Name: (S,R,S)-AHPC-C10-NH2 dihydrochloride
Brand: BOC Sciences
Price: 399 USD
Availability: MadeToOrder

Purity

≥95% by HPLC

Solubility

In DMSO: 250 mg/mL (364.02 mM; Need ultrasonic)<br/>In H2O: 250 mg/mL (364.02 mM; Need ultrasonic)

Storage

Store at -20°C

Shipping

Room temperature in continental US; may vary elsewhere.

IUPACName

(2S,4R)-1-[(2S)-2-(11-aminoundecanoylamino)-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide;dihydrochloride

Synonyms

VH032-C10-NH2 dihydrochloride

InChI Key

AANLWYRSPUHEKW-MIZQACOZSA-N

InChI

1S/C33H51N5O4S.2ClH/c1-23-29(43-22-36-23)25-16-14-24(15-17-25)20-35-31(41)27-19-26(39)21-38(27)32(42)30(33(2,3)4)37-28(40)13-11-9-7-5-6-8-10-12-18-34;;/h14-17,22,26-27,30,39H,5-13,18-21,34H2,1-4H3,(H,35,41)(H,37,40);2*1H/t26-,27+,30-;;/m1../s1

SMILES

Cl.Cl.CC1=C(SC=N1)C1=CC=C(CNC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@@H](NC(=O)CCCCCCCCCCN)C(C)(C)C)C=C1

Background Introduction

(S,R,S)-AHPC-C10-NH2 dihydrochloride is a specialized E3 ligase ligand-linker conjugate widely used in the development of PROTACs (Proteolysis Targeting Chimeras). As a derivative of the AHPC ligand, it selectively binds to the von Hippel-Lindau (VHL) E3 ubiquitin ligase. The C10 amino-linked structure provides a versatile functional handle, enabling seamless conjugation with diverse target-binding moieties for efficient protein degradation studies.

Mechanism

The mechanism of action of (S,R,S)-AHPC-C10-NH2 dihydrochloride leverages its high affinity and specificity for the VHL E3 ubiquitin ligase. When incorporated into a PROTAC molecule, the AHPC moiety binds to VHL, while the amino group at the C10 linker site allows attachment to a ligand for a protein of interest. This heterobifunctional molecule brings the target protein into close proximity with the VHL complex, which, in turn, facilitates ubiquitination and subsequent proteasomal degradation of the target. This targeted approach ensures selective depletion of disease-relevant proteins, overcoming many drawbacks of traditional inhibition.

Applications

(S,R,S)-AHPC-C10-NH2 dihydrochloride is a critical intermediate for the synthesis of VHL-based PROTACs and molecular glues. Its utility spans research and drug discovery applications, including targeted protein degradation, elucidation of protein function, validation of novel therapeutic targets, and development of next-generation therapeutics for cancer, neurodegenerative disorders, and other diseases. The product's linker with a terminal amine allows for flexible conjugation strategies, supported by robust structure-activity relationships (SAR) studies in medicinal chemistry and chemical biology applications.

• Amine-terminated C10 linker ensures flexible and efficient conjugation with target warheads for PROTAC synthesis.
• High affinity for VHL E3 ligase enables selective and potent degradation of target proteins in cellular assays.

1. Investigation of a dual CD chiral CE system for separation of glitazone compounds

Babak Jamali, Inga Bjørnsdottir, Claus Cornett, Steen Honoré Hansen Electrophoresis. 2009 Aug;30(16):2853-61.doi: 10.1002/elps.200800812.

A dual CD-CE method for chiral separation of enantiomers of pioglitazone, rosiglitazone and balaglitazone was investigated for the purpose of optimizing the chiral separation. In a previous work a dual CD chiral CE method was used for investigation of glitazone compounds in drug substance and pharmaceutical formulation and the studies showed that all studied glitazones were racemic mixtures. This CE method could separate the enantiomers with a resolution (R(S)) of about 3. However, another study on single glitazone enantiomers pointed out that a higher R(S) is needed to achieve more accurate results for separation of a small amount of one enantiomer in the presence of a high amount of the other enantiomers. The focus of this investigation was thus directed toward the effect of CDs and the pH of the running buffer to achieve a better enantioseparation. Initially CE systems with each of heptakis(2,6-di-O-methyl)-beta-CD (DM-beta-CD) and heptakis(6-sulfobutylether)-beta-CD (SB-beta-CD) as single CD added were investigated at three different pH values (2.5, 5.0 and 9.3). After having chosen the best of these three pH values a dual CD system was further investigated and optimized. The optimization work was then focused on the concentration of the two CDs and the pH of the running buffer and was performed using factorial design experiments. A mixture of a DM-beta-CD and SB-beta-CD was found to be optimal and necessary to achieve enantioseparation with sufficiently high R(S). In order to further verify the importance of the SB-beta-CD, a CE system with the DM-beta-CD added and substitution or partial substitution of the SB-beta-CD by SDS was studied for comparison. (1)H-NMR studies were performed to get a more detailed understanding of the interactions between the glitazones and the CDs used.The optimized dual CD-CE method for chiral separation of the enantiomers of pioglitazone, rosiglitazone and balaglitazone using a running buffer containing 50 mM borate buffer pH 9.7, 12 mM of SB-beta-CD and 3 mM of DM-beta-CD provided a high R(S) (R(S) between 5.5 and 8.8).

