149648-52-2

Usage

Uses

Used in Pharmaceutical Industry:
7-Phenylcarbamoylheptanoic acid is used as a key intermediate in the production of histone deacetylase inhibitors for the treatment of various diseases, including cancer. These inhibitors play a crucial role in regulating gene expression and cellular processes, making them potential therapeutic agents.
Used in Epigenetic Research:
7-Phenylcarbamoylheptanoic acid is also utilized in the field of epigenetic research, where it contributes to the development of novel compounds that can modulate histone deacetylase activity. This research has the potential to lead to the discovery of new treatments for a wide range of diseases, including neurological disorders and cardiovascular conditions.
Used in Drug Development:
As a chemical intermediate, 7-Phenylcarbamoylheptanoic acid is employed in the development of new drugs targeting epigenetic mechanisms. Its unique properties allow for the creation of compounds with improved efficacy, selectivity, and reduced side effects, ultimately benefiting patients and advancing the field of medicine.

InChI:InChI=1/C14H19NO3/c16-13(15-12-8-4-3-5-9-12)10-6-1-2-7-11-14(17)18/h3-5,8-9H,1-2,6-7,10-11H2,(H,15,16)(H,17,18)

Upstream product

• 505-48-6 octane-1,8-dioic acid 
• 62-53-3 aniline 
• 14354-86-0 suberic dianilide 
• 10521-06-9 oxonane-2,9-dione 
• 162853-41-0 8-oxo-8-(phenylamino)octanoic acid methyl ester 
• 5698-29-3 oxonan-2-one 
• 3946-32-5 suberic acid monomethyl ester 
• 41624-92-4 methyl 8-chloro-8-oxooctanoate 

Downstream Products

• 162853-41-0 8-oxo-8-(phenylamino)octanoic acid methyl ester 
• 651768-07-9 N¹-methoxy-N¹-methyl-N⁸-phenyloctanediamide 
• 852619-59-1 octanedioic acid phenylamide (2-tritylsulfanyl-ethyl)-amide 
• 931415-43-9 2,3,4,6-tetra-O-acetyl-1-O-7-(phenylcarbamoyl)hepthydroxamoyl-β-D-galactopyranose 
• 931415-42-8 methyl 2,3,4-tri-O-acetyl-1-O-7-(phenylcarbamoyl)hepthydroxamoyl-β-D-glucopyranosyluronate 
• 1155413-88-9 4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl 8-oxo-8-(phenylamino)octanoate 
• 1280574-16-4 ethyl 3,10-dioxo-10-(phenylamino)decanoate 
• 1305124-48-4 N-Phenyloctanediamide 

Relevant academic research and scientific papers

Platinum(IV) prodrugs multiply targeting genomic DNA, histone deacetylases and PARP-1

Several Pt(IV) prodrugs containing SAA, a histone deacetylases inhibitor, were designed and prepared for multiply targeting genomic DNA, histone deacetylases and PARP-1. The resulting Pt(IV) prodrug had significantly strong antiproliferative activity against the tested cancer cell lines, especially SAA1, derived from the conjugation of cisplatin and SAA, had potent ability to overcome cisplatin resistance. Under the combined action of DNA platination and inhibition of HDACs and PARP-1 activity, the cytotoxic activity of SAA1 was 174-fold higher than cisplatin against cisplatin-resistant SGC7901/CDDP cancer cells. The mechanism of action of SAA1 was preliminarily investigated, in which cellular uptake, cell apoptosis and cell cycle arrest as well as western blot analysis were made by treating SAA1 with SGC7901/CDDP cells. Besides, HDACs inhibition activity and PARP-1 enzyme inhibition of SAA1 were also studied.

2-Hydroxypropyl-β-cyclodextrin is the active component in a triple combination formulation for treatment of Niemann-Pick C1 disease

Niemann-Pick type C1 (NPC1) disease is a fatal neurovisceral disease for which there are no FDA approved treatments, though cyclodextrin (HPβCD) slows disease progression in preclinical models and in an early phase clinical trial. Our goal was to evaluate the mechanism of action of a previously described combination-therapy, Triple Combination Formulation (TCF) – comprised of the histone deacetylase inhibitor (HDACi) vorinostat/HPβCD/PEG – shown to prolong survival in Npc1 mice. In these studies, TCF's benefit was attributed to enhanced vorinostat pharmacokinetics (PK). Here, we show that TCF reduced lipid storage, extended lifespan, and preserved neurological function in Npc1 mice. Unexpectedly, substitution of an inactive analog for vorinostat in TCF revealed similar efficacy. We demonstrate that the efficacy of TCF was attributable to enhanced HPβCD PK and independent of NPC1 protein expression. We conclude that although HDACi effectively reduce cholesterol storage in NPC1-deficient cells, HDACi are ineffective in vivo in Npc1 mice.

Hypoxia-activated pro-drugs of the KDAC inhibitor vorinostat (SAHA)

Hypoxia (lower than normal oxygen) is a characteristic of most solid tumours that results in poor cancer patient prognosis. The difference in cellular environment between normoxia (21percent oxygen) or physoxia (4–7.5percent oxygen) and hypoxia (2.0percent oxygen) causes increased resistance to radio- and chemotherapy, but also provides the opportunity to selectively release hypoxia-activated pro-drugs. This approach potentially allows targeting of chemotherapies, including lysine deacetylase (KDAC) inhibitors, to the hypoxic fraction of cells. Here, we report initial work on the development of KDAC inhibitors that are selectively released in hypoxic conditions. We have shown that the addition of a 4-nitrobenzyl (NB) or 1-methyl-2-nitroimidazole (NI) bioreductive group onto the hydroxamic acid moiety of SAHA, giving NB-SAHA and NI-SAHA, abolishes KDAC inhibition activity. Both NB-SAHA and NI-SAHA undergo enzyme-mediated bioreduction, in a hypoxia-dependent manner, to release SAHA selectively in 0.1percent oxygen. This work provides an important foundation for further investigations into the targeted release of KDAC inhibitors in hypoxic tumours.

