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

Research output: Contribution to journalArticle

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

Original languageEnglish
Pages (from-to)2911-2935
Number of pages25
JournalJournal of Medicinal Chemistry
Volume56
Issue number7
Early online date21 Mar 2013
DOIs
E-pub ahead of print21 Mar 2013
Published11 Apr 2013

King's Authors

Abstract

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–MPB 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-κB with its cognate DNA binding sequence.

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