2. Estrogen levels in nipple aspirate fluid and serum during a randomized soy trial

Gertraud Maskarinec, Nicholas J Ollberding, Shannon M Conroy, Yukiko Morimoto, Ian S Pagano, Adrian A Franke, Elisabet Gentzschein, Frank Z Stanczyk Cancer Epidemiol Biomarkers Prev. 2011 Sep;20(9):1815-21.doi: 10.1158/1055-9965.EPI-11-0363.Epub 2011 Jul 8.

Background:On the basis of hypothesized protective effect, we examined the effect of soy foods on estrogens in nipple aspirate fluid (NAF) and serum, possible indicators of breast cancer risk.

3. Interactions of non-charged tadalafil stereoisomers with cyclodextrins: capillary electrophoresis and nuclear magnetic resonance studies

Ida Fejős, Adrienn Kazsoki, Tamás Sohajda, Ede Márványos, Balázs Volk, Lajos Szente, Szabolcs Béni J Chromatogr A. 2014 Oct 10;1363:348-55.doi: 10.1016/j.chroma.2014.08.045.Epub 2014 Aug 19.

The single isomer drug R,R-tadalafil (Cialis) contains two chiral centers thus four stereoisomers (R,R-, S,S-, S,R- and R,S-tadalafil) exist, however, only the most potent inhibitor, the R,R-tadalafil is in clinical use. In our study, over 20 charged cyclodextrin (CD) derivatives were studied for enantiospecific host-guest type interactions in CD-modified capillary electrophoresis. Tadalafil stereoisomers are non-charged; therefore, their electrophoretic separation poses a challenge. Several candidates of both positively and negatively charged hosts were found to be effective for the enantioseparation. Eight out of the beta derivatives and three of alpha derivatives (including sulfated, sulfoalkylated, carboxyalkylated and amino derivatives) resolved all four stereoisomers partially or completely. Cavity size-dependent absolute enantiomer migration order (EMO) reversals were observed in the case of sulfopropyl-alpha (EMO: R,S; S,R; R,R; S,S) and sulfopropyl-beta (S,S; R,R; S,R; R,S) derivatives, while substituent-dependent partial EMO reversals were detected for sulfobutyl-ether-alpha (R,S; S,R; S,S; R,R) and sulfated-alpha-CD (R,R; S,S; R,S; S,R) selectors. Complexation-induced (1)H NMR chemical shift changes reflected that the benzodioxole moiety plays a major role in cavity size-dependent EMO reversal. Sulfobutyl-ether-alpha-CD was the only selector that provided the desired EMO in which the clinically applied eutomer R,R-tadalafil migrates last. Finally, an electrophoretic method applying a background electrolyte (BGE) containing 75 mM Tris-acetic acid buffer (pH 4.75) and 7 mM sulfobutyl-ether-alpha-CD was developed for the baseline resolution of all isomers at 25 °C and +25 kV applied voltage.

The (S,R,S)-AHPC-C10-NH2 dihydrochloride serves as a versatile E3 Ligase Ligand-Linker Conjugate in the realm of PROTACs, facilitating targeted protein degradation through its strategic design, which includes a well-balanced linker, a potent ligand, and a reactive site for efficient coupling with target protein ligands. The following provides a detailed description of this molecule.

Linker: The linker in this molecule is a C10 aliphatic chain, offering a moderate length that provides flexibility necessary for optimal spatial arrangement. Its non-cleavable nature ensures stability during the degradation process, enhancing the efficacy of the PROTAC.

Ligand: The ligand component is derived from AHPC, a potent E3 ligase recruiter, characterized by its stereochemistry that ensures high affinity and specificity for the targeted E3 ligase, thereby promoting effective ubiquitination of the target protein.

Reactive Site: The reactive site features a primary amine group, which is well-suited for coupling with electrophilic groups on the target protein ligand. Recommended reaction types include amide bond formation and reductive amination, offering robust and stable linkages.

Recommended Target Protein Ligand: The ideal warhead for this conjugate is an electrophilic moiety such as a chloroacetamide, which can efficiently form covalent bonds with the reactive site. This provides enhanced selectivity and potency in targeting proteins for degradation, making it suitable for experimental studies focused on elucidating protein function and interactions.

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* Our calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C₁V₁ = C₂V₂