Tanespimycin

17-AAG is a potent HSP90 inhibitor with an IC50 of 5 nM, having a 100-fold higher binding affinity for tumour cell derived HSP90 than normal cell derived HSP90.

(+) -Geldanamycin (5.1 mg, 9. 0 mol) was stirred with allylamine (10.0 ul, 0.13 mmol) in chloroform (1.5 ml) at room temperature. Upon the complete conversion of GA shown by thin layer chromatography (18 hours), the mixture was washed with brine, dried over anhydrous sodium sulfate, and concentrated. Separation by flash column chromatography on silica gel (hexane/ethyl acetate) gave the product as a purple solid (5.3 mg, 99percent). IR (KBr) (can~') 3464, 3333, 2958, 2929, 2825, 1728, 1691, 1652, 1571, 1485, 1372, 1323, 1189, 1101, 1057; UV (95percent EtOH) (nm) 332 (s = 2. 0 x 104) ;'H NMR (CDC13, 500 MHz) 8 9. 14 (s, 1H), 7.28 (s, 1H), 6.93 (bd, J= 11.5 Hz, 1H), 6.56 (bdd, J= 11. 5, 11. 0 Hz, 1H), 6.38 (bt, J= 6. 0 Hz, 1H), 5.94-5. 81 (m, 3H), 5.30-5. 24 (m, 2H), 5.17 (s, 1H), 4.82 (bs, 2H), 4.29 (bd, J= 10.0 Hz, 1H), 4.21 (bs, 1H), 4.18-4. 08 (m, 2H), 3.55 (ddd, J= 9.0, 6.5, 2.0 Hz, 1H), 3.43 (ddd, J= 9.0, 3.0, 3.0 Hz, 1H), 3. 34 (s, 3H), 3.25 (s, 3H), 2.72 (dqd, J= 9.5, 7.0, 2.0 Hz, 1H), 2.63 (d, J= 14.0 Hz, 1H), 2.34 (dd, J= 14. 0, 11. 0 Hz, 1H), 2.00 (bs, 3H), 1.78 (d, J= 1.0 Hz, 3H), 1.78-1. 74 (m, 2H), 1.74-1. 67 (m, 1H), 0.99-0. 95 (m, 6H) ; 3C NMR (CDC13, 125 MHz, assignment of protonated carbons aided by DEPT) 8 183.8 (18-C), 180.9 (21-C), 168.4 (1-C), 156.0 (7- OzCNHz), 144.6 (17-C), 141.2 (20-C), 135.8 (5-C), 134.9 (2-C), 133.7 (9-C), 132.7 (8-C), 132.5 (3'-C), 126.9 (4-C), 126.5 (3-C), 118.5 (3'-C), 108.8 (19-C), 108.7 (16-C), 81.6 (7-C), 81.4 (12-C), 81.2 (6-C), 72.6 (11-C), 57.1 (6-or 12-OCH3), 56.7 (6-or 12-OCH3), 47.8 (1'-C), 35.0 (13-C), 34.3 (15-C), 32.3 (10-C), 28.4 (14-C), 22.9 (14-CH3), 12.8 (8-CH3), 12.6 (2-CH3), 12.3 (10-CH3); HRMS (FAB) found 586.3120 [M+H] +, calcd. 586.3129 for C31H44N30g.17-AAG was synthesized in the lab from geldanamycin (GA) (LC Laboratories, Woburn, MA). Briefly, 100 mg of GA (0.2 mmol) was dissolved in 2 mL of dry CHTo 45.0 g (80.4 mmol) of geldanamycin in 1.45 L of dry THF in a dry 2 L flask was added drop-wise over 30 minutes 36.0 mL (470 mmol) of allyl amine in 50 mL of dry THF. The reaction mixture was stirred at room temperature under nitrogen for 4 hr at which time TLC analysis indicated the reaction was complete [(GDM: bright yellow: Rf=0.40; (5percent MeOH-95percent CHClTo 45.0 g (80.4 mmol) of geldanamycin in 1.45 L of dry THF in a dry 2 L flask was added drop-wise over 30 minutes 36.0 mL (470 mmol) of allyl amine in 50 mL of dry THF. The reaction mixture was stirred at room temperature under nitrogen for 4 hr at which time TLC analysis indicated the reaction was complete [(GDM: bright yellow: Rf=0.40; (5percent MeOH-95percent CHClTo 45.0 g (80.4 mmol) of geldanamycin in 1.45 L of dry THF in a dry 2 L flask was added drop-wise over 30 minutes, 36.0 mL (470 mmol) of allyl amine in 50 mL of dry THF. The reaction mixture was stirred at room temperature under nitrogen for 4 hr at which time TLC analysis indicated the reaction was complete [(GDM: bright yellow: Rf=0.40; (5percent MeOH-95percentCHCl3); 17-AAG: purple: Rf=0.42 (5percent MeOH-95percent CHCl3)]. The solvent was removed by rotary evaporation and the crude material was slurried in 420 mL of H2O:EtOH (90:10) at 25° C., filtered and dried at 45° C. for 8 hr to give 40.9 g (66.4 mmol) of 17 purple crystals (82.6percent yield, >98percent pure by HPLC monitored at 254 nm). MP 206-212° C. as determined using differential scanning colorimetry (DSC). 1H NMR and HPLC are consistent with the desired product.To a solution of geldanamycin (20.0 g, 35.7 mmol, 1 eq.) in DCM (750 mL) was added allylamine (53 mL, 714 mmol, 20 eq) at room temperature and under nitrogen atmosphere.

Geldanamycin is a potent inhibitor of Hsp90 that exhibits severe hepatotoxicity when used in vivo. 17-AAG is an analog of geldanamycin which has potent in vivo activity and reduced toxicity. Like other Hsp90 inhibitors, 17-AAG has diverse anti-tumor actions and has potential in treating certain types of cancer. 17-AAG inhibits the growth of prostate cancer cell lines (IC50 = 25-45 nM). 17-AAG promotes the degradation of HER2 and induces growth arrest and apoptosis in breast cancer cells overexpressing HER2 (IC50 = 4-72 nM).

Molecular Weight:585.7
XLogP3:2.6
Hydrogen Bond Donor Count:4
Hydrogen Bond Acceptor Count:9
Rotatable Bond Count:7
Exact Mass:585.30501534
Monoisotopic Mass:585.30501534
Topological Polar Surface Area:166
Heavy Atom Count:42
Complexity:1210
Defined Atom Stereocenter Count:6
Undefined Bond Stereocenter Count:3
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes