Fig. 1

Chemical synthesis of alendronate conjugates of CGS21680 (3, 8a–8c) and the control alendronate functionalized congeners containing PEG (10a,b). Synthesis of PEGylated alendronic acid conjugates of A2A agonist CGS21680 (3, 8a,b,c) and its control compounds, PEGylated alendronic acids (10a,b). Reagents and conditions: (a) DMF, NHS, DIPEA, EDC.HCl, rt, 18h; (b) DIPEA, alendronic acid, H2O, rt, 18h, 6–22%; (c) DIPEA, NH2-PEG6-COOtBu, rt, 18h, 34%; (d) 1M HCl, 65 °C, 1h, 67%; (e) 30% TFA in DCM, 1h; quantitative (f) DIPEA, NH2-PEGn-COOH, H2O, rt, 18h, 50–62%; (g) (i) DMF, HATU, rt, 45min; (ii) DMF, DIPEA, NH2-PEG6-COOH.TFA, rt, 2h, 70–78%; (h) (i) DMF, HATU, rt, 45min; (ii) DMF, A [TBA]3, DIPEA, rt, 3h, 45–62%; (i) THF, DIPEA, (Boc)2O, rt, 18h, 73%