Synthesis and Biological Properties of Enkephalin-like Peptides Containing Adamantylalanine in Position 4 and 5

The syntheses of seven [D -ala-²]-enkephalin analogues, H-Tyr-ala-Gly-X-Y, with X-Y = Phe-Ada-OH, Phe-ada-OH, Phe-Ada-NH₂, Phe-ada-NH₂, Ada-Leu-OH, Ada-Leu-NH₂, and Ada-Ada-NH₂ are described. The compounds with Y = Ada (= L -Ada) or ada (= D -Ada) show pronounced morphine-like activities in certain bioassays, whereas those with X = Ada were most inactive. The analogues were used to explore the influence of steric, electronic, and hydrophobic properties of the side chains of X and Y on opioid activity (see [14]).     

Synthesis of a Novel Tricyclic Dipeptide Template and Its Incorporation into a Cyclic Peptide Mimetic Containing an NPNA Motif

A novel tricyclic dipeptide template, formally derived by coupling (2S,4S)-4-aminoproline (Pro(NH₂)) and (S)-2-(carboxymethyl)proline (Pro(CH₂COOH)) as a diketopiperazine, has been synthesized in a form suitable for solid-phase peptide synthesis using Fmoc chemistry. This template was incorporated into the cyclic molecule cyclo(-Ala¹-Asn²-Pro³-Asn⁴-Ala⁵-Ala⁶-Temp-) (Temp = template), whose conformation in H₂O was studied by NMR methods. Average solution structures derived by restrained simulated annealing point to a highly populated βI-turn within the Asn-Pro-Asn-Ala motif and also indicate which conformations are likely to be preferred by the template.     

Protein-Loop Mimetics: A Diketopiperazine-Based Template to Stabilize Loop Conformations in Cyclic Peptides Containing the NPNA and RGD Motifs

We explore here an approach to mimic the structures and biological functions of protein loops in small synthetic molecules, by grafting the loop of interest onto an organic template comprising a bicyclic diketopiperazine, prepared by the formal coupling of (2S,4S)-4-aminoproline (Pro(NH₂)) and aspartic acid (Asp). The Fmoc-protected template 4 is used to prepare cyclo(-Ala¹-Asn²-Pro³-Asn⁴-Ala⁵- Ala⁶-Temp-) ( 5 ) and cyclo(-Ala¹-Arg²-Gly³-Asp⁴-Temp-) ( 6 ) (where Temp = template derived from 4 ), containing the Asn-Pro-Asn-Ala (NPNA) and Arg-Gly-Asp (RGD) motifs. The conformational properties of these molecules are studied in aqueous solution by NMR and simulated-annealing methods. The NPNA motif, an immunodominant epitope on the circumsporozoite surface protein of the malaria parasite Plasmodium falciparum, is shown to adopt a stable type-I β-turn in 5 . The template in 5 adopts a preferred conformation with Pro(NH₂)χ₁ ≈? ?35° and the Asp moiety χ₁ ≈? 70°. A different template conformation is inferred for 6 , with Pro(NH₂)χ₁ ≈? 0°, but the ARGD loop appears by NMR to undergo rapid conformational averaging. Solid-phase binding assays reveal that 6 displays modest antagonist activity towards both the integrin α_IIbβ₃ and α_vβ₃ receptors.     

The Synthesis of [4-Carboranylalanine, 5-Leucine]-Enkephalin (Including an Improved Preparation of t-Butoxycarbonyl-L-o-carboranylalnine,New Derivatives of L-Propargylglycine,and a Note on Melanotropic and Opiate Receptor Binding Characteristics)

The title compound, an analogue of [Leu⁵]-enkephalin with L -o-carboranylalanine replacing L -phenylalanine in position 4, was prepared by fragment condensation. The analogue has a 3-fold higher affinity for rat brain opiate receptors in the [³H]naloxone competition assay than natural [Leu⁵]-enkephalin. Like [Leu⁵]-enkephalin and N^a-acetyl-[Leu⁵]-enkephalin, the N-terminal tripeptide fragment, H · Tyr-Gly-Gly · OH, had no melanotropic activity in the Rana pipiens frog skin assay. A convenient, direct synthesis of methyl t-butoxycarbonyl-L -propargylglycinate is described, and the ¹³C-NMR. spectra of L -o-carboranylalanine recorded. The procedure was extended to the preparation of BOC · Car-Leu · OMe from BOC · Pra-Leu · OMe. A number of new propargylglycine derivatives are reported.     

