65646-68-6

Basic information

• Product Name: 4-HYDROXYPHENYLRETINAMIDE
• Synonyms: 4-HYDROXYPHENYLRETINAMIDE;4HPR;FENRETINIDE;p-Hydroxyphenylretinamide;4-HPR, Fenretinide, N-(4-Hydroxyphenyl)retinamide;(2E,4E,6E,8E)-N-(4-Hydroxyphenyl)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenamide;Fenretinimide;Fenretinide(4-HPR)
• CAS NO: 65646-68-6
• Molecular Formula: C₂₆H₃₃NO₂
• Molecular Weight: 391.55
• EINECS: 200-256-5
• Product Categories: Intermediates & Fine Chemicals;Pharmaceuticals;Retinoids;Intracellular receptor;Drug Analogues;Inhibitors
• Mol File: 65646-68-6.mol

Chemical Properties

• Melting Point: 162-163°C
• Boiling Point: 597.6 ºC at 760 mmHg
• Flash Point: 315.2 ºC
• Appearance: Yellow Powder
• Density: 1.081 g/cm³
• Vapor Pressure: 7.07E-15mmHg at 25°C
• Refractive Index: 1.607
• Storage Temp.: −20°C
• Solubility: Chloroform (Slightly), Methanol (Slightly)
• PKA: 9.98±0.26(Predicted)
• Stability: Light Sensitive - Protect from Light Exposure
• Merck: 14,3998
• CAS DataBase Reference: 4-HYDROXYPHENYLRETINAMIDE(CAS DataBase Reference)
• NIST Chemistry Reference: 4-HYDROXYPHENYLRETINAMIDE(65646-68-6)
• EPA Substance Registry System: 4-HYDROXYPHENYLRETINAMIDE(65646-68-6)

Safety Data

• Hazard Codes: T
• Statements: 60-61-20/21/22-36/37/38
• Safety Statements: 53-26-36/37/39-45-52
• WGK Germany: 3
• RTECS: VH6420000
• Hazardous Substances Data: 65646-68-6(Hazardous Substances Data)

Usage

Uses

Used in Oncology:
4-Hydroxyphenylretinamide is used as a chemopreventive agent for the growth modulation of oncogene-induced prostate cancer in the mouse prostate reconstitution model system. It has shown potential effectiveness in the chemoprevention of human prostate cancer, making it a promising candidate for further research and development in the field of oncology.
Used in Pharmaceutical Industry:
As a synthetic analog of Vitamin A and a retinoic acid receptor ligand, 4-Hydroxyphenylretinamide has potential applications in the pharmaceutical industry for the development of novel therapeutic agents targeting various diseases and conditions. Its unique properties and interactions with retinoic acid receptors make it a valuable compound for drug discovery and design.

Biological Activity

Synthetic retinoid agonist. Antiproliferative, antioxidant and anticancer agent with a long half-life in vivo . Apoptotic effects appear to be mediated by a mechanism distinct from that of 'classical' retinoids.

Biochem/physiol Actions

Vitamin A acid analogue with antiproliferative activity; induces apoptosis in malignant hemopoietic cell lines.

references

[1] roberto benelli, stefano monteghirfo, roberta venè, francesca tosettiand nicoletta ferrari.the chemopreventive retinoid 4hpr impairs prostate cancer cell migration and invasion by interfering with fak/akt/gsk3β pathway andβ-catenin stability. molecular cancer.2010, 9:142-154.[2] anita l. sabichi, denver t. hendricks, mary a. bober, michael j. birrer. retinoic acid receptorβexpression and growthinhibition of gynecologic cancer cells by thesynthetic retinoidn-(4-hydroxyphenyl) retinamide. journal of the national cancer institute. 1998, 90(8): 597-605.[3] shi-yong sun, ping yue, and reuben lotan. induction of apoptosis by n-(4-hydroxyphenyl)retinamide andits association with reactive oxygen species, nuclearretinoic acid receptors, and apoptosis-related genes in human prostate carcinoma cells.molecular pharmacology. 1999, 55:403–410.

