The various applications of hydrogen isotopes (deuterium, D, and tritium, T) in the physical and life sciences demand a range of methods for their installation in an array of molecular architectures. ...In this Review, we describe recent advances in synthetic C−H functionalisation for hydrogen isotope exchange.
Spoilt for choice: The various applications of hydrogen isotopes in the physical and life sciences demand a range of methods for the installation of deuterium and tritium in an array of molecular architectures. In this Review, recent advances in synthetic C−H functionalisation for hydrogen isotope exchange are discussed.
Site‐selective incorporation of deuterium into biologically active compounds is of high interest in pharmaceutical industry. We present a mild and environmentally benign metal‐free method for the ...remote selective radical C−H monodeuteration of aliphatic C−H bonds in various amides with inexpensive heavy water (D2O) as the deuterium source. The method uses the easily installed N‐allylsulfonyl moiety as an N‐radical precursor that generates the remote C‐radical via site‐selective 1,5‐ or 1,6‐hydrogen atom transfer (HAT). Methyl thioglycolate, that readily exchanges its proton with D2O, serves as the radical deuteration reagent and as a chain‐carrier. The highly site‐selective monodeuteration has been applied to different types of unactivated sp3‐C−H bonds and also to the deuteration of C−H bonds next to heteroatoms. The potential utility of this method is further demonstrated by the site‐selective incorporation of deuterium into natural product derivatives and drugs.
Radical C−H Deuteration: A environmentally benign metal‐free method for remote radical C−H deuteration at various unactivated sp3‐C−H bonds including primary C−H bonds next to heteroatoms for the δ‐deuteration of primary amines, γ‐deuteration of aliphatic acids and α‐deuteration of secondary amines has been developed.
This review summarizes the highlights of aliphatic C (sp3)‐H carbon hydrogen isotope exchange (HIE) methods developed in the last 10 years. In particular, new highly selective and reactive protocols ...in the areas of nanoparticle and metal‐catalyzed homogeneous catalysis are reported.
This review gives an overview of aliphatic C (sp3)‐H carbon hydrogen isotope exchange (HIE) methods developed in the last 10 years. In particular, new highly selective and reactive protocols in the areas of nanoparticle and metal‐catalyzed homogeneous catalysis are reported.
The increasing demand for stable isotopically labeled compounds has led to an increased interest in H/D-exchange reactions at carbon centers. Today deuterium-labeled compounds are used as internal ...standards in mass spectrometry or to help elucidate mechanistic theories. Access to these deuterated compounds takes place significantly more efficiently and more cost effectively by exchange of hydrogen by deuterium in the target molecule than by classical synthesis. This Review will concentrate on the preparative application of the H/D-exchange reaction in the preparation of deuterium-labeled compounds. Advances over the last ten years are brought together and critically evaluated.
For the first time, we describe highly selective homogeneous iridium‐catalyzed hydrogen isotope exchange (HIE) of unactivated C(sp3) centers in aliphatic amides. When using the commercially available ...Kerr catalyst, the HIE with a series of common antibody–drug conjugate (ADC) linker side chains proceeds with high yields, high regioselectivity, and with deuterium incorporation up to 99 %. The method is fully translatable to the specific requirements of tritium chemistry and its effectiveness was demonstrated by direct tritium labelling of a maytansinoid. The scope of the method can be extended to simple amino acids, with high HIE activity observed for glycine and alanine. In di‐ and tripeptides, a very interesting protecting‐group‐dependent tunable selectivity was observed. DFT calculations gave insight into the energies of the transition states, thereby explaining the observed selectivity and the influence of the amino acid protecting groups.
Available in HD: A directed, highly selective iridium‐catalyzed hydrogen isotope exchange (HIE) of unactivated C(sp3) centers in aliphatic amides was developed. This reaction presents a powerful new tool for deuterium or tritium labelling of complex drug candidates and glycines with tunable selectivity.
The selective activation of sp3 carbon–hydrogen bonds in the presence of multiple C–H bonds is challenging and remains of supreme importance in chemical research. Late-stage modification of complex ...molecules via sp3 C–H activation is of high prevalence in organic synthesis. Herein, we describe the activation of a C(sp3)–H bond in the α-position to an amine via a carbanion intermediate. In the presence of several α-amine sites, only one specific position is selectively activated. Applying this protocol, the proposed carbanion intermediate was effectively trapped with different electrophiles such as deuterium (D+), tritium (T+), or carbonyl compounds compiling over 50 examples. Further, this methodology was used to install deuterium or tritium in different drug-derivatives (>10 drugs) at a selected position in a late-stage functionalization. In addition, the protocol is suitable for a gram-scale synthesis, and a detailed mechanistic investigation has been carried out to support our hypothesis.
