“Clickable” Vitamin B12 Derivative

A “clickable” vitamin B₁₂ derivative possessing the azide functionality at the 5′‐position was synthesized by means of a two‐step procedure on the gram scale. The reaction of cobalamin with mesyl chloride (MsCl) afforded the 5′‐OMs derivative, which was subsequently transformed to the desired 5′‐azide, the structure of which was confirmed using X‐ray analysis. It proved to be reactive in the azide–alkyne 1,3‐dipolar cycloaddition reaction to give substituted triazoles in high yields. A study of the reaction conditions and the scope of the process are reported.     

Cyclic Peptides as Drugs for Intracellular Targets: The Next Frontier in Peptide Therapeutic Development

Developing macrocyclic peptides that can reach intracellular targets is a significant challenge. This review discusses the most recent strategies used to develop cell permeable cyclic peptides that maintain binding to their biological target inside the cell. Macrocyclic peptides are unique from small molecules because traditional calculated physical properties are unsuccessful for predicting cell membrane permeability. Peptide synthesis and experimental membrane permeability is the only strategy that effectively differentiates between cell permeable and cell impermeable molecules. Discussed are chemical strategies, including backbone N-methylation and stereochemical changes, which have produced molecular scaffolds with improved cell permeability. However, these improvements often come at the expense of biological activity as chemical modifications alter the peptide conformation, frequently impacting the compound's ability to bind to the target. Highlighted is the most promising approach, which involves side-chain alterations that improve cell permeability without impact binding events.     

Gold‐Catalyzed Asymmetric Allylic Substitution of Free Alcohols: An Enantioselective Approach to Chiral Chromans with Quaternary Stereocenters for the Synthesis of Vitamin E and Analogues

The enantioselective synthesis of α‐ and γ‐tocopherol (the most biologically active members of vitamin E family) and analogues has been accomplished employing a new enantioselective gold catalyzed intramolecular allylic alkylation reaction followed by an olefin cross‐metathesis as key steps. The methodology proved to be applicable to different olefins highlighting its potential for the synthesis of diverse libraries.     

Zinc Substitution of Cobalt in Vitamin B12: Zincobyric acid and Zincobalamin as Luminescent Structural B12‐Mimics

Replacing the central cobalt ion of vitamin B₁₂ by other metals has been a long‐held aspiration within the B₁₂‐field. Herein, we describe the synthesis from hydrogenobyric acid of zincobyric acid ( Znby ) and zincobalamin ( Znbl ), the Zn‐analogues of the natural cobalt‐corrins cobyric acid and vitamin B₁₂, respectively. The solution structures of Znby and Znbl were studied by NMR‐spectroscopy. Single crystals of Znby were produced, providing the first X‐ray crystallographic structure of a zinc corrin. The structures of Znby and of computationally generated Znbl were found to resemble the corresponding Co^II‐corrins, making such Zn‐corrins potentially useful for investigations of B₁₂‐dependent processes. The singlet excited state of Znby had a short life‐time, limited by rapid intersystem crossing to the triplet state. Znby allowed the unprecedented observation of a corrin triplet (E^T=190 kJ mol^?1) and was found to be an excellent photo‐sensitizer for ¹O₂ (Φ_Δ=0.70).     

Selective Targeting of Tumor and Stromal Cells By a Nanocarrier System Displaying Lipidated Cathepsin B Inhibitor

Cathepsin B (CtsB) is a lysosomal cysteine proteinase that is specifically translocated to the extracellular milieu during cancer progression. The development of a lipidated CtsB inhibitor incorporated into the envelope of a liposomal nanocarrier (LNC‐NS‐629) is described. Ex vivo and in vivo studies confirmed selective targeting and internalization of LNC‐NS‐629 by tumor and stromal cells, thus validating CtsB targeting as a highly promising approach to cancer diagnosis and treatment.     

Experimental Study of Hydrogen Bonding Potentially Stabilizing the 5′‐Deoxyadenosyl Radical from Coenzyme B12

Coenzyme B₁₂ can assist radical enzymes that accomplish the vicinal interchange of a hydrogen atom with a functional group. It has been proposed that the Co? C bond homolysis of coenzyme B₁₂ to cob(II)alamin and the 5′‐deoxyadenosyl radical is aided by hydrogen bonding of the corrin C19? H to the 3′‐O of the ribose moiety of the incipient 5′‐deoxyadenosyl radical, which is stabilized by 30 kJ mol^?1 (B. Durbeej et al., Chem. Eur. J. 2009 , 15, 8578–8585). The diastereoisomers (R)‐ and (S)‐2,3‐dihydroxypropylcobalamin were used as models for coenzyme B₁₂. A downfield shift of the NMR signal for the C19? H proton was observed for the (R)‐isomer (δ=4.45 versus 4.01 ppm for the (S)‐isomer) and can be ascribed to an intramolecular hydrogen bond between the C19? H and the oxygen of CHOH. Crystal structures of (R)‐ and (S)‐2,3‐dihydroxypropylcobalamin showed C19? H???O distances of 3.214(7) Å (R‐isomer) and 3.281(11) Å (S‐isomer), which suggest weak hydrogen‐bond interactions (?ΔG<6 kJ mol^?1) between the CHOH of the dihydroxypropyl ligand and the C19? H. Exchange of the C19? H, which is dependent on the cobalt redox state, was investigated with cob(I)alamin, cob(II)alamin, and cob(III)alamin by using NMR spectroscopy to monitor the uptake of deuterium from deuterated water in the pH range 3–11. No exchange was found for any of the cobalt oxidation states. 3′,5′‐Dideoxyadenosylcobalamin, but not the 2′,5′‐isomer, was found to act as a coenzyme for glutamate mutase, with a 15‐fold lower k_cat/K_M than 5′‐deoxyadenosylcobalamin. This indicates that stabilization of the 5′‐deoxyadenosyl radical by a hydrogen bond that involves the C19? H and the 3′‐OH group of the cofactor is, at most, 7 kJ mol^?1 (?ΔG). Examination of the crystal structure of glutamate mutase revealed additional stabilizing factors: hydrogen bonds between both the 2′‐OH and 3′‐OH groups and glutamate 330. The actual strength of a hydrogen bond between the C19? H and the 3′‐O of the ribose moiety of the 5′‐deoxyadenosyl group is concluded not to exceed 6 kJ mol^?1 (?ΔG).     

