Unsymmetrical DNA cross-linking agents: combination of the CBI and PBD pharmacophores.
A set of 10 compounds, each combining the seco-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (seco-CBI) and pyrrolo[2,1-c][1,4]benzodiazepine (PBD) pharmacophores, was designed and prepared. These compounds were anticipated to cross-link between N3 of adenine and N2 of guanine in the minor groove of DNA. The compounds, which differ in the chain length separating the two alkylation subunits, and the configuration of the CBI portion, showed great variation in cellular toxicity (over 4 orders of magnitude in a cell line panel) with the most potent example exhibiting IC50s in the pM range. Cytotoxicity correlated with the ability of the compounds to cross-link naked DNA. Cross-linking was also observed in living cells, at much lower concentrations than for a related symmetrical PBD dimer. A thermal cleavage assay was used to assess sequence selectivity, demonstrating that the CBI portion controlled the alkylation sites, while the PBD substituent increased the overall efficiency of alkylation. Several compounds were tested for in vivo activity using a tumor growth delay assay against WiDr human colon carcinoma xenografts, with one compound (the most cytotoxic and most efficient cross-linker) showing a statistically significant increase in survival time following a single iv dose.
Tercel
Moana
M
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand. m.tercel@auckland.ac.nz
Stribbling
Stephen M
SM
Sheppard
Hilary
H
Siim
Bronwyn G
BG
Wu
Kent
K
Pullen
Susan M
SM
Botting
K Jane
KJ
Wilson
William R
WR
Denny
William A
WA
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001569:Benzodiazepines / Q000737:chemistry*; D001570:Benzodiazepinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020552:Comet Assay; D003432:Cross-Linking Reagents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003521:Cyclopropanes / Q000737:chemistry*; D004273:DNA, Neoplasm / Q000737:chemistry*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011758:Pyrroles / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
C474823:8-((6-(1-(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benzo(e)indol-3-yl)-6-oxohexyl)oxy)-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo(2,1-c)(1,4)benzodiazepin-5-one; D018906:Antineoplastic Agents, Alkylating; D001570:Benzodiazepinones; D003432:Cross-Linking Reagents; D003521:Cyclopropanes; D004273:DNA, Neoplasm; D007211:Indoles; D011758:Pyrroles; D001569:Benzodiazepines