in combination with other treatments may be beneficial. 51 With the exception of BDNF, we found significant differences or tendencies for differences between the groups showing that the levels of the analyzed substances in plasma for UC patients were higher than those for the colonic carcinoma patients.…”

Update 1 of: Over One Hundred Peptide-Activated G Protein-Coupled Receptors Recognize Ligands with Turn Structure

“…Decreased affinity is associated with loss of hydrogen bond interactions due to a conformational change . Analogues that include α-helix or β-turn constraints in substance P, such as Aib or Acp (1-amino cyclopentane carboxylic acid), have shown potent anticancer activity . Structures of nonmammalian tachykinins such as eledoisin 109 , kassinin 110 , uperolein 111 , or phyllomedusin 112 show helical turns in SDS or DPC micelles …”

“…578 Analogues that include R-helix or β-turn constraints in substance P, such as Aib or Acp (1-amino cyclopentane carboxylic acid), have shown potent anticancer activity. 579 Structures of nonmammalian tachykinins such as eledoisin 109, kassinin 110, uperolein 111, or phyllomedusin 112 show helical turns in SDS or DPC micelles. [580][581][582][583] Turns have been stabilized in various cyclic analogues of substance P, such as 113, that are highly selective for NK-1 over NK-2 receptors.…”