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Aminohexylgeldanamycin Sale

(Synonyms: AHGDM) 目录号 : GC61563

Aminohexylgeldanamycin(AHGDM),Geldanamycin的衍生物,是一种热休克蛋白90(HSP90)抑制剂。Aminohexylgeldanamycin具有抗血管生成和抗肿瘤活性。

Aminohexylgeldanamycin Chemical Structure

Cas No.:485395-71-9

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5 mg
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产品描述

Aminohexylgeldanamycin (AHGDM), a Geldanamycin derivative, is a potent HSP90 inhibitor. Aminohexylgeldanamycin shows antiangiogenic and antitumor activities[1].

HPMA copolymer-aminohexylgeldanamycin conjugates target cell surface expressed GRP78 in prostate cancer[2].

[1]. Greish K, et al. Anticancer and antiangiogenic activity of HPMA copolymer-aminohexylgeldanamycin-RGDfK conjugates for prostate cancer therapy. J Control Release. 2011;151(3):263-270. [2]. Larson N, et al. HPMA copolymer-aminohexylgeldanamycin conjugates targeting cell surface expressed GRP78 in prostate cancer. Pharm Res. 2010;27(12):2683-2693.

Chemical Properties

Cas No. 485395-71-9 SDF
别名 AHGDM
Canonical SMILES O=C(C(NCCCCCCN)=C1C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)/C=C(C)/[C@H](OC(N)=O)[C@@H](OC)/C=C\C=C(C)\C2=O)C=C(N2)C1=O
分子式 C34H52N4O8 分子量 644.8
溶解度 DMSO: 200 mg/mL (310.17 mM) 储存条件 -20°C, protect from light
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1 mM 1.5509 mL 7.7543 mL 15.5087 mL
5 mM 0.3102 mL 1.5509 mL 3.1017 mL
10 mM 0.1551 mL 0.7754 mL 1.5509 mL
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Research Update

HPMA copolymer-aminohexylgeldanamycin conjugates targeting cell surface expressed GRP78 in prostate cancer

Pharm Res 2010 Dec;27(12):2683-93.PMID:20845065DOI: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.

Targetable HPMA copolymer-aminohexylgeldanamycin conjugates for prostate cancer therapy

Pharm Res 2009 Jun;26(6):1407-18.PMID:19225872DOI:10.1007/s11095-009-9851-0.

Purpose: This study focuses on the synthesis and characterization of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-cyclo-RGD (Arg-Gly-Asp) conjugates for delivery of geldanamycin to prostate tumors. Materials and methods: HPMA copolymers containing Aminohexylgeldanamycin (AH-GDM) with and without the targeting peptide RGDfK were synthesized and characterized. Drug release from copolymers was evaluated using cathepsin B. Competitive binding of copolymer conjugates to alpha(v)beta(3) integrin was evaluated in prostate cancer (PC-3) and endothelial (HUVEC) cell lines and in vitro growth inhibition was assessed. The maximum tolerated dose for single i.v. injections of free drug and the conjugates was established in nude mice. Results: HPMA copolymers containing AH-GDM and RGDfK showed active binding to the alpha(v)beta(3) integrin similar to that of free peptide. Similarly, growth inhibition of cells by conjugates was comparable to that of the free drug. Single intravenous doses of HPMA copolymer-AH-GDM-RGDfK conjugates in mice were tolerated at 80 mg/kg drug equivalent, while free drug caused morbidity at 40 mg/kg. No signs of toxicity were present in mice receiving HPMA copolymer-AH-GDM-RGDfK over the 14-day evaluation period. Conclusion: Results of in vitro activity and in vivo tolerability experiments hold promise for the utility of HPMA copolymer-AH-GDM-RGDfK conjugates for treatment of prostate cancer with greater efficacy and reduced toxicity.

Anticancer and antiangiogenic activity of HPMA copolymer-aminohexylgeldanamycin-RGDfK conjugates for prostate cancer therapy

J Control Release 2011 May 10;151(3):263-70.PMID:21223983DOI:10.1016/j.jconrel.2010.12.015.

Tumor progression is dependent on neoangiogenesis for blood supply. Neovasculature over-express α(v)β(3) integrins which recognize the Arg-Gly-Asp (RGD) sequence in the extracellular matrix. N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers containing side chains terminated in cyclic RGD analogs such as RGDfK show increased accumulation in prostate tumors. Geldanamycin and their derivatives (e.g., Aminohexylgeldanamycin (AH-GDM)) are benzoquinone ansamycins that have both antiangiogenic and antitumor activity. In this work the antiangiogenic and antitumor activities of targetable HPMA copolymer-RGDfK-AH-GDM conjugates were compared with non-targetable systems in vitro and in vivo. Copolymer-drug conjugates containing RGDfK in the side chains showed superior activity against endothelial and prostate cancer cell lines in vitro, as well as higher inhibition of angiogenesis in vivo. At equimolar doses of the drug, the RGDfK containing conjugates showed significantly higher antitumor activity in nude mice bearing DU-145 human prostate cancer xenografts. These findings suggest the utility of HPMA copolymer-RGDfK conjugates for targeted delivery of geldanamycin analogs with a dual mode of action.

In vitro synergistic action of geldanamycin- and docetaxel-containing HPMA copolymer-RGDfK conjugates against ovarian cancer

Macromol Biosci 2014 Dec;14(12):1735-47.PMID:25185891DOI:10.1002/mabi.201400360.

HPMA copolymer-RGDfK (HPMA-RGDfK) conjugates bearing either Aminohexylgeldanamycin (AHGDM) or docetaxel (DOC) were synthesized and characterized. In vitro stability and binding were evaluated. Cytotoxicity toward ovarian cancer cells was evaluated and the ability of the conjugates to induce cell death was assessed by combination index analysis. Conjugates bearing AHGDM were more stable and exhibited slower drug release than those bearing DOC. Both conjugates demonstrated the ability to bind to avb3 integrins. In combination, HPMA-RGDfK conjugates demonstrated marked synergism as compared to their non-targeted counterparts and free drug controls. HPMA-RGDfK conjugates bearing AHGDM and DOC induce synergistic cytotoxicity in vitro, suggesting their potential as a promising combination therapy.

Synergistic enhancement of cancer therapy using a combination of heat shock protein targeted HPMA copolymer-drug conjugates and gold nanorod induced hyperthermia

J Control Release 2013 Aug 28;170(1):41-50.PMID:23602864DOI: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.