Design, synthesis and biological evaluation of quinazoline–phosphoramidate mustard conjugates as anticancer drugs

Study of the cytotoxic and genotoxic potential of the carbonyl ruthenium(II) compound, ct‐[RuCl(CO)(dppb)(bipy)]PF6 [dppb = 1,4‐bis(diphenylphosphino)butane and bipy = 2,2′‐bipyridine], by in vitro and in vivo assays

“…Today, the main problem of the administration of anticancer drugs is their toxicity, which causes severe side effects by damaging healthy cells along the chemotherapeutic process (Caley & Jones, ; Husseinia et al, ; Novak, Büchel, Keppler, & Jakupec, ). Classical anticancer drugs inhibit cell replication and transcription through the direct or indirect interaction with DNA, and induce mutagenic, cytotoxic, genotoxic and carcinogenic effects (Chen, Chang, & Cheng, ; Fonseca et al, ; Lin et al, ). For example the platinum‐based drugs such as cisplatin and other square‐planar platinum analogs (carboplatin and oxaliplatin), which, despite their success as chemotherapeutics, cause renal failure and nephrotoxicity, peripheral neuropathy, hepatic toxicity, myelotoxicity, gastrointestinal toxicity, ototoxicity, hematological toxicity and drug resistance (Bergamo et al, ; Brock et al, ; Gatti, Cassinelli, Zaffaroni, Lanzi, & Perego, ; Grozav et al, ; Keppler, Berger, & Heim, ; Mengoli, Parmeggiani, Mengoli, Grinzi, & Tolomelli, ; Muggia, ; Quasthoff & Hartung, ).…”

“…Today, the main problem of the administration of anticancer drugs is their toxicity, which causes severe side effects by damaging healthy cells along the chemotherapeutic process (Caley & Jones, 2012;Husseinia et al, 2013;Novak, Büchel, Keppler, & Jakupec, 2016). Classical anticancer drugs inhibit cell replication and transcription through the direct or indirect interaction with DNA, and induce mutagenic, cytotoxic, genotoxic and carcinogenic effects (Chen, Chang, & Cheng, 2017;Fonseca et al, 2017;Lin et al, 2017).…”

3D-QSAR, molecular docking, and dynamics simulation of quinazoline–phosphoramidate mustard conjugates as EGFR inhibitor

“…17 compounds of quinazoline-phosphoramidate mustard conjugates were selected based on the literature study (Lin et al, 2017). Based on a random selection, the compounds were grouped into a training set (13 compounds) and a test set (four compounds) (Table 1) by considering structural diversity and distribution of biological data.…”

“…The third-generation EGFR inhibitors such as rociletinib and avitinib (Walter et al, 2013) were developed; however, it was reported that the hyperglycemia was observed in NSCLC patients who used Rociletinib (Chen et al, 2018;Yver, 2016). Lin et al (2017) designed and synthesized a series of phosphoramide mustard functionality, which was incorporated into the quinazoline scaffold, and their potential as EGFR inhibitors for the treatment of lung cancer was investigated. It was found that the designed compound could inhibit EGFR with IC 50 at the nanomolar range and showed no acute toxicity to mice at a single dose up to 900 mg/kg.…”

Drug discovery and computational strategies in the multitarget drugs era

“…Among these drugs, another term is "cocktail therapy," which is based on the combination of several drugs in clinical practice, in which these various drugs can act on several targets and may have synergistic effects in treatment. However, these effects may be hindered by disadvantages, which involve the pharmacokinetics of these compounds, the various side effects that each drug can cause, and the possible interactions between the drugs administered (Lin et al, 2017;Li et al, 2016).…”