GC-Targeted C8-Linked Pyrrolobenzodiazepine鈥揃iaryl Conjugates with Femtomolar in Vitro Cytotoxicity and in Vivo Antitumor Activity in Mouse Models

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• 作者：Khondaker M. Rahman ; Paul J. M. Jackson ; Colin H. James ; B. Piku Basu ; John A. Hartley ; Maria de la Fuente ; Andreas Schatzlein ; Mathew Robson ; R. Barbara Pedley ; Chris Pepper ; Keith R. Fox ; Philip W. Howard ; David E. Thurston
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：April 11, 2013
• 年：2013
• 卷：56
• 期：7
• 页码：2911-2935
• 全文大小：966K
• 年卷期：v.56,no.7(April 11, 2013)
• ISSN：1520-4804

文摘

DNA binding 4-(1-methyl-1H-pyrrol-3-yl)benzenamine (MPB) building blocks have been developed that span two DNA base pairs with a strong preference for GC-rich DNA. They have been conjugated to a pyrrolo[2,1-c][1,4]benzodiazepine (PBD) molecule to produce C8-linked PBD鈥揗PB hybrids that can stabilize GC-rich DNA by up to 13-fold compared to AT-rich DNA. Some have subpicomolar IC₅₀ values in human tumor cell lines and in primary chronic lymphocytic leukemia cells, while being up to 6 orders less cytotoxic in the non-tumor cell line WI38, suggesting that key DNA sequences may be relevant targets in these ultrasensitive cancer cell lines. One conjugate, 7h (KMR-28-39), which has femtomolar activity in the breast cancer cell line MDA-MB-231, has significant dose-dependent antitumor activity in MDA-MB-231 (breast) and MIA PaCa-2 (pancreatic) human tumor xenograft mouse models with insignificant toxicity at therapeutic doses. Preliminary studies suggest that 7h may sterically inhibit interaction of the transcription factor NF-魏B with its cognate DNA binding sequence.