title: Diastereomer-specific effects of double-stranded peptides conjugated with -L-Tyr-L-Phe- or -L-Tyr-D-Phe- residues on tyrosine phosphorylation and inhibition of src(ts)NRK, A431, MCF-7, and DU145 cell growth.
abstract: The interaction between growth inhibition and chirality, especially of diastereomers, has an important modifying effect on cancer cell proliferation. Previously, we have reported on the design, synthesis, and chemical properties of a series of novel, double-stranded peptides, (y-AA-x-AA)(2)-(CH(2))(12), with -y-AA-x-AA- and -z-AA-y-AA-x-AA- sequences conjugated to the spacer. Here, we extend those results by showing that (D-, L-) and (L-, D-) diastereomers are more potent inhibitors of tyrosine phosphorylation than (L-, L-). Although the replacement of the L-Phe-L-Phe sequence with L-Tyr-L-Phe produces a less active inhibitor, the double-stranded peptide conjugated with L-Tyr-D-Phe is more active than that conjugated with L-Tyr-L-Phe. In addition, we show that SDS-PAGE gel profiles of tyrosine phosphorylation following treatment with bis(y-Tyr-x-Phe)-N,N-dodecane-1,12-diamine appear very similar to profiles of tyrosine phosphorylation following treatment with an analog of the tyrosine kinase inhibitor, erbstatin. Moreover, the level of autophosphorylation of the epidermal growth factor receptor kinase domain (EGFRKD) treated with bis(L-Tyr-D-Phe)-N,N-dodecane-1,12-diamine was lower than that seen following treatment with bis(L-Phe-D-Phe)-N,N-dodecane-1,12-diamine. These data provide new insights for the control of cancer cell proliferation through drug designs which replace the less active -L-Phe-L-Phe- (and -D-Phe-L-Phe-) with the more active -L-Tyr-L-Phe- (and -L-Tyr-D-Phe-) sequence.
authors.affiliation: Division of Analytical Chemistry of Medicines, Showa Pharmaceutical University, Machida, Tokyo, Japan. kobayasi@ac.shoyaku.ac.jp
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Nahomi
authors.initials: N
authors.lastname: Atuchi
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Wakamatsu
authors.forename: Mayuko
authors.initials: M
authors.lastname: Hattori
authors.forename: Ayumi
authors.initials: A
authors.lastname: Kawada
authors.forename: Kouji
authors.initials: K
authors.lastname: Asano
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004591:Electrophoresis, Polyacrylamide Gel; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism; D014443:Tyrosine / Q000378:metabolism
chemical_list: D010455:Peptides; D014443:Tyrosine; D066246:ErbB Receptors