InChI:InChI=1/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+

Upstream product

• 53839-60-4 retinoyl chloride 
• 123-30-8 4-amino-phenol 
• 302-79-4 all-trans-retinoic-acid 

Downstream Products

• 75664-77-6 all-trans-N-<4-(Pivaloyloxy)phenyl>retinamide 
• 75858-21-8 4-{(2E,4E,6E,8E)-[3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexenyl)nona-2,4,6,8-tetraenoylamino]}-phenyl propionate 
• 79965-10-9 4-Methoxyfenretinide 
• 1276090-87-9 4'-hydroxy 4-HPR 

Relevant articles and documents

Fenretinide derivatives act as disrupters of interactions of serum retinol binding protein (sRBP) with transthyretin and the sRBP receptor

Serum retinol binding protein (sRBP) is released from the liver as a complex with transthyretin (TTR), a process under the control of dietary retinol. Elevated levels of sRBP may be involved in inhibiting cellular responses to insulin and in generating first insulin resistance and then type 2 diabetes, offering a new target for therapeutic attack for these conditions. A series of retinoid analogues were synthesized and examined for their binding to sRBP and their ability to disrupt the sRBP-TTR and sRBP-sRBP receptor interactions. A number inhibit the sRBP-TTR and sRBP-sRBP receptor interactions as well as or better than Fenretinide (FEN), presenting a potential novel dual mechanism of action and perhaps offering a new therapeutic intervention against type 2 diabetes and its development. Shortening the chain length of the FEN derivative substantially abolished binding to sRBP, indicating that the strength of the interaction lies in the polyene chain region. Differences in potency against the sRBP-TTR and sRBP-sRBP receptor interactions suggest variant effects of the compounds on the two loops of sRBP guarding the entrance of the binding pocket that are responsible for these two protein-protein interactions.

Preparation of amides of retinoic acid via mixed anhydride and mixed carbonate intermediates

Processes for preparing amides of retinoic acid are disclosed. Intermediates useful in the preparation of amides of retinoic acid are also disclosed. In one version of the invention, fenretinide is produced via activation of retinoic acid (tretinoin) via its corresponding mixed anhydride or mixed carbonate followed by reaction of the activated intermediate with 4-aminophenol. Other amides of retinoic acid and isomers of retinoic acid, such as the 9-cis-form or 13-cis-form can also be made by this invention.

Solid phase-assisted synthesis and screening of a small library of N-(4-hydroxyphenyl)retinamide (4-HPR) analogs

Using solid phase-assisted synthesis and purification, a 49 member library of analogs of the mammary tumor chemopreventive retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) has been prepared. After prescreening for growth inhibitory activity in human mammary tumor cells (MCF-7) in culture, most of those analogs which showed activity (12 of them) were assayed for apoptosis-inducing activity in the MCF-7 cells. At least 3 of the analogs (13, 24, and 28) showed activity approaching that of 4-HPR.

Synthesis and biological activity of novel retinamide and retinoate derivatives

Retinoic acid and its amide derivative, N-(4-hydroxyphenyl)retinamide (4-HPR), have been proposed as chemopreventative and chemotherapeutic agents. However, their low cytotoxic activity and water solubility limit their clinical use. In this study, we synthesized novel retinoid derivatives with improved cytotoxicity against cancer cells and increased hygroscopicity. Our syntheses were preceded by selective O-acylation and N-acylation, which led to the production of retinoate and retinamide derivatives, respectively, in one pot directly from aminophenol derivatives and retinoic acid without protection. Transcription assays in COS-1 cells indicated that the N-acylated derivatives (2A - 5A) and 4-HPR (1A) were much weaker ligands for all three subtypes of retinoic acid receptor (RAR) than all-trans retinoic acid (ATRA), although they showed some selectivity for RARβ and RARγ. In contrast, the O-acylated retinoate derivatives (1B - 5B) activated all three RAR isotypes without specificity to an extent similar to ATRA. The cytotoxicity was determined using an MTT assay with HCT116 colon cancer cells, and the IC 50 of N-acylated retinamide derivative 4A and O-acylated retinoate derivative 5B was 1.67 μM and 0.65 μM, respectively, which are about five and 13-fold better than that of 4-HPR (8.21 μM), a prototype N-acylated derivative. When retinoate derivative 5B was coupled to organic acid salts, the resulting salt derivatives 5C and 5D had RAR activation and cytotoxicity similar to those of 5B. These data may delineate the relationship between the structure and function of retinoate and retinamide derivatives.

A simple, general and efficient method for O and N-retinoylation. Application to the synthesis of 2-retinoyl-lecithin

The synthesis of the new 1-stearoyl-2-retinoyl-glycero-3- phosphorylcholine by coupling of retinoic acid and lysolecithin with DCC- DMAP (1.2 eq.) is reported. This method is applied to O and N-retinoylation of uncharged organic substrates such as aliphatic alcohols, free hydroxyl anomeric sugars, aromatic amines and C-protected α-aminoacids.

Synthesis and properties of some 13-cis- and all-trans-retinamides

Several 13-cis-retinamides were synthesized from 13-cis-retinoic acid via either 13-cis-retinoyl chloride or 13-cis-1-retinoylimidazole. All-trans-retinoylglycine was prepared from all-trans-retinoyl chloride and ethyl glycinate. Detailed procedures were developed for the preparation of other all-trans-retinamides on a large scale for studies of the chemoprevention of cancer.