Natural Macrocycles Research Articles

Chiral Macroheterocycles as Inducers of Helical Liquid Crystals: Molecular Design, Specialty of Functioning

AbstractThe mini‐review is devoted to the influence of the structure and properties of chiral macroheterocyclic dopants on the induction of helical liquid‐crystalline phases. Using the example of solutions of synthetic porphyrins, camphor substituted hemiporphyrazines and tetrapyrazinoporphyrazines, as well as chemically modified natural macrocycles based on chlorin e6 derivatives and their metal complexes in nematic liquid crystals, the features of the mesomorphic, dielectric and rheological properties of induced spiral mesophases are discussed.

Increasing Reaction Rates of Water-Soluble Porphyrins for 64Cu Radiopharmaceutical Labeling.

Searching for new compounds and synthetic routes for medical applications is a great challenge for modern chemistry. Porphyrins, natural macrocycles able to tightly bind metal ions, can serve as complexing and delivering agents in nuclear medicine diagnostic imaging utilizing radioactive nuclides of copper with particular emphasis on 64Cu. This nuclide can, due to multiple decay modes, serve also as a therapeutic agent. As the complexation reaction of porphyrins suffers from relatively poor kinetics, the aim of this study was to optimize the reaction of copper ions with various water-soluble porphyrins in terms of time and chemical conditions, that would meet pharmaceutical requirements and to develop a method that can be applied for various water-soluble porphyrins. In the first method, reactions were conducted in a presence of a reducing agent (ascorbic acid). Optimal conditions, in which the reaction time was 1 min, comprised borate buffer at pH 9 with a 10-fold excess of ascorbic acid over Cu2+. The second approach involved a microwave-assisted synthesis at 140 °C for 1-2 min. The proposed method with ascorbic acid was applied for radiolabeling of porphyrin with 64Cu. The complex was then subjected to a purification procedure and the final product was identified using high-performance liquid chromatography with radiometric detection.

Modular Biomimetic Strategy Enabled Discovery of Simplified Pseudo-Natural Macrocyclic P-Glycoprotein Inhibitors Capable of Overcoming Multidrug Resistance.

Natural macrocycles have shown impressive activity to overcome P-glycoprotein (P-gp)-mediated multidrug resistance (MDR). However, the total synthesis and structural modification of natural macrocycles are challenging, which would hamper the deeper investigations of their structure-activity relationship (SAR) and drug likeness. Herein, we describe a modular biomimetic strategy to expeditiously achieve a new class of macrocycles featuring polysubstituted 1,3-diene, which efficiently inhibited P-gp and reversed MDR in cancer cells. The SAR analysis revealed that the size and linker of the macrocycles are important structural characteristics to restore activity. Particularly, 32 containing a naphthyl group and (d)-Phe moiety has higher potency with an excellent reversal fold than verapamil at a concentration of 5 μM, which induces conformational change of P-gp and inhibits its function instead of altering P-gp expression. Furthermore, 23 and 32 were identified to be attractive leads, which possess a good pharmacokinetic profile and antitumor activity in a KBV200 xenograft mouse model.

Efficient Synthesis for a Wide Variety of Patellamide Derivatives and Phosphatase Activity of Copper-Patellamide Complexes.

Copper complexes of patellamides have shown catalytic activity in a variety of reactions but their biological function remains unknown. There are significant differences between the natural macrocycles and synthetic analogues in the various catalytic activities. It therefore is essential to be able to perform in vivo and ex vivo reference measurements with the natural patellamide macrocycles, very similar derivatives and a large range of synthetic analogues. The preparative method described allows for a highly adaptable synthetic process producing building blocks for a large range of patellamide derivatives: apart from natural compounds, a new synthetic patellamide was prepared that does not have any substituents at any of the four heterocycles. Together with the variation of substituents at the aliphatic backbone, this allowed to elucidate the catalytic activity for phosphoester hydrolysis as a function of the structure and dynamics of the dicopper(II)‐patellamide complexes, both by experiment and DFT‐based mechanistic studies.

Interplay among Conformation, Intramolecular Hydrogen Bonds, and Chameleonicity in the Membrane Permeability and Cyclophilin A Binding of Macrocyclic Peptide Cyclosporin O Derivatives.