Opioid Peptides Determination by Tyrosinase-Modified Oxygen Electrode

Abstract

Opioid peptides morphiceptin (Tyr-Pro-Phe-Pro-NH₂), [D-Ala², D-Leu⁵]-enkephalin (Tyr-D-Ala-Gly-Phe-D-Leu, DADLE) and [D-Thr²]-Leu-enkephalin-Thr (Tyr-D-Thr-Gly-Phe-Leu-Thr, DTLET) containing tyrosine has been studied in the reaction with mushroom tyrosinase immobilized on Clark-type oxygen electrode. A 4–6-times higher response is observed for tyrosine compared to peptides. The detection limit of the tyrosinase-modified electrode for DADLE, morphiceptin and DTLET was 6 μM, 9 μM and 16 μM, respectively.     

The effect of the amido substituent on polymer molecular weight in propene homopolymerisation by titanium cyclopentadienyl‐amide catalysts

In the homopolymerisation of propene by the cyclopentadienyl‐amide titanium catalyst systems [η⁵,η¹‐C₅H₄(CH₂)₂NR]TiCl₂/MAO and [η⁵,η¹‐C₅H₄(CH₂)₂NR]Ti(CH₂Ph)₂/B(C₆F₅)₃ (R = ^tBu, ⁱPr, Me), the catalyst with the smallest substituent (Me) on the amido moiety consistently gives the highest polymer molecular weight. This differs from the trend usually observed in related catalysts with tetramethylcyclopentadienyl‐amide ancillary ligands, where larger amide substituents result in higher molecular weights. Based on the present information a hypothesis is formulated in which an increased cation‐anion interaction for the less sterically hindered catalyst is responsible for disfavouring chain transfer relative to chain growth.     

Synthesis of 2-Phenyl-3-oxa-5-azatricyclo[4.4.0.02 , 7]decan-4-one

Cleavage of the lactone ring in 7-phenylbicyclo[3.1.1]heptan-6,7-carbolactone by the action of ammonia and hydrazine and subsequent oxidative cyclization of the resulting hydroxy amide and hydroxy hydrazide gave a cyclic carbamate, 3-oxa-5-azatricyclo[4.4.0.0^{2 , 7}]decan-4-one.     

Synthesis of liphophilic substituted ACTH-peptides

With a view to rendering ACTH peptides absorbable by the oral route, a series of such peptides with increased lipophilic character was built up. This paper describes the synthesis of eleven derivatives of the ACTH peptide [D -Ser¹, Lys^17,18]-β-corticotrophin-(1–19)-nonadeca-peptide, containing lipophilic alkyl substituents of different kinds and sizes, bound to the carboxyl of terminal proline either by ester or amide linkage. The unsubstituted peptide [D -Ser¹, Lys^17,18]-β-corticotrophin-(1–19)-nonadecapeptide, and its C-terminal amide were also synthesized.     

A Tricyclic Template Derived from (2S,4R)-4-Hydroxyproline for the Synthesis of Protein Loop Mimetics

A tricyclic diketopiperazine, formally derived by coupling (2S,4S)-4-aminoproline (Pro(NH₂)) and (2S,4R)-4-(carboxymethyl)proline (Pro(CH₂COOH)), is synthesized starting from readily available (2S,4R)-4-hydroxyproline. The resulting tricyclic template has carboxy and amino groups to which a peptide chain may be attached. The Fmoc-protected template 5 is incorporated into the cyclic molecule cyclo(-Ala¹-Asn²-Pro³-Asn⁴-Ala⁵-) ( 6 ) where Pro(NH₂)⁷ = Pro(CH₂COOH)⁸ represents the template, using solid-phase peptide synthesis with cyclization in solution. The molecule is shown by NMR and dynamic simulated annealing methods to adopt a preferred conformation in aqueous solution, which includes an extended backbone at the residues Asn²-Pro³-Asn⁴, and a type-Iβ-turn at . These studies show that this novel template may be used in the synthesis of cyclic peptide and protein mimetics having defined secondary structure in aqueous environments.     

