Fenretinide
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MedKoo CAT#: 205430

CAS#: 65646-68-6

Description: Fenretinide is an orally-active synthetic phenylretinamide analogue of retinol (vitamin A) with potential antineoplastic and chemopreventive activities. Fenretinide binds to and activates retinoic acid receptors (RARs), thereby inducing cell differentiation and apoptosis in some tumor cell types. This agent also inhibits tumor growth by modulating angiogenesis-associated growth factors and their receptors and exhibits retinoid receptor-independent apoptotic properties.


Chemical Structure

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Fenretinide
CAS# 65646-68-6

Theoretical Analysis

MedKoo Cat#: 205430
Name: Fenretinide
CAS#: 65646-68-6
Chemical Formula: C26H33NO2
Exact Mass: 391.25113
Molecular Weight: 391.54572
Elemental Analysis: C, 79.76; H, 8.50; N, 3.58; O, 8.17

Price and Availability

Size Price Availability Quantity
100.0mg USD 150.0 Same day
200.0mg USD 250.0 Same day
500.0mg USD 550.0 Same day
1.0g USD 950.0 Same day
2.0g USD 1750.0 Same day
5.0g USD 3950.0 Same day
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Synonym: 4-HPR; McNR-1967; McNR1967; McNR 1967; HPR; Fenretinide

IUPAC/Chemical Name: (2E,4E,6E,8E)-N-(4-hydroxyphenyl)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenamide

InChi Key: AKJHMTWEGVYYSE-FXILSDISSA-N

InChi Code: InChI=1S/C26H33NO2/c1-19(11-16-24-21(3)10-7-17-26(24,4)5)8-6-9-20(2)18-25(29)27-22-12-14-23(28)15-13-22/h6,8-9,11-16,18,28H,7,10,17H2,1-5H3,(H,27,29)/b9-6+,16-11+,19-8+,20-18+

SMILES Code: O=C(NC1=CC=C(O)C=C1)/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)CCCC2(C)C

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >5 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Fenretinide (4-HPR) is a synthetic retinoid deriverative, binding to the retinoic acid receptors (RAR) at concentrations necessary to induce cell death.
In vitro activity: 4-HPR inhibited OVCAR-5 cell proliferation and viability at concentrations higher than 1 microM, with 70-90% growth inhibition at 10 microM. 4-HPR (1 microM) significantly inhibited OVCAR-5 invasion after 3 days preincubation. In view of the importance of the cytoskeleton in cell motility, we examined the action of 4-HPR on the actin cytoskeleton and on FAK phosphorylation. In OVCAR-5 cells treated with 1 mM fenretinide for 3 days, actin cytoskeleton stress fibers were disrupted and FAK tyrosine phosphorylation was elevated dose-dependently. Endothelial cells treated with 1 microM 4-HPR failed to form tubes, but formed small cellular aggregates. Reference Anticancer Res. 2005 Jan-Feb;25(1A):249-53. http://ar.iiarjournals.org/cgi/pmidlookup?view=long&pmid=15816545
In vivo activity: Fenretinide was shown previously to improve insulin resistance in diet-induced obese mice. The proposed mechanism was that it promotes the urinary excretion of RBP4, an adipose-derived secretagogue implicated in insulin resistance. However, subsequent studies revealed that the compound could combat hepatic steatosis and obesity in RBP4-null mice, suggesting the existence of other targets that mediated its antidiabetic actions. To determine whether fenretinide is able to target the sphingolipid synthesis pathway in vivo, lipids from soleus muscle and liver of mice 12 h after the delivery of the drug by intraperitoneal injection were measured. The single injection of the drug only slightly reduced muscle ceramide levels, but robustly increased dihydroceramide levels (Fig. 5, A and B). A similar, although less robust, effect was observed in the liver (Fig. 5, C and D). However, although fenretinide had a more pronounced effect on shorter acyl chain dihydroceramide species (e.g. C16) in muscle, it appeared to affect a longer chain species more specifically in the liver (C24). This is consistent with the recent observation that the dominant ceramide synthase in the liver (CerS2) makes predominantly longer ceramides. Altogether, these data again indicate that fenretinide modulates sphingolipid levels and are highly suggestive that it inhibits Des1 in vivo. Reference: J Biol Chem. 2012 May 18;287(21):17426-17437. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22474281/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 130.0 332.01
Ethanol 78.0 199.21

Preparing Stock Solutions

The following data is based on the product molecular weight 391.54572 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
In vitro protocol: 1. Bikman BT, Guan Y, Shui G, Siddique MM, Holland WL, Kim JY, Fabriàs G, Wenk MR, Summers SA. Fenretinide prevents lipid-induced insulin resistance by blocking ceramide biosynthesis. J Biol Chem. 2012 May 18;287(21):17426-17437. doi: 10.1074/jbc.M112.359950. Epub 2012 Apr 2. PMID: 22474281; PMCID: PMC3366851. 2. Golubkov V, Garcia A, Markland FS. Action of fenretinide (4-HPR) on ovarian cancer and endothelial cells. Anticancer Res. 2005 Jan-Feb;25(1A):249-53. PMID: 15816545.
In vivo protocol: 1. Bikman BT, Guan Y, Shui G, Siddique MM, Holland WL, Kim JY, Fabriàs G, Wenk MR, Summers SA. Fenretinide prevents lipid-induced insulin resistance by blocking ceramide biosynthesis. J Biol Chem. 2012 May 18;287(21):17426-17437. doi: 10.1074/jbc.M112.359950. Epub 2012 Apr 2. PMID: 22474281; PMCID: PMC3366851.

