Characterization of the potency of epidermal growth factor (EGFR)-DNA targeting combi-molecules containing a hydrolabile carbamate at the 3-position of the triazene chain.
Previous strategies for stabilizing combi-triazenes were based on masking the 1,2,3-triazene chain with a 3-acetoxymethylene group. The half-lives of the latter molecules were only ca 5 min longer than those of their parent 1,2,3-triazenes. The novel combi-molecules described herein contain a hydrolysable carbamate group that modulates their kinetics of degradation. Their half-lives were prolonged by ca 20-55 min when compared with their acetoxymethyltriazene counterparts. While they decomposed slowly in serum-containing medium, their intracellular decomposition was extremely rapid. They blocked EGFR tyrosine kinase in an isolated enzyme assay and in MDA-MB-468 breast cancer cells. Similarly, they all induced a dose-dependent DNA damage and G2/M cell cycle arrest in MDA-MB-468 cells, except the most stable compound ZRL2 (a 3-vinyl carbamate). ZRL4 (a chloromethyl carbamate) was the most potent and ZRL2 was the least active of the series against MDA-MB-468 cells. In selectivity assay with NIH-3T3 and NIH-3T3/HER-14, all compounds selectively blocked proliferation of NIH-3T3/HER-14. ZRS1 exerted the strongest growth inhibitory potency of the series. The results in toto suggest that ZRL2, despite being the most stable compound, could not hydrolyze at a rate that permitted the generation of DNA damaging species, thereby behaving primarily as an EGFR inhibitor. Thus the study permitted the definition of an optimized combi-molecule as one that decomposes at a rate that is slower than that of acetoxymethyltriazenes, but rapid enough to generate strong EGFR-DNA targeting potential and growth inhibition. Based on the latter criteria, ZRS1 and ZRL4 were tested in vivo and ZRS1 has proven the more effective.
MacPhee
Meaghan
M
Cancer Drug Research Laboratory, Department of Medicine, Division of Medical Oncology, McGill University Health Center/Royal Victoria Hospital, Montreal, Quebec, Canada.
Rachid
Zakaria
Z
Todorova
Margarita
M
Qiu
Qiyu
Q
Belinsky
Gina
G
Jean-Claude
Bertrand J
BJ
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002219:Carbamates / Q000737:chemistry* / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D057075:Enzyme Assays; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D051379:Mice; D008856:Microscopy, Fluorescence; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D014226:Triazenes / Q000737:chemistry* / Q000494:pharmacology*
D000970:Antineoplastic Agents; D002219:Carbamates; D004273:DNA, Neoplasm; D047428:Protein Kinase Inhibitors; D014226:Triazenes; D004815:Epidermal Growth Factor; D066246:ErbB Receptors