Synthesis and complexation properties towards metal ions of new tri-substituted thiacalix[4]arenes

New thiacalix[4]arenes appended with three amide functions have been prepared. Their conformations have been solved thanks to ¹H NMR 2D correlation spectroscopy (COSY) and nuclear overhauser and exchange spectroscopy (NOESY). The complexation ability of these ligands towards various metal ions (Cd^2 + , Pb^2 + , Pd^2 + , Ni^2 + , Hg^2 + , Hg⁺, Ag⁺, Zn^2 +  and Cu^2 + ) has been investigated by the UV–vis absorption and the stoichiometry of the metal–ligand complexes was determined.     

C-Glucosylflavonoid biosynthesis from 2-hydroxynaringenin by Desmodium uncinatum (Jacq.) (Fabaceae)

[2′,3′,5′,6′-²H₄]-2-Hydroxynaringenin is synthesised and incubated with commercially available UDP-glucose and the crude protein extract from Desmoduim uncinatum leaves. The organic extract produces isotopically labelled [2′,3′,5′,6′-²H₄]-vitexin and [2′,3′,5′,6′-²H₄]-isovitexin. Repeating the experiment with denatured protein or replacing the 2-hydroxynaringenin with [2′,3′,5′,6′-²H₄]-apigenin or [2′,3′,5′,6′-²H₄]-naringenin results in no observable incorporation. 2-Hydroxynaringenin is therefore the substrate for C-glucosylflavonoid biosynthesis in D. uncinatum.     

Complexation Properties of N,N′,N″,N′′′‐[1,4,7,10‐Tetraazacyclododecane‐1,4,7,10‐tetrayltetrakis(1‐oxoethane‐2,1‐diyl)]tetrakis[glycine] (H4dotagl). Equilibrium,Kinetic, and Relaxation Behavior of the Lanthanide(III) Complexes

Eu³⁺, Dy³⁺, and Yb³⁺ complexes of the dota‐derived tetramide N,N′,N″,N′′′‐[1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetrayltetrakis(1‐oxoethane‐2,1‐diyl)]tetrakis[glycine] (H₄dotagl) are potential CEST contrast agents in MRI. In the [Ln(dotagl)] complexes, the Ln³⁺ ion is in the cage formed by the four ring N‐atoms and the amide O‐atom donor atoms, and a H₂O molecule occupies the ninth coordination site. The stability constants of the [Ln(dotagl)] complexes are ca. 10 orders of magnitude lower than those of the [Ln(dota)] analogues (H₄dota=1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid). The free carboxylate groups in [Ln(dotagl)] are protonated in the pH range 1–5, resulting in mono‐, di‐, tri‐, and tetraprotonated species. Complexes with divalent metals (Mg²⁺, Ca²⁺, and Cu²⁺) are also of relatively low stability. At pH>8, Cu²⁺ forms a hydroxo complex; however, the amide H‐atom(s) does not dissociate due to the absence of anchor N‐atom(s), which is the result of the rigid structure of the ring. The relaxivities of [Gd(dotagl)] decrease from 10 to 25°, then increase between 30–50°. This unusual trend is interpreted with the low H₂O‐exchange rate. The [Ln(dotagl)] complexes form slowly, via the equilibrium formation of a monoprotonated intermediate, which deprotonates and rearranges to the product in a slow, OH^?‐catalyzed reaction. The formation rates are lower than those for the corresponding Ln(dota) complexes. The dissociation rate of [Eu(dotagl)] is directly proportional to [H⁺] (0.1–1.0M HClO₄); the proton‐assisted dissociation rate is lower for [Eu(H₄dotagl)] (k₁=8.1?10^?6 M ^?1 s^?1) than for [Eu(dota)] (k₁=1.4?10^?5 M ^?1 s^?1).     

