Amino acid/spermine conjugates: Polyamine amides as potent spermidine uptake inhibitors

被引：49

作者：

Burns, MR ^{[1
]}

Carlson, CL ^{[1
]}

Vanderwerf, SM ^{[1
]}

Ziemer, JR ^{[1
]}

Weeks, RS ^{[1
]}

Cai, F ^{[1
]}

Webb, HK ^{[1
]}

Graminski, GF ^{[1
]}

机构：

[1] Oridigm Corp, Seattle, WA 98103 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2001年 / 44卷 / 22期

关键词：

D O I：

10.1021/jm0101040

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

In this paper we describe the synthesis and characterization of a series of simple spermine/amino acid conjugates, some of which potently inhibit the uptake of spermidine into MDAMB-231 breast cancer cells. The presence of an amide in the functionalized polyamine appeared to add to the affinity for the polyamine transporter. The extensive biological characterization of an especially potent analogue from this series, the Lys-Spm conjugate (31), showed this molecule will be an extremely useful tool for use in polyamine research. It was shown that the use of 31 in combination with DFMO led to a cytostatic growth inhibition of a variety of cancer cells, even when used in the presence of an extracellular source of transportable spermidine. It was furthermore shown that this combination effectively reduced the cellular levels of putrescine and spermidine while not affecting the levels of spermine. These facts together with the nontoxic nature of 31 make it a novel lead for further anticancer development.

引用

页码：3632 / 3644

页数：13

共 61 条

[1] INTRACELLULAR PUTRESCINE AND SPERMIDINE DEPRIVATION INDUCES INCREASED UPTAKE OF THE NATURAL POLYAMINES AND METHYLGLYOXAL BIS(GUANYLHYDRAZONE) [J].