Comparative analysis of the dual EGFR-DNA targeting and growth inhibitory properties of 6-mono-alkylamino- and 6,6-dialkylaminoquinazoline-based type II combi-molecules.

Abstract

Over the past decade, we described a novel tumour targeted approach that sought to design "combi-molecules" to hit two distinct targets in tumour cells. Here, to generate small combi-molecules with strong DNA damaging potential while retaining EGFR inhibitory potency, we developed the first synthetic strategy to access the 6-N, N-disubstituted quinazoline scaffold and designed JS61 to possess a nitrogen mustard function directly attached to the 6-position of the quinazoline ring. We compared its biological activity with that of structures containing either a hemi mustard or a non-alkylating substituent. Surprisingly, the results showed that JS61, while capable of inducing strong DNA damage, exhibited moderate EGFR inhibitory potency. In contrast, "combi-molecules" with no bulky substituent at the N-6 position (e.g. ZR2002 and JS84) showed stronger EGFR and growth inhibitory potency than JS61 in a panel of lung cancer cells. To rationalize these results, X-ray crystallography and molecular modeling studies were undertaken, and the data obtained indicated that bulkiness of the 6-N,N-disubstituted moieties hinder its binding to the ATP site and affects binding reversibility.

• Authors: Julie Schmitt, Elliot Goodfellow, Shanlong Huang, Christopher Williams, Izabela N F Gomes, Marcela N Rosa, Rui M Reis, Richard Yang, Hatem M Titi, Bertrand J Jean-Claude
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 192 Pg. 112185 (Apr 15 2020) ISSN: 1768-3254 [Electronic] France
• PMID: 32145644 (Publication Type: Comparative Study, Journal Article)
• Copyright: Copyright © 2020. Published by Elsevier Masson SAS.

Chemical References

• Antineoplastic Agents
• Quinazolines
• DNA
• calf thymus DNA
• EGFR protein, human
• ErbB Receptors

Topics

• A549 Cells
• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cattle
• Cell Proliferation (drug effects)
• Crystallography, X-Ray
• DNA (drug effects)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Humans
• Models, Molecular
• Molecular Structure
• Quinazolines (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Tumor Cells, Cultured