Phanstiel O, Kaur N, Delcros J-G
Department of Chemistry, University of Central Florida, Orlando, FL 32816-2366, USA.
Amino Acids. 2007 Aug;33(2):305-13. doi: 10.1007/s00726-007-0527-y. Epub 2007 Apr 6.
A series of polyamine conjugates were synthesized and evaluated for their ability to target the polyamine transporter (PAT) in two Chinese hamster ovary (CHO) cell lines (PAT-active CHO and PAT-inactive CHOMG). This systematic study identified salient features of the polyamine architecture required to target and enter cells via the PAT. Indeed, the separation of charges, the degree of N-alkylation, and the spacer unit connecting the N(1)-terminus to the appended cytotoxic component (anthracene) were found to be key contributors to optimal delivery via the PAT. Using the CHO screen, the homospermidine motif (e.g., 4,4-triamine) was identified as a polyamine vector, which could enable the selective import of large N(1)-substituents (i.e., naphthylmethyl, anthracenylmethyl and pyrenylmethyl), which were cytotoxic to cells. The cell selectivity of this approach was demonstrated in B-16 murine melanoma cells and normal melanocytes (Mel-A). Three polyamine areas (recognition and transport, vesicle sequestration and polyamine-target interactions) were identified for future research.
合成了一系列多胺缀合物，并评估了它们靶向两种中国仓鼠卵巢（CHO）细胞系（具有多胺转运蛋白活性的CHO和无多胺转运蛋白活性的CHOMG）中多胺转运蛋白（PAT）的能力。这项系统性研究确定了通过PAT靶向并进入细胞所需的多胺结构的显著特征。确实，电荷分离、N-烷基化程度以及连接N(1)端与附加细胞毒性成分（蒽）的间隔单元被发现是通过PAT实现最佳递送的关键因素。利用CHO筛选，高亚精胺基序（例如，4,4-三胺）被鉴定为一种多胺载体，它能够实现对细胞具有细胞毒性的大的N(1)-取代基（即萘甲基、蒽甲基和芘甲基）的选择性导入。这种方法的细胞选择性在B-16小鼠黑色素瘤细胞和正常黑素细胞（Mel-A）中得到了证实。确定了三个多胺研究领域（识别与转运、囊泡隔离和多胺-靶点相互作用）以供未来研究。