Delivery of myo‐Inositol Hexakisphosphate to the Cell Nucleus with a Proline‐Based Cell‐Penetrating Peptide

Inositol hexakisphosphate (InsP₆) is a central member of the inositol phosphate messengers in eukaryotic cells. Tools to manipulate the level of InsP₆, particularly with compartment selectivity, are needed to enable functional cellular studies. We present cationic octa‐(4S)guanidiniumproline ( Z8 ) for the delivery of InsP₆ into the cell nucleus. CD spectroscopy, binding affinity, dynamic light scattering, and computational studies revealed that Z8 binds tightly to InsP₆ and upon binding undergoes a conformational change from a PPII‐helical structure to a structure that forms aggregates. The unique conformational features of the cationic oligoproline enable complex formation and cellular delivery of InsP₆ with considerably greater efficacy than the flexible counterpart octaarginine.     

Hydroxyapatite Hierarchically Nanostructured Porous Hollow Microspheres: Rapid,Sustainable Microwave‐Hydrothermal Synthesis by Using Creatine Phosphate as an Organic Phosphorus Source and Application in Drug Delivery and Protein Adsorption

Hierarchically nanostructured porous hollow microspheres of hydroxyapatite (HAP) are a promising biomaterial, owing to their excellent biocompatibility and porous hollow structure. Traditionally, synthetic hydroxyapatite is prepared by using an inorganic phosphorus source. Herein, we report a new strategy for the rapid, sustainable synthesis of HAP hierarchically nanostructured porous hollow microspheres by using creatine phosphate disodium salt as an organic phosphorus source in aqueous solution through a microwave‐assisted hydrothermal method. The as‐obtained products are characterized by powder X‐ray diffraction (XRD), Fourier‐transform IR (FTIR) spectroscopy, SEM, TEM, Brunauer–Emmett–Teller (BET) nitrogen sorptometry, dynamic light scattering (DLS), and thermogravimetric analysis (TGA). SEM and TEM micrographs show that HAP hierarchically nanostructured porous hollow microspheres consist of HAP nanosheets or nanorods as the building blocks and DLS measurements show that the diameters of HAP hollow microspheres are within the range 0.8–1.5 μm. The specific surface area and average pore size of the HAP porous hollow microspheres are 87.3 m²g^?1 and 20.6 nm, respectively. The important role of creatine phosphate disodium salt and the influence of the experimental conditions on the products were systematically investigated. This method is facile, rapid, surfactant‐free and environmentally friendly. The as‐prepared HAP porous hollow microspheres show a relatively high drug‐loading capacity and protein‐adsorption ability, as well as sustained drug and protein release, by using ibuprofen as a model drug and hemoglobin (Hb) as a model protein, respectively. These experiments indicate that the as‐prepared HAP porous hollow microspheres are promising for applications in biomedical fields, such as drug delivery and protein adsorption.     

Dendrimer Functionalization with a Membrane‐Interacting Domain of Herpes Simplex Virus Type 1: Towards Intracellular Delivery

A poly(amide)‐based dendrimer was synthesized and functionalized with the membrane‐interacting peptide gH(625–644) (gH625) derived from the herpes simplex virus type 1 (HSV‐1) envelope glycoprotein H, which has previously been shown to assist in delivering large cargoes across the cellular membrane. We demonstrate that the attachment of the gH625 peptide sequence to the termini of a dendrimer allows the conjugate to penetrate into the cellular matrix, whereas the unfunctionalized dendrimer is excluded from translocation. The peptide‐functionalized dendrimer is rapidly taken into the cells mainly through a non‐active translocation mechanism. Our results suggest that the presented peptidodendrimeric scaffold may be a promising material for efficient drug delivery.     

Vitamin B12 Phosphate Conjugation and Its Effect on Binding to the Human B12‐Binding Proteins Intrinsic Factor and Haptocorrin

The binding of vitamin B₁₂ derivatives to human B₁₂ transporter proteins is strongly influenced by the type and site of modification of the cobalamin original structure. We have prepared the first cobalamin derivative modified at the phosphate moiety. The reaction conditions were fully optimized and its limitations examined. The resulting derivatives, particularly those bearing terminal alkyne and azide groups, were isolated and used in copper‐catalyzed alkyne–azide cycloaddition reactions (CuAAC). Their sensitivity towards light revealed their potential as photocleavable molecules. The binding abilities of selected derivatives were examined and compared with cyanocobalamin. The interaction of the alkylated derivatives with haptocorrin was less affected than the interaction with intrinsic factor. Furthermore, the configuration of the phosphate moiety was irrelevant to the binding process.