A macrocyclic peptide scaffold with well-established structure-property relationship is desirable for tackling undruggable targets. Here, we adopted a natural macrocycle, cyclosporin O (CsO) and its derivatives (CP1-3), and evaluated the impact of conformation on membrane permeability, cyclophilin A (CypA) binding, and the pharmacokinetic (PK) profile. In nonpolar media, CsO showed a similar conformation to cyclosporin A (CsA), a well-known chameleonic macrocycle, but less chameleonic behavior in a polar environment. The weak chameleonicity of CsO resulted in decreased membrane permeability; however, the more rigid conformation of CsO was not detrimental to its PK profile. CsO exhibited a higher plasma concentration than CsA, which resulted from minimal CypA binding and lower accumulation in red blood cells and moderate oral bioavailability (F = 12%). Our study aids understanding of CsO, a macrocyclic peptide that is less explored than CsA but with greater potential for diversity generation and rational design.

Cyclodextrins: promising scaffolds for MRI contrast agents.

Magnetic resonance imaging (MRI) is a powerful tool for non-invasive, high-resolution three-dimensional medical imaging of anatomical structures such as organs and tissues. The use of contrast agents based on gadolinium chelates started in 1988 to improve the quality of the image, since researchers and industry focused their attention on the development of more efficient and stable structures. This review is about the state of the art of MRI contrast agents based on cyclodextrin scaffolds. Chemical engineering strategies are herein reported including host–guest inclusion complexation and covalent linkages. It also offers descriptions of the MRI properties and in vitro and in vivo biomedical applications of these emerging macrostructures. It highlights that these supramolecular associations can improve the image contrast, the sensitivity, and the efficiency of MRI diagnosis by targeting cancer tumors and other diseases with success proving the great potential of this natural macrocycle.

Topological Glycopolymers as Agglutinator and Inhibitor: Cyclic versus Linear.

Carbohydrates play an important role in biological processes for their specific interactions with proteins. Cyclic glycopolymers are promising to mimic the topology of natural macrocycle-biomacromolecules due to their unique architecture of lacking chain ends. To systematically study the effect of glycopolymer architecture on the interactions with protein, the cyclic glycopolymers bearing galactose side-chain (cyclic PMAGn ) with three degrees of polymerization (n = 14, 24, 47) are prepared for the first time. The cyclic PMAGn exhibits unique properties in agglutinating and inhibiting proteins in subsequent studies by comparison with the linear precursor with the same molecular weights. More impressively, the cyclic PMAGn highlight the improved performance of cyclic architecture. For example, the cyclic PMAGn shows superior inhibition abilities to suppress amyloid formation from amyloid β protein fragment 1-42 aggregation and block the specific interaction between bacteria and galactose-modified surface compared to that of respective linear counterpart. This interesting finding suggests that the architecture of cyclic glycopolymers may be capable of optimizing the ability to bind or inhibit proteins in biological processes.

The Hydrogenobyric Acid Structure Reveals the Corrin Ligand as an Entatic State Module Empowering B12 Cofactors for Catalysis.

The B12 cofactors instill a natural curiosity regarding the primordial selection and evolution of their corrin ligand. Surprisingly, this important natural macrocycle has evaded molecular scrutiny, and its specific role in predisposing the incarcerated cobalt ion for organometallic catalysis has remained obscure. Herein, we report the biosynthesis of the cobalt‐free B12 corrin moiety, hydrogenobyric acid (Hby), a compound crafted through pathway redesign. Detailed insights from single‐crystal X‐ray and solution structures of Hby have revealed a distorted helical cavity, redefining the pattern for binding cobalt ions. Consequently, the corrin ligand coordinates cobalt ions in desymmetrized “entatic” states, thereby promoting the activation of B12‐cofactors for their challenging chemical transitions. The availability of Hby also provides a route to the synthesis of transition metal analogues of B12.

Macrocyclic Control in Helix Mimetics.

The α-helix is the most commonly found natural secondary structure in proteins and is intrinsic to many protein-protein interactions involved in important biological functions. Novel peptides designed to mimic helices found in nature employ a variety of methods to control their structure. These approaches are significant due to potential applications in developing new therapeutic agents and materials. Over the years, many strategies have emerged to influence, initiate, and propagate helical content in short, synthetic peptides. Early innovations used the natural macrocycle tether of disulfide bond formation, metal-mediated or lactam group addition as a means to prompt helical formation. These examples have been applied to a host of peptides as inhibitors toward relevant diseases including cancer, viral and bacterial infection. In the most recent decades, hydrocarbon bridges to "staple" peptides across side chains or hydrogen bond surrogates in the backbone of peptides have been effective in producing biologically functional, helical peptidomimetics with non-natural elements, increased protease resistance and potency in vitro and in vivo. Modern methods expand and elaborate these, with applications of functional peptides from both synthetic and recombinant origins. Overall, efforts persist using these strategies to create peptides with great biological potential and a better understanding of the control of helical structure in protein folding.

