Linker Length Modulates DNA Cross-Linking Reactivity and Cytotoxic Potency of C8/CE' Ether-Linked C"-exo-Unsaturated Pyrrolo [2,1-c] [1,4]benzodiazepine (PBD) Dimers

Stephen J. Gregson, Philip W. Howard, Darren R. Gullick, Anzu Hamaguchi, Kathryn E. Corcoran, Natalie A. Brooks, John A. Hartley, Terence C. Jenkins, Sejal Patel, Matthew J. Guille, David E. Thurston

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Abstract

A C2/C2‘-exo-unsaturated pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimer 4b (DRG-16) with a C8−O(CH2)nO−C8‘ diether linkage (n = 5) has been synthesized that shows markedly superior in vitro cytotoxic potency (e.g., >3400-fold in IGROV1 ovarian cells) and interstrand DNA cross-linking reactivity (>10-fold) compared to the shorter homologue 4a (SJG-136; n = 3). In contrast, for the C-ring unsubstituted series, the corresponding n = 5 dimer (3c) is generally less cytotoxic and has a lower interstrand cross-linking reactivity compared to its shorter n = 3 homologue (3a). Dimer 4b cross-links DNA with >10-fold efficiency compared to 4a, and also inhibits the activity of the restriction endonuclease BamH1 more efficiently than either 3a or 4a. The C2-exo-unsaturated PBD dimers 4a,b are not only more effective than their C-ring saturated counterparts in terms of induced ΔTm shift, but they also exert this effect more rapidly. Thus, while 3a and 3c exert 68 and 35% of their maximum effect immediately upon interaction with DNA, this level increases to 76 and 97% for 4a and 4b, respectively. Molecular modeling shows a rank order of 4b (n = 5) > 4a (n = 3) > 3a (n = 3) > 3c (n = 5) in terms of binding energy toward duplexes containing embedded target 5‘-GAT1-2C cross-link sequences, reflecting the superior fit of the C2-exo-unsaturated rather than saturated C-rings of the PBD dimers. A novel synthesis of core synthetic building blocks for PBD dimers via stepwise Mitsunobu reaction and nitration with Cu(NO3)2 is also reported.
Original languageEnglish
Pages (from-to)1161-1174
Number of pages14
JournalJournal of Medicinal Chemistry
Volume47
Issue number5
DOIs
Publication statusPublished - 26 Feb 2004

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