Diastereomeric selective effects of double-stranded peptides conjugated with -Phe-Phe- residue for growth inhibition and permeability of Ca(2+) on A431, src(ts)NRK, and A549 cells proliferation.
Our aim in this study is to elucidate the correlations between inhibition and chirality, especially, diastereomer, against cell proliferation of double-stranded peptides. In previous studies, we reported on the design, synthesis, and chemical properties on a series of novel double-stranded peptides, (y-AA-x-AA)(2)-spacer(S) (AA=amino acid, S=spacer, symbols x and y represent L- or D-forms, and (y-, x-) as represent of the symbol) conjugated with -y-AA-x-AA- and -z-AA-y-AA-x-AA- sequences to a spacer of carbon number n. The inhibition of A431 and src(ts)NRK cells growth by four diastereomers of the N(1),N(12)-bis(y-Phe-x-Phe)dodecanediamines (n=12) increased in the following order: (L-, L-)<(D-, D-)<(L-, D-)<(D-, L-). A similar trend was seen in the order for the activity of (y-AA-x-AA)(2)-spacer(S) with a spacer of carbon number n=2, 3, 4, 5, 6, and 12 against the cell growth inhibition. To understand the mechanism of diasteromer selective cell growth inhibition, the correlations between chirality and cell growth inhibition were investigated from the measurement of the changes in cytosolic Ca(2+) concentration (=[Ca(2+)](c)) of A431 cells. Although less active N(1),N(12)-bis(L-Phe-L-Phe)dodecanediamine increases cytosolic [Ca(2+)](c), more active diasteromers, N(1),N(12)-bis(L-Phe-D-Phe)dodecanediamine and N(1),N(12)-bis(D-Phe-L-Phe)dodecanediamine, decrease cytosolic [Ca(2+)](c) in A431 cell. This study provides diastereomeric effected new insights - this controls the polarity of double-stranded peptides - into the control of tumor cell proliferation and design of the uptake by penetration through the cell membrane of drugs.
Kobayashi
Shigeki
S
Department of Analytical Chemistry of Medicines, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan. kobayasi@ac.shoyaku.ac.jp
Wakamatsu
Hidetaka
H
Atuchi
Nahomi
N
Miyajima
Rie
R
Kawada
Ayumi
A
Hattori
Mayuko
M
D002118:Calcium / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism
D010455:Peptides; D002118:Calcium