Phakellistatins: An Underwater Unsolved Puzzle

A critical summary on the discovery of the nineteen members of the phakellistatin family (phakellistatin 1–19), cytotoxic proline-rich cyclopeptides of marine origin, is reported. Isolation, structural elucidation, and biological properties of the various-sized natural macrocycles are described, along with the total syntheses and the enigmatic issues of the cytotoxic activity reproducibility.

Cytotoxic turrianes from Kermadecia elliptica: Hemisynthesis and biological activities of kermadecin A derivatives

Kermadecin A is a cytotoxic natural macrocycle, containing a bisresorcinol and a pyran ring. A series of derivatives has been synthesized from the natural product in order to investigate the role of the different substructures in the biological activity. In this series, free phenolic groups play an essential role in the biological activity as demonstrated by the poor activity exhibited by alkylated derivatives. Interestingly, biological activity can be restored by oxidation of the double bond 27,28 of the pyran ring. Nevertheless, if this double bond of kermadecin A is only reduced, then the biological activity is not affected.

The mechanism of patellamide macrocyclization revealed by the characterization of the PatG macrocyclase domain

Peptide macrocycles are found in many biologically active natural products. Their versatility, resistance to proteolysis and ability to traverse membranes has made them desirable molecules. Although technologies exist to synthesize such compounds, the full extent of diversity found among natural macrocycles has yet to be achieved synthetically. Cyanobactins are ribosomal peptide macrocycles encompassing an extraordinarily diverse range of ring sizes, amino acids and chemical modifications. We report the structure, biochemical characterization and initial engineering of the PatG macrocyclase domain of Prochloron sp. from the patellamide pathway that catalyzes the macrocyclization of linear peptides. The enzyme contains insertions in the subtilisin fold to allow it to recognize a three-residue signature, bind substrate in a preorganized and unusual conformation, shield an acyl-enzyme intermediate from water and catalyze peptide bond formation. The ability to macrocyclize a broad range of nonactivated substrates has wide biotechnology applications.

Metátese de olefinas aplicada ao fechamento de anéis: uma ferramenta poderosa para a síntese de macrociclos naturais

For a quarter of a century, metathesis has become indispensable for the synthesis of natural and non-natural products, particularly of biologically active compounds. This review illustrates through a maximum of appropriate examples the power and the versatility of the metathesis ring-closure (RCM) reaction as a key ring-closure methodology for the synthesis of natural macrocycles. Its high functional group compatibility as well as the possibility of further transformations makes this reaction a powerful tool in the cases where the structural framework and function requirements are difficult to meet.

Natural macrocyclic molecules have a possible limited structural diversity

This paper examines ring size patterns of natural product macrocycles. Evidence is presented that natural macrocycles containing 14-, 16-, and 18-membered rings are of frequent occurrence based on a data mining study. The results raise a question about the limited diversity of macrocycle ring sizes and the nature of the constraints that may cause them. The data suggest that the preference bears no relationship to the odd-even frequency in natural fatty acids. The trends reported here, along with those reported previously (Wessjohann et al. (2005) Mol Divers 9:171), may be generalized to better understand the possible structure preferences of natural macrocycles.

Rapid Combinatorial Access to Macrocyclic Ansapeptoids and Ansapeptides with Natural-Product-like Core Structures

14-Membered ansa-cyclopeptide alkaloids are among the most abundant natural macrocycles and thus valuable templates for diversity-oriented synthesis with biological relevance. A rapid synthesis of the core structure is conceivable by a combination of an Ugi four-component reaction with bifunctional building blocks to form the dipeptoid part, followed by a suitable macrocyclization reaction. The latter step is crucial, and an uncommon macroetherification gave the best results. The use of ammonium salts allows direct access to peptides instead of peptoids. Depending on the substitution pattern, some cyclopeptoids show planar chirality despite free rotation of the phenylene group. © Georg Thieme Verlag Stuttgart.

Molecular recognition by natural macrocycles. I. d-tubocurarine as a host molecule for organic anions.

The binding of 8-anilino-1-naphthalenesulfonate and 15 anions of substituted benzoic, aliphatic dicarboxylic, and N-acetyl-alpha-amino acids to a macrocyclic alkaloid d-tubocurarine in aqueous solution has been studied by fluorometry, conductometry, and 1H NMR. The binding constants vary from ca. 50 to 3300 M-1 depending on the guest structure, charge and hydrophobicity. The results of fluorescence and NMR studies show that the host-guest complexation of the anions of aromatic acids involves the formation of a salt bridge between the quaternary nitrogen of the alkaloid and the anionic group of the guest as well as hydrophobic/Van der Waals interactions between the guest and host aromatic moieties. The binding of dianions of aliphatic dicarboxylic acids most probably is purely electrostatic. In general, d-tubocurarine possesses binding ability comparable to that of synthetic cyclophanes. It binds enantiospecifically anions of N-acetyl-alpha-amino acids and discriminates between positional isomers of anions of hydroxy and carboxy substituted benzoic acids.

