Chapter I. Synthesis, modification and bioactivity of bicyclic thieno[3,2-D]pyrimidines

1.1.19Two series of thienopyrimidine derives
There are two reaction system (A and B). Two series of thienopyrimidine derivatives (A, B) bearing chromone moiety were designed and synthesized. All the compounds were evaluated for inhibitory activity against mTOR kinase at a concentration of 10uM. Four selected compounds were further evaluated for the IC50 values against mTOR kinase, PI3Ka kinase and two cancer cell lines. Some of the target compounds exhibited moderate to excellent mTOR/PI3Ka kinase inhibitory activity and cytotoxicity Structureeactivity relationships (SARs) and docking studies indicated that the chromone moiety is necessary for the potent antitumor activity and cytotoxicity of these compounds. Substitution of the chromone moiety at the 6-position has a significant impact to the inhibitory activity, in particular a carboxylic acid group, produced the best potency[40-42].


Synthetic routes of target compounds A and B. Reagents and conditions: (a) 5 eq urea, 180 C, 2 h; (b) POCl3, DMF (cat.), reflux, 8 h; (c) 2.1 eq morpholine, MeOH, 0C, 30 min, r.t., 1-2 h; (d) 80% NH2NH2*H2O,reflux, 8-10 h; (e) EtOH, reflux, 2-4h.
The preparation of target compounds A and B is described in Schemes 1 and 2. The structures and the predicted values of target compounds are shown inTable 1. The substituted 4-oxo-4H-chromene-3-carbaldehydes 4a-k were synthesized through the procedures reported previously by our group. The synthesis of compounds 10a-k was similar to the procedures previously reported. The key intermediate 9 condensed with substituted 4-oxo-4H-chromene-3-carbaldehydes 4a-k to afford target compounds10aek, respectively. Compounds 16a-j were synthesized from methyl 2-aminothiophene-3-carboxylate 11 through five steps. The commercially available methyl 2-aminothiophene-3-carboxylate 11 was condensed with urea at 180C for 2 h to give thienopyrimidinedione 12. Chlorination of 12 with POCl3and DMF (cat.) for 8 h at 115 C afforded 13 as yellow solid. Substitution reaction of 13 with morpholine at room temperature to yielded 14 which was then condensed with 4a-j to furnish compounds 16a-j, respectively[43-45].
In summary, two series of thieno-pyrimidine derivatives bearing chromone moieties were designed, synthesized and evaluated for inhibitory activity against mTOR kinase, PI3Kakinase and cytotoxicity of two cancer cell lines in vitro. The pharmacological results indicated that most of the synthesized compounds displayed more mTOR inhibition than compounds reported in previous articles and two compounds (16h-i) inhibited mTOR at lower doses and were more cytotoxic than lead compoundI. And three compounds also displayed moderate to excellent PI3Kakinase inhibition activity with IC50values from 1.805mM to 2.352mM. The initial SARs and docking studies showed that the chromone moieties were necessary for the activity of these compounds. Variations in substitutions of the chromone moieties had a significant impact on the activity. Substitutions of chromone moiety at the 6-position have a significant impact to the inhibitory activity, in particular a carboxylic acid group, produced the best potency[46-48].