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Aminohexylgeldanamycin - CAS 485395-71-9 Catalog number: BADC-00834
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Aminohexylgeldanamycin, a derivative of Geldanamycin, is a potent HSP90 inhibitor with antiangiogenic and antitumor activities.
Category
ADCs Cytotoxin
Product Name
Aminohexylgeldanamycin
CAS
485395-71-9
Catalog Number
BADC-00834
Molecular Formula
C34H52N4O8
Molecular Weight
644.80
Target
Ordering Information
| Catalog Number | Size | Price | Quantity |
|---|---|---|---|
| BADC-00834 | -- | $-- |
Description
Aminohexylgeldanamycin, a derivative of Geldanamycin, is a potent HSP90 inhibitor with antiangiogenic and antitumor activities.
Synonyms
AHGDM; Geldanamycin, 17-[(6-aminohexyl)amino]-17-demethoxy-; 2-Azabicyclo[16.3.1]docosa-4,6,10,18,21-pentaene-3,20,22-trione, 9-[(aminocarbonyl)oxy]-19-[(6-aminohexyl)amino]-13-hydroxy-8,14-dimethoxy-4,10,12,16-tetramethyl-, (4E,6Z,8S,9S,10E,12S,13R,14S,16R)-
IUPAC Name
[(4E,6Z,8S,9S,10E,12S,13R,14S,16R)-19-(6-aminohexylamino)-13-hydroxy-8,14-dimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl] carbamate
Canonical SMILES
CC1CC(C(C(C=C(C(C(C=CC=C(C(=O)NC2=CC(=O)C(=C(C1)C2=O)NCCCCCCN)C)OC)OC(=O)N)C)C)O)OC
InChI
InChI=1S/C34H52N4O8/c1-20-16-24-29(37-15-10-8-7-9-14-35)26(39)19-25(31(24)41)38-33(42)21(2)12-11-13-27(44-5)32(46-34(36)43)23(4)18-22(3)30(40)28(17-20)45-6/h11-13,18-20,22,27-28,30,32,37,40H,7-10,14-17,35H2,1-6H3,(H2,36,43)(H,38,42)/b13-11-,21-12+,23-18+/t20-,22+,27+,28+,30-,32+/m1/s1
InChIKey
FEKZHEHNADINKB-OLLHKAICSA-N
Density
1.2±0.1 g/cm3
Solubility
Soluble in DMSO
Appearance
Solid
Purity
≥95%
Shelf Life
0-4℃ for short term (days to weeks), or -20℃ for long term (months).
Shipping
Room temperature, or blue ice upon request.
Storage
Store at -20°C, protect from light
Boiling Point
847.9±65.0°C at 760 mmHg
Form
Solid
1. HPMA copolymer-aminohexylgeldanamycin conjugates targeting cell surface expressed GRP78 in prostate cancer
Hamidreza Ghandehari, Daniel B Pike, Nate Larson, Alexander Malugin, Abhijit Ray Pharm Res . 2010 Dec;27(12):2683-93. doi: 10.1007/s11095-010-0267-7.
Purpose:This study focused on the synthesis and in vitro characterization of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates for the delivery of geldanamycin to prostate cancer tumors. Conjugates were modified to incorporate WIFPWIQL peptide, which binds to cell-surface-expressed Glucose-regulated protein 78.Methods:HPMA copolymers containing aminohexylgeldanamycin with and without WIFPWIQL peptide were synthesized and characterized, and stability in pH 7.4 and pH 5.0 buffers, complete cell culture medium, and fetal bovine serum was evaluated. The comparative cell surface expression of GRP78 in DU145 and PC3 cell lines was assessed and competitive binding to cell surface expressed GRP78 evaluated. The ability of the conjugates to inhibit cell growth was also evaluated in vitro.Results:HPMA copolymer-aminohexylgeldanamycin conjugates were stable with maximal release observed in fetal bovine serum at 37°C of approximately 10% in 72 h. HPMA copolymers bearing WIFPWIQL peptide bound to cell surface expressed GRP78 with affinities comparable to free WIFPWIQL peptide and demonstrated increased cytotoxicity as compared to untargeted conjugates.Conclusion:HPMA copolymer aminohexylgeldanamycin conjugates bearing WIFPWIQL peptide have the ability to bind to cell-surface-expressed GRP78 and inhibit the growth of human prostate cancer cells, suggesting that the conjugates have the potential to target solid prostate cancer tumors.
