Hydrophilic camptothecin analogs that form extremely stable cleavable complexes with DNA and topoisomerase I.
Hydrophilic camptothecin analogs that form extremely stable cleavable complexes with DNA and topoisomerase I.
复制标题
亲水性喜树碱类似物，与 DNA 和拓扑异构酶 I 形成极其稳定的可裂解复合物。
DOI：
10.1158/0008-5472.can-04-1885
复制
发表时间：
2004
期刊：
影响因子：
--
通讯作者：
VonHoff,DanielD
中科院分区：
文献类型：
--
作者：
Wadkins,RandyM;Bearss,David;Manikumar,Govindarajan;Wani,MansukhlalC;Wall,MonroeE;VonHoff,DanielD
Camptothecin (CPT) analogs that form more stable ternary complexes with DNA and topoisomerase I (termed cleavable complexes) show greater activity in their ability to inhibit tumor cell line growth in preclinical studies. Based on our earlier work, we hypothesized that analogs bearing hydrogen bonding moieties at the 7- through 10-position of CPT would result in more stable cleavable complexes. Consequently, we synthesized analogs with 7-mono-, 7-di-, and 7-trihydroxymethylaminomethyl groups. These analogs showed increasing cleavable complex stability as the number of hydroxyl groups was increased. The 7-trihydroxymethylaminomethyl analog of 10,11-methylenedioxycamptothecin (THMAM-MD) showed remarkable ternary complex stability with a half-life of 116 minutes. This is an order of magnitude more stable than any previously examined analog. Ourin vitroanalysis demonstrated that these analogs were all potent topoisomerase I poisons and could inhibit tumor cell growth in culture. We studied the effects of THMAM-MDin vivoin severe combined immunodeficient mice bearing HT-29 colon cancer and MiaPaCa-2 pancreatic cancer tumors. The THMAM-MD analog showed excellent, persisting activity in inhibiting tumor growth with both lines. Taken together, our results suggest that CPTs with hydrophilic, hydrogen-bonding groups at the 7-position hold the promise of excellent clinical activity.