Human glucose transporters (GLUTs) are responsible for cellular uptake of hexoses. Elevated expression of GLUTs, particularly GLUT1 and GLUT3, is required to fuel the hyperproliferation of cancer ...cells, making GLUT inhibitors potential anticancer therapeutics. Meanwhile, GLUT inhibitor-conjugated insulin is being explored to mitigate the hypoglycemia side effect of insulin therapy in type 1 diabetes. Reasoning that exofacial inhibitors of GLUT1/3 may be favored for therapeutic applications, we report here the engineering of a GLUT3 variant, designated GLUT3exo, that can be probed for screening and validating exofacial inhibitors. We identify an exofacial GLUT3 inhibitor SA47 and elucidate its mode of action by a 2.3 Å resolution crystal structure of SA47-bound GLUT3. Our studies serve as a framework for the discovery of GLUTs exofacial inhibitors for therapeutic development.
The preparation of N‐heterocyclic carbene‐stabilized iridium nanoparticles and their application in hydrogen isotope exchange reactions is reported. These air‐stable and easy‐to‐handle iridium ...nanoparticles showed a unique catalytic activity, allowing selective and efficient hydrogen isotope incorporation on anilines using D2 or T2 as isotopic source. The usefulness of this transformation has been demonstrated by the deuterium and tritium labeling of diverse complex pharmaceuticals.
Iridium nanoparticles stabilized by N‐heterocyclic carbenes were prepared and applied in hydrogen isotope exchange reactions. These air‐stable and easy‐to‐handle nanoparticles allowed selective and efficient hydrogen isotope incorporation on anilines using D2 or T2 as isotopic source. Their usefulness was demonstrated by the deuterium and tritium labeling of diverse complex pharmaceuticals.
Purpose
The primary aim of this study was to determine cabazitaxel’s affinity for the
ABCB1
/P-glycoprotein (P-gp) transporter compared to first-generation taxanes.
Methods
We determined the kinetics ...of drug accumulation and retention using
14
C-labeled taxanes in multidrug-resistant (MDR) cells. In addition, membrane-enriched fractions isolated from doxorubicin-selected MES-SA/Dx5 cells were used to determine sodium orthovanadate-sensitive ATPase stimulation after exposure to taxanes. Custom
3
H-azido-taxane analogues were synthesized for the photoaffinity labeling of P-gp.
Results
The maximum intracellular drug concentration was achieved faster with
14
C-cabazitaxel (5 min) than
14
C-docetaxel (15–30 min). MDR cells accumulated twice as much cabazitaxel than docetaxel, and these levels could be restored to parental levels in the presence of the P-gp inhibitor PSC-833 (valspodar). Efflux in drug-free medium confirmed that MDR cells retained twice as much cabazitaxel than docetaxel. There was a strong association (
r
2
= 0.91) between the degree of taxane resistance conferred by P-gp expression and the accumulation differences observed with the two taxanes. One cell model expressing low levels of P-gp was not cross-resistant to cabazitaxel while demonstrating modest resistance to docetaxel. Furthermore, there was a 1.9 × reduction in sodium orthovanadate-sensitive ATPase stimulation resulting from treatment with cabazitaxel compared to docetaxel. We calculated a dissociation constant (Kd) value of 1.7 µM for
3
H-azido-docetaxel and ~ 7.5 µM for
3
H-azido-cabazitaxel resulting in a 4.4 × difference in P-gp labeling, and cold docetaxel was a more effective competitor than cabazitaxel.
Conclusion
Our studies confirm that cabazitaxel is more active in
ABCB1
(+) cell models due to its reduced affinity for P-gp compared to docetaxel.
Conventional thermal and microwave conditions were compared for hydrogen–deuterium (H/D) exchange reactions of aminobenzoic acids catalysed by NaBD4‐activated Pd/C or RhCl3 with D2O as the deuterium ...source. We also investigated different NaBD4‐activated metal catalysts (including Pd/C, RhCl3 and Pt/C) under microwave conditions for an efficient H/D exchange of aromatic and heterocyclic compounds. Even higher deuterium incorporations were obtained for Pd/C and Pt/C catalyst mixtures due to the previously observed synergistic effect. Finally, we have applied these optimised conditions for one‐step syntheses of the MS standards of several pharmaceutically active compounds.
Efficient hydrogen–deuterium exchange of aromatic and heterocyclic compounds under microwave conditions by using NaBD4‐activated Pd/C, RhCl3 and Pt/C catalysts is reported (see scheme). Even higher deuterium incorporations were obtained for mixtures of Pd/C and Pt/C catalysts due to a synergistic effect.
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