| Identification | Back Directory | [Name]
Wortmannin-Rapamycin Conjugate | [CAS]
1067892-47-0 | [Synonyms]
ATASUAOFUAOSAN-NVEIXTJJSA-N
Wortmannin-Rapamycin Conjugate
Rapamycin, 42-[8-[(1E,4S,4aR,5R,6aS,7S,9aR)-5-(acetyloxy)-1-[[[3-(dimethylamino)propyl]methylamino]methylene]-1,2,4,4a,5,6,6a,7,8,9,9a,10-dodecahydro-11-hydroxy-4-(methoxymethyl)-4a,6a-dimethyl-2,10-dioxocyclopenta[5,6]naphtho[1,2-c]pyran-7-yl] octanedioate] | [Molecular Formula]
C88H131N3O23 | [MOL File]
1067892-47-0.mol | [Molecular Weight]
1598.99 |
| Hazard Information | Back Directory | [Description]
Phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) act synergistically in promoting cancer. Wortmannin is a potent inhibitor of PI3K enzymes, while rapamycin blocks mTOR Complex 1 TORC1. Wortmannin-rapamycin conjugate consists of analogs of 17-hydroxy wortmannin and rapamycin conjugated via a prodrug linker. Hydrolysis of the prodrug linker in vivo releases the inhibitors. The wortmannin-rapamycin conjugate inhibits the growth of HT-29 colon tumors and A498 renal tumors in mice better than rapamycin alone. Also, the conjugate, when given in combination with the VEGF-blocker bevacizumab, produces substantial regression of larger A498 tumors. Finally, the wortmannin-rapamycin conjugate is tolerated better than an equivalent mixture of the inhibitors. | [Uses]
Wortmannin-Rapamycin Conjugate 1 (compound 7c) is a furan ring-opened derivative of wortmannin-rapamycin conjugate with potent antitumor activities and a fine water solubility. Wortmannin-Rapamycin Conjugate 1 can inhibit the AKT phosphorylation in the tumor and can be used for cancer research[1]. | [in vivo]
Wortmannin-Rapamycin Conjugate 1 (3,5 mg/kg, i.v., weekly for 13 d) exerts significant antitumor activity on U87MG mouse xenogrgaft model[1].
Wortmannin-Rapamycin Conjugate 1 (15 mg/kg, i.v., 2 h) significantly inhibits the AKT phosphorylation in the tumor of U87MG mouse xenogrgaft model[1].
Wortmannin-Rapamycin Conjugate 1 (15 mg/kg, i.v., weekly for 20 d ) completely inhibits the growth of HT29 colon tumor, a non-sensitive colon tumor model to rapamycin or wortmannin analogues in tumor-bearing mice[1].
Wortmannin-Rapamycin Conjugate 1 (30 mg/kg, i.v., weekly for 38 d ) exerts a substantial regression of larger A498 tumors with 200 μg Bevacizumab (HY-P9906) in A498 tumor-bearing mice[1].
| Animal Model: | HT29 bearing nude mice[1] | | Dosage: | 15 mg/kg, weekly for 20 d | | Administration: | Intravenous injection (i.v.) | | Result: | Showed no significant growth in tumor volume while an equivalent physical mixture of the Rapamycin and Wortmannin derivative was poorly tolerated. |
| [References]
[1] Ayral-Kaloustian S, et al. Hybrid inhibitors of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR): design, synthesis, and superior antitumor activity of novel wortmannin-rapamycin conjugates. J Med Chem. 2010 Jan 14;53(1):452-9. DOI:10.1021/jm901427g |
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BOC Sciences
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