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

Abstract

DNA binding 4-(1-methyl-1<i>H</i>-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-<i>c</i>]­[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, <b>7h</b> (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 <b>7h</b> may sterically inhibit interaction of the transcription factor NF-κB with its cognate DNA binding sequence