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

Design and Synthesis of a Trifunctional Molecular System “Programmed” to Block Epidermal Growth Factor Receptor Tyrosine Kinase, Induce High Levels of DNA Damage, and Inhibit the DNA Repair Enzyme (Poly(ADP-ribose) Polymerase) in Prostate Cancer Cells

“…The DNA-based reactivity of JS230 was assessed in vitro using a direct chemical reaction with 2′-deoxyguanosine (dG) under physiological conditions according to a protocol by Haapala et al (see the Supporting Information, Figure S20). DNA damaging agents like busulfan and nitrogen mustards are known to react mainly with the N 7 position of guanine in DNA. , As depicted in Figure , hydrolytic product 4 was detected in the reaction mixture, as previously described . Although an aziridinium ion formation cannot be monitored, we surmise that compound 4 results from the hydrolysis of the latter intermediate I 1 –I 2 , as previously reported for nitrogen mustards .…”

“…20,21 As depicted in Figure 3, hydrolytic product 4 was detected in the reaction mixture, as previously described. 22 Although an aziridinium ion formation cannot be monitored, we surmise that compound 4 results from the hydrolysis of the latter intermediate I 1 −I 2 , as previously reported for nitrogen mustards. 23 By contrast, the clinical alkylating drug busulfan is known to alkylate DNA through direct nucleophilic substitution (S N 2).…”

Anticancer activity of pyrimidodiazepines based on 2-chloro-4-anilinoquinazoline: synthesis, DNA binding and molecular docking

“…Halogenated bond formation is also observed by the 2-chlorine atom of the quinazoline 16c for both the interaction with EGFR and DNA, which could induce an additive or synergistic effect in antiproliferative activity. 52 Further, the interaction of 16a into VEGFR-2 receptor, presents the same tendency of hydrogen bond formation but in smaller number in comparison to 16c-DNA.…”

Molecular Analysis of the Superior Efficacy of a Dual Epidermal Growth Factor Receptor (EGFR)-DNA-Targeting Combi-Molecule in Comparison with Its Putative Prodrugs 6-Mono-Alkylamino- and 6,6-Dialkylaminoquinazoline in a Human Osteosarcoma Xenograft Model

“…We demonstrated that this strategy culminated into strong levels of apoptosis in tumor cells [ 9 , 10 , 11 , 12 , 13 ]. The studies on the designs of the combi-molecules led to their classification into two types: Type I combi-molecules [ 2 , 3 , 4 , 5 , 6 , 8 , 9 , 10 , 11 , 12 ] require hydrolysis to generate DNA-alkylating species, whereas type II combi-molecules [ 13 , 14 , 15 , 16 , 17 , 18 ] are chimeric systems capable of eliciting dual biological activity without a requirement for metabolic activation. In vitro, the most potent type II combi-molecules reported by our laboratory are mustard conjugates directly attached to the quinazoline ring [ 13 , 14 , 19 ].…”