2. Synergistic enhancement of cancer therapy using a combination of heat shock protein targeted HPMA copolymer-drug conjugates and gold nanorod induced hyperthermia
Hamidreza Ghandehari, Nick Frazier, Adam Gormley, Nate Larson J Control Release . 2013 Aug 28;170(1):41-50. doi: 10.1016/j.jconrel.2013.04.006.
In the field of nanomedicine, selective delivery to cancer cells is a common goal, where active targeting strategies are often employed to increase tumor accumulation. In this study, tumor hyperthermia was utilized as a means to increase the active delivery of heat shock protein (HSP) targeted N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-drug conjugates. Following hyperthermia, induced expression of cell surface heat shock protein (HSP) glucose regulated protein 78 kDa (GRP78) was utilized for targeted drug therapy. Conjugates bearing the anticancer agents aminohexylgeldanamycin (AHGDM), docetaxel (DOC), or cisplatin and the GRP78 targeting peptide WDLAWMFRLPVG were synthesized and characterized. Binding to cell surface expressed heat shock protein GRP78 on the surface of human prostate cancer DU145 cells was evaluated. HSP targeted AHGDM and DOC conjugates demonstrated active binding comparable to native targeting peptide. They were then assessed in vitro for the ability to synergistically induce cytotoxicity in combination with moderate hyperthermia (43 °C, 30 min). HSP targeted DOC conjugates exhibited high potency against DU145 cells with an IC₅₀ of 2.4 nM. HSP targeted AHGDM and DOC conjugates demonstrated synergistic effects in combination with hyperthermia with combination index values of 0.65 and 0.45 respectively. Based on these results, HSP targeted DOC conjugates were selected for in vivo evaluation. In DU145 tumor bearing mice, a single treatment of tumor hyperthermia, induced via gold nanorod mediated plasmonic photothermal therapy, and intravenous administration of HSP targeted HPMA copolymer-docetaxel at 10mg/kg resulted in maintained tumor regression for a period of 30 days. These results demonstrate the potential for tumor hyperthermia to increase the delivery of HSP targeted macromolecular chemotherapeutics.
3. Biodistribution of HPMA copolymer-aminohexylgeldanamycin-RGDfK conjugates for prostate cancer drug delivery
Hamidreza Ghandehari, Sandra Geyser-Stoops, Mark P Borgman, Omer Aras, Edward A Sausville Mol Pharm . 2009 Nov-Dec;6(6):1836-47. doi: 10.1021/mp900134c.
N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer-RGD (Arg-Gly-Asp) conjugates targeting the alpha(v)beta(3) integrin present on angiogenic blood vessels and some tumor types have shown increased accumulation in solid tumors and possess properties that suggest their use for site-specific drug delivery. Geldanamycin (GDM) is a benzoquinoid ansamycin that binds to heat-shock protein 90 (HSP90), effective for the treatment of multiple cancer types including prostate, but has dose-limiting cytotoxicity. We recently reported the synthesis of HPMA copolymer-aminohexyl-geldanamycin (AH-GDM) conjugates containing RGDfK that demonstrated favorable properties of drug release, in vitro binding to the alpha(v)beta(3) integrin, cytotoxicity in human prostate cancer cells, and tolerability in nude mice greater than 2-fold equivalent free drug doses. In this study the biodistribution of 125I-radiolabeled HPMA copolymer-AH-GDM conjugates with and without RGDfK in both non-tumor-bearing and DU145 prostate tumor xenograft-bearing nude mice was evaluated. At 60 mg/kg drug equivalent polymer doses in non-tumor-bearing mice both conjugates showed fast elimination from blood and decreasing accumulation in all other organs. Kidney accumulation predominated and was higher for the conjugate containing RGDfK. In tumor-bearing mice, trace quantities of the conjugate containing RGDfK showed increased tumor accumulation as compared to the conjugate without RGDfK. Also evaluated were free drug concentrations in prostate tumor xenografts following treatments of 30 and 60 mg/kg drug-equivalent copolymer conjugates (with and without RGDfK) compared with 30 mg/kg free AH-GDM. Overall, 60 mg/kg treatment of RGDfK-containing conjugate showed significantly higher (p < 0.001) tumor drug concentrations compared with all other treatments. The targetable conjugates can effectively deliver higher amounts of geldanamycin to the tumor compared to nontargetable systems.
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