Synthesis, DNA interactions and biological activity of DNA minor groove targeted polybenzamide-linked nitrogen mustards.
A series of polybenzamide DNA minor groove binding ligands bearing either one or two monofunctional mustards have been synthesised, and their cytotoxicities and interactions with DNA have been studied. Analogues with two alkylating functions (e.g. compounds 7 and 14) are the most cytotoxic, with 7 being 1000-fold more potent than the clinical mustard chlorambucil against P388 leukemia in culture, as well as being more potent in vivo. Monofunctional analogues were also significantly more cytotoxic than chlorambucil, despite bearing much less reactive mustard species. These results support the concept that targeting nitrogen mustard alkylating agents to DNA by attachment to DNA-affinic carriers can greatly enhance cytotoxicity due to alkylation, and that even for such DNA-targeted mustards, crosslinking is a more toxic event than monoalkylation. Close analogues of 7 differing only in their radius of curvature, appear to alkylate and crosslink DNA in similar fashion, yet have widely differing cytotoxicities. The most cytotoxic compound (7) possesses a geometry most complementary to that of duplex DNA, suggesting that the most toxic lesions are those which result in least DNA distortion, thus being less easily recognised by DNA repair systems.
Atwell
G J
GJ
Cancer Research Laboratory, School of Medicine, University of Auckland, New Zealand.
Yaghi
B M
BM
Turner
P R
PR
Boyd
M
M
O'Connor
C J
CJ
Ferguson
L R
LR
Baguley
B C
BC
Denny
W A
WA
D000478:Alkylation; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry / Q000494:pharmacology*; D001483:Base Sequence; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006868:Hydrolysis; D007700:Kinetics; D007941:Leukemia P388 / Q000188:drug therapy; D008024:Ligands; D008466:Mechlorethamine / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship
D018906:Antineoplastic Agents, Alkylating; D001549:Benzamides; D008024:Ligands; D008466:Mechlorethamine; C037689:benzamide; D004247:DNA