Type II combi-molecules: design and binary targeting properties of the novel triazolinium-containing molecules JDD36 and JDE05.
We recently designed molecules termed "type II combi-molecules" to block the epidermal growth factor receptor and to damage DNA without the requirement for hydrolytic cleavage. Here, we studied two such combi-molecules (JDD36 and JDE05), containing a novel quinazoline-linked chloroethyltriazolinium system. The epidermal growth factor receptor-targeting potential of these novel structures was studied by ELISA for isolated epidermal growth factor receptor and by Western blotting for whole-cell assays. DNA damage was analyzed using the single-cell microelectrophoresis comet assay. Antiproliferative effects were determined by the sulforhodamine B assay. JDD36 showed an IC50 of 0.6 micromol/l in the ELISA for epidermal growth factor receptor tyrosine kinase, a dose-dependent inhibition of epidermal growth factor receptor phosphorylation and significant levels of DNA damage in the human DU145 prostate cancer cell line. JDD36 was an overall 2- to 15-fold stronger antiproliferative agent than JDE05 that showed potent epidermal growth factor receptor inhibitory activity (IC50 epidermal growth factor receptor, 0.035 micromol/l) but weak DNA-damaging potential. In a panel of LNCaP erbB transfectants, in contrast to JDE05, JDD36 showed remarkable and selective potency against the LNCaPerbB2 transfectant. The results in toto suggest that the overall superior potency of JDD36 when compared with JDE05 may be imputed to its balanced binary epidermal growth factor receptor-DNA-targeting properties that may induce a tandem blockade of epidermal growth factor receptor-mediated mitogenic signaling while depleting alternative survival mechanism by damaging DNA.
Qiu
Qiyu
Q
Cancer Drug Research Laboratory, Department of Medicine, Division of Medical Oncology, McGill University Health Center/Royal Victoria Hospital, Montreal, Quebec, Canada.
Domarkas
Juozas
J
Banerjee
Ranjita
R
Katsoulas
Athanasia
A
McNamee
James P
JP
Jean-Claude
Bertrand J
BJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects; D016503:Drug Delivery Systems; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000187:drug effects; D018773:Genes, erbB-1 / Q000187:drug effects / Q000235:genetics; D018734:Genes, erbB-2 / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology
D000970:Antineoplastic Agents