Histone Deacetylase 2 (HDAC2) Inhibitors Containing Boron

Histone deacetylase enzymes (HDACs) are responsible for the global silencing of tumour-suppressor genes. Treatment with a histone deacetylase inhibitor (HDACi) can reverse this process and restore normal cell function. Herein, we report a small series of boron-based (boronic acid, boronate ester and closo-1,2-carborane) HDAC2 inhibitors with IC50 values in the nanomolar range. The boronate ester 4 b was the most potent compound assessed in this study (IC50=40.6±1.5 nM), followed closely by the 1,2-closo-carborane (IC50=42.9±1.5 nM). Compound 4 b exceeds the potency of the related gold-standard HDAC pan-inhibitor vorinostat (1) toward this particular HDAC isoform.

H2O2/Peroxynitrite-Activated Hydroxamic Acid HDAC Inhibitor Prodrugs Show Antileukemic Activities against AML Cells

Occurrence of acute myeloid leukemia (AML) results in abundant endogenous reactive oxygen species (ROS)/reactive nitrogen species (RNS) in AML cells and in disease-relevant microenvironments. Histone deacetylase inhibitor (HDACi) prodrug approach was designed accordingly by masking the hydroxamic acid zinc binding group with hydrogen peroxide (H2O2)/peroxynitrite (PNT)-sensitive, self-immolative aryl boronic acid moiety. Model prodrugs 5-82 and 5-23 were activated in AML cells to release cytotoxic HDACis, evidenced by inducing acetylation markers and reducing viability of AML cells. Intracellular activation and antileukemic activities of prodrug were increased or decreased by ROS/PNT inducers and scavengers, respectively. Prodrugs 5-82 and 5-23 also enhanced the potency of chemotherapy drug cytarabine, supporting the potentials of this prodrug class in combinatorial treatment.

The involvement of the mitochondrial amidoxime reducing component (MARC) in the reductive metabolism of hydroxamic acidsS

The mitochondrial amidoxime reducing component is a recently discovered molybdenum enzyme in mammals which, in concert with the electron transport proteins cytochrome b5 and NADH cytochrome b5 reductase, catalyzes the reduction of N-oxygenated structures.

An Endogenous Reactive Oxygen Species (ROS)-Activated Histone Deacetylase Inhibitor Prodrug for Cancer Chemotherapy

Suberoylanilide hydroxamic acid (SAHA, vorinostat) is a potent small-molecule pan-inhibitor of histone deacetylases (HDACs) approved for treatment of cutaneous T-cell lymphoma (CTCL). However, SAHA exhibits poor selectivity for cancer cells over noncancer cells. With an aim to improving its selectivity for cancer cells, we generated a novel SAHA prodrug (SAHA-OBP) that is activated in the presence of hydrogen peroxide, a reactive oxygen species (ROS) known to be overexpressed in cancer cells. The high endogenous ROS content in cancer cells triggers rapid removal of the 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl carbonyl (OBP) cap to release active SAHA. The SAHA-OBP prodrug demonstrates selective activity against multiple cancer cell lines such as HeLa, MCF-7, MDA-MB-231, and B16-F10, while remaining benign toward noncancer cells. The downstream effects of SAHA released from SAHA-OBP in cancer cells is the induction of apoptosis. SAHA-OBP was also found to be effective on multicellular tumor spheroids (MCTS). The SAHA prodrug designed in this study undergoes rapid ROS-dependent activation and imparts much-needed selectivity to SAHA for cancer cells.

Metal-Free Synthesis of N-Aryl Amides using Organocatalytic Ring-Opening Aminolysis of Lactones

Catalytic ring-opening of bio-sourced non-strained lactones with aromatic amines can offer a straightforward, 100 % atom-economical, and sustainable pathway towards relevant N-aryl amide scaffolds. Herein, the first general, metal-free, and highly efficient N-aryl amide formation is reported from poorly reactive aromatic amines and non-strained lactones under mild operating conditions using an organic bicyclic guanidine catalyst. This protocol has high application potential as exemplified by the formal syntheses of drug-relevant molecules.

Structural Requirements of Histone Deacetylase Inhibitors: SAHA Analogs Modified on the Hydroxamic Acid

Histone deacetylase (HDAC) proteins have emerged as targets for anti-cancer therapeutics, with several inhibitors used in the clinic, including suberoylanilide hydroxamic acid (SAHA, vorinostat). Because SAHA and many other inhibitors target all or most o

Photoorganocatalytic One-Pot Synthesis of Hydroxamic Acids from Aldehydes

An efficient one-pot synthesis of hydroxamic acids from aldehydes and hydroxylamine is described. A fast, visible-light-mediated metal-free hydroacylation of dialkyl azodicarboxylates was used to develop the subsequent addition of hydroxylamine hydrochloride. A range of aliphatic and aromatic aldehydes were employed in this reaction to give hydroxamic acids in high to excellent yields. Application of the current methodology was demonstrated in the synthesis of the anticancer medicine vorinostat.