Purnell Bethany, Sato Atsushi, O'kelley Amanda, Price Carly, Summerville Kaitlin, Hudson Stephen, O'hare Caroline, Kiakos Konstantinos, Asao Tetsuji, Lee Moses, Hartley John A
Department of Chemistry, Furman University, 3300 Pointsett Highway, Greenville, SC 29613, USA.
Bioorg Med Chem Lett. 2006 Nov 1;16(21):5677-81. doi: 10.1016/j.bmcl.2006.08.005. Epub 2006 Aug 21.
The design and synthesis of three novel bisalkylating agents derived from the achiral seco-duocarmycin or CC-1065 analogs and pyrrolobenzodiazepines (PBDs) are described: achiral seco-CBI (cyclopropanebenz[e]indoline)-PBD 11, achiral seco-CI-PBD 12, and achiral seco-CBI dimer 13. Compounds 11 and 12 demonstrated enhanced cytotoxicity over the monomer counterparts against the growth of P815 murine mastocytoma cells in culture. Conjugate 11 was found to covalently react with adenine-N3 positions within the minor groove at AT-rich sequences and to produce DNA interstrand crosslinks. Both compounds were found to induce apoptosis in P815 cells. Due to its poor water solubility, dimer 13 did not give any appreciable DNA binding or cytotoxicity.
本文描述了三种新型双烷基化剂的设计与合成，这些双烷基化剂衍生自非手性的开环多卡霉素或CC-1065类似物与吡咯并苯并二氮杂卓（PBDs）：非手性开环CBI（环丙烷并苯[e]吲哚）-PBD 11、非手性开环CI-PBD 12和非手性开环CBI二聚体13。化合物11和12在体外培养中对P815小鼠肥大细胞瘤细胞的生长显示出比单体对应物更强的细胞毒性。共轭物11被发现可与富含AT序列的小沟内的腺嘌呤-N3位置发生共价反应，并产生DNA链间交联。两种化合物都被发现可诱导P815细胞凋亡。由于其水溶性差，二聚体13未表现出任何明显的DNA结合或细胞毒性。