Molecular recognition by natural macrocycles. Part II. Esterolytic activity and chiral discrimination of amino acid derivatives by the zwitterionic form of (+)-tubocurarine †

The esterase and complexation properties of the zwitterionic form of a macrocyclic alkaloid (+)-tubocurarine possessing two phenolic nucleophilic groups are described. Cleavage of 4-nitrophenyl esters of N-protected phenylalanine enantiomers involves reaction paths with one and two alkaloid molecules. Substrate binding enantioselectivity is large and is opposite to the kinetic enantioselectivity, leading to the modest observed enantioselectivity of the reaction, which reaches a maximum (kL/kD ≈ 1.5) at ca. 0.002 mol dm–3 alkaloid concentration and practically disappears on going to 0.01 mol dm–3 alkaloid solution. Addition of boric acid initially enhances the reaction rate and enantiospecificity, but in more concentrated borate solutions the expected inhibition due to blocking of the phenolate groups is observed. For the first time reported for an alkaloid, the esterolytic activity of (+)-tubocurarine towards 4-nitrophenyl acetate falls on a common Bronsted plot together with cyclodextrins and some synthetic macrocycles. Binding of enantiomers of differently charged derivatives of alanine, phenylalanine and β-phenylethylamine to the zwitterionic form of (+)-tubocurarine in aqueous solution was studied by 1H NMR and fluorescence titration. The binding constants vary from <5 dm3 mol–1 for alanine to ca. 50 dm3 mol–1 for phenylalanine derivatives and the binding enantioselectivity varies from marginal for N-acetylphenylalanine enantiomers to a quite notable, three-fold differentiation between L- and D-phenylalanine. While the enantiospecificity depends primarily on electrostatic interactions, the overall stability is determined by guest hydrophobicity. This conclusion was confirmed by docking calculations for enantiomers of phenylalanine. Addition of amino acid derivatives to solutions containing (+)-tubocurarine and highly fluorescent 8-anilinonaphthalenesulfonate anion leads to enantioselective spectral responses which are indicative of formation of ternary complexes.

Molecular recognition by natural macrocycles. I. d-tubocurarine as a host molecule for organic anions

The binding of 8-anilino-1-naphthalenesulfonate and 15 anions of substituted benzoic, aliphatic dicarboxylic, and N-acetyl-α-amino acids to a macrocyclic alkaloid d-tubocurarine in aqueous solution has been studied by fluorometry, conductometry, and 1H NMR. The binding constants vary from ca. 50 to 3300 M−1 depending on the guest structure, charge and hydrophobicity. The results of fluorescence and NMR studies show that the host-guest complexation of the anions of aromatic acids involves the formation of a salt bridge between the quaternary nitrogen of the alkaloid and the anionic group of the guest as well as hydrophobic/Van der Waals interactions between the guest and host aromatic moieties. The binding of dianions of aliphatic dicarboxylic acids most probably is purely electrostatic. In general, d-tubocurarine possesses binding ability comparable to that of synthetic cyclophanes. It binds enantiospecifically anions of N-acetyl-α-amino acids and discriminates between positional isomers of anions of hydroxy and carboxy substituted benzoic acids.

Molecular Recognition by Natural Macrocycles. I. d‐Tubocurarine as a Host Molecule for Organic Anions

The binding of 8-anilino-1-naphthalenesulfonate and 15 anions of substituted benzoic, aliphatic dicarboxylic, and N-acetyl-α-amino acids to a macrocyclic alkaloid d-tubocurarine in aqueous solution has been studied by fluorometry, conductometry, and 1H NMR. The binding constants vary from ca. 50 to 3300 M−1 depending on the guest structure, charge and hydrophobicity. The results of fluorescence and NMR studies show that the host-guest complexation of the anions of aromatic acids involves the formation of a salt bridge between the quaternary nitrogen of the alkaloid and the anionic group of the guest as well as hydrophobic/Van der Waals interactions between the guest and host aromatic moieties. The binding of dianions of aliphatic dicarboxylic acids most probably is purely electrostatic. In general, d-tubocurarine possesses binding ability comparable to that of synthetic cyclophanes. It binds enantiospecifically anions of N-acetyl-α-amino acids and discriminates between positional isomers of anions of hydroxy and carboxy substituted benzoic acids.