GC-Targeted
C8-Linked Pyrrolobenzodiazepine–Biaryl
Conjugates with Femtomolar in Vitro Cytotoxicity and in Vivo Antitumor
Activity in Mouse Models
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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
IC<sub>50</sub> 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