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 1: Armstrong JL, Martin S, Illingworth NA, Jamieson D, Neilson A, Lovat PE, Redfern CP, Veal GJ. The impact of retinoic acid treatment on the sensitivity of neuroblastoma cells to fenretinide. Oncol Rep. 2012 Jan;27(1):293-8. doi: 10.3892/or.2011.1479. Epub 2011 Sep 29. PubMed PMID: 21964808.

2: Fang H, Harned TM, Kalous O, Maldonado V, Declerck YA, Reynolds CP. Synergistic Activity of Fenretinide and the Bcl-2 Family Protein Inhibitor ABT-737 against Human Neuroblastoma. Clin Cancer Res. 2011 Nov 8. [Epub ahead of print] PubMed PMID: 21933888.

3: Villablanca JG, London WB, Naranjo A, McGrady P, Ames MM, Reid JM, McGovern RM, Buhrow SA, Jackson H, Stranzinger E, Kitchen BJ, Sondel PM, Parisi MT, Shulkin B, Yanik GA, Cohn SL, Reynolds CP. Phase II Study of Oral Capsular 4-Hydroxyphenylretinamide (4-HPR/Fenretinide) in Pediatric Patients with Refractory or Recurrent Neuroblastoma: A Report from the Children's Oncology Group. Clin Cancer Res. 2011 Nov 1;17(21):6858-6866. Epub 2011 Sep 9. PubMed PMID: 21908574; PubMed Central PMCID: PMC3207022.

4: Carr AJ, Vugler AA, Yu L, Semo M, Coffey P, Moss SE, Greenwood J. The expression of retinal cell markers in human retinal pigment epithelial cells and their augmentation by the synthetic retinoid fenretinide. Mol Vis. 2011;17:1701-15. Epub 2011 Jun 25. PubMed PMID: 21738400; PubMed Central PMCID: PMC3130725.

5: Desai KG, Mallery SR, Holpuch AS, Schwendeman SP. Development and in vitro-in vivo evaluation of fenretinide-loaded oral mucoadhesive patches for site-specific chemoprevention of oral cancer. Pharm Res. 2011 Oct;28(10):2599-609. Epub 2011 Jun 15. PubMed PMID: 21674264; PubMed Central PMCID: PMC3171589.

6: Campos-Sandoval JA, Redondo C, Kinsella GK, Pal A, Jones G, Eyre GS, Hirst SC, Findlay JB. Fenretinide derivatives act as disrupters of interactions of serum retinol binding protein (sRBP) with transthyretin and the sRBP receptor. J Med Chem. 2011 Jul 14;54(13):4378-87. Epub 2011 Jun 7. PubMed PMID: 21591606.

7: Rahmaniyan M, Curley RW Jr, Obeid LM, Hannun YA, Kraveka JM. Identification of dihydroceramide desaturase as a direct in vitro target for fenretinide. J Biol Chem. 2011 Jul 15;286(28):24754-64. Epub 2011 May 4. PubMed PMID: 21543327; PubMed Central PMCID: PMC3137051.

8: Kummar S, Gutierrez ME, Maurer BJ, Reynolds CP, Kang M, Singh H, Crandon S, Murgo AJ, Doroshow JH. Phase I trial of fenretinide lym-x-sorb oral powder in adults with solid tumors and lymphomas. Anticancer Res. 2011 Mar;31(3):961-6. PubMed PMID: 21498721.

9: Cooper JP, Hwang K, Singh H, Wang D, Reynolds CP, Curley RW Jr, Williams SC, Maurer BJ, Kang MH. Fenretinide metabolism in humans and mice: utilizing pharmacological modulation of its metabolic pathway to increase systemic exposure. Br J Pharmacol. 2011 Jul;163(6):1263-75. doi: 10.1111/j.1476-5381.2011.01310.x. PubMed PMID: 21391977; PubMed Central PMCID: PMC3144539.

10: Yang H, Zhan Q, Wan YJ. Enrichment of Nur77 mediated by retinoic acid receptor β leads to apoptosis of human hepatocellular carcinoma cells induced by fenretinide and histone deacetylase inhibitors. Hepatology. 2011 Mar;53(3):865-74. doi: 10.1002/hep.24101. Epub 2011 Feb 11. PubMed PMID: 21319187; PubMed Central PMCID: PMC3077573.



Additional Information

Fenretinide (4-hydroxy(phenyl)retinamide; 4-HPR) (INN) is a synthetic retinoid deriverative. Retinoids are substances related to vitamin A. It has been investigated for potential use in the treatment of cancer, as well as in the treatment of cystic fibrosis,  rheumatoid arthritis, acne, psoriasis, and has been found to also slow the production and accumulation of a toxin that leads to vision loss in Stargardt's patients.
 
In cancer studies, Fenretinide treatment may cause ceramide (a wax-like substance) to build up in tumor cells and is associated with the accumulation of reactive oxygen species (ROS), resulting in cell death through apoptosis and/or necrosis. Fenretinide accumulates preferentially in fatty tissue such as the breast, which may contribute to the effectiveness of fenretinide against breast cancer. Phase III clinical trial data has suggested that fenretinide reduces breast cancer relapse in pre-menopausal women . Common side effects associated with fenretinide treatment include skin dryness and night-blindness, which is reversible upon cessation of treatment. Specific types of cancer under investigation include or have included ovarian, prostate, cervical, lung, renal, bladder, breast, glioma, skin, head and neck carcinoma, Non-Hodgkin's lymphoma, neuroblastoma, and Ewing's sarcoma. (source: http://en.wikipedia.org/wiki/Fenretinide).