抄録
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 srctsNRK cells growth by four diastereomers of the N1,N12-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 Ca2+ concentration (=[Ca2+]c) of A431 cells. Although less active N1,N12-bis(L-Phe–L-Phe)dodecanediamine increases cytosolic [Ca2+]c, more active diasteromers, N1,N12-bis(L-Phe–D-Phe)dodecanediamine and N1,N12-bis(D-Phe–L-Phe)dodecanediamine, decrease cytosolic [Ca2+]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.