Six,Seven or Eight Coordinate FeII,CoII or NiII Complexes of Amide‐Appended Tetraazamacrocycles for ParaCEST Thermometry

Fe^II, Co^II and Ni^II complexes of two tetraazamacrocycles (1,4,8,11‐tetrakis(carbamoylmethyl)‐1,4,8,11‐tetraazacyclotetradecane ( L1 ) and 1,4,7,10‐tetrakis(carbamoylmethyl)‐1,4,7,10‐tetraazacyclododecane ( L2 ) show promise as paraCEST agents for registration of temperature (paraCEST=paramagnetic chemical exchange saturation transfer). The Fe^II, Co^II and Ni^II complexes of L1 show up to four CEST peaks shifted ≤112 ppm, whereas analogous complexes of L2 show only a single CEST peak at ≤69 ppm. Comparison of the temperature coefficients (C_T) of the CEST peaks of [Co( L2 )]²⁺, [Fe( L2 )]²⁺, [Ni( L1 )]²⁺ and [Co( L1 )]²⁺ showed that a CEST peak of [Co( L1 )]²⁺ gave the largest C_T (?0.66 ppm ^oC^?1 at 4.7 T). NMR spectral and CEST properties of these complexes correspond to coordination complex symmetry as shown by structural data. The [Ni( L1 )]²⁺ and [Co( L1 )]²⁺ complexes have a six‐coordinate metal ion bound to the 1‐, 4‐amide oxygen atoms and four nitrogen atoms of the tetraazamacrocycle. The [Fe( L2 )]²⁺ complex has an unusual eight‐coordinate Fe^II bound to four amide oxygen atoms and four macrocyclic nitrogen atoms. For [Co( L2 )]²⁺, one structure has seven‐coordinate Co^II with three bound amide pendents and a second structure has a six‐coordinate Co^II with two bound amide pendents.     

Breaking the Mirror: pH‐Controlled Chirality Generation from a meso Ligand to a Racemic Ligand

To study the conversion from a meso form to a racemic form of tetrahydrofurantetracarboxylic acid (H₄L), seven novel coordination polymers were synthesized by the hydrothermal reaction of Zn(NO₃)₂ ? 6 H₂O with (2S,3S,4R,5R)‐H₄L in the presence of 1,10‐phenanthroline (phen), 2,2′‐bipyridine (2,2′‐bpy), or 4,4′‐bipyridine (4,4′‐bpy): [Zn₂{(2S,3S,4R,5R)‐L}(phen)₂(H₂O)] ? 2 H₂O ( 1 ), [Zn₄{(2S,3R,4R,5R)‐L}{(2S,3S,4S,5R)‐L}(phen)₂(H₂O)₂] ( 2 ), [Zn₂{(2S,3S,4R,5R)‐L}(H₂O)₂] ? H₂O ( 3 ), [Zn₄{(2S,3R,4R,5R)‐L}{(2S,3S,4S,5R)‐L} (2,2′‐bpy)₂(H₂O)₂] ? 2 H₂O ( 4 ), [Zn₂ {(2S,3S,4R,5R)‐L}(2,2′‐bpy)(H₂O)] ( 5 ), [Zn₄{(2S,3R,4R,5R)‐L}{(2S,3S,4S,5R)‐L} (4,4′‐bpy)₂(H₂O)₂] ( 6 ), and [Zn₂ {(2S,3S,4R,5R)‐L}(4,4′‐bpy)(H₂O)] ? 2 H₂O ( 7 ). These complexes were obtained by control of the pH values of reaction mixtures, with an initial of pH 2.0 for 1 , 2.5 for 2 , 4 , and 6 , and 4.5 for 3 , 5 , and 7 , respectively. The expected configuration conversion has been successfully realized during the formation of 2 , 4 , and 6 , and the enantiomers of L, (2S,3R,4R,5R)‐L and (2S,3S,4S,5R)‐L, are trapped in them, whereas L ligands in the other four complexes retain the original meso form, which indicates that such a conversion is possibly pH controlled. Acid‐catalyzed enol–keto tautomerism has been introduced to explain the mechanism of this conversion. Complex 1 features a simple 1D metal–L chain that is extended into a 3D supramolecular structure by π–π packing interactions between phen ligands and hydrogen bonds. Complex 2 has 2D racemic layers that consist of centrosymmetric bimetallic units, and a final 3D supramolecular framework is formed by the interlinking of these layers through π–π packing interactions of phen. Complex 3 is a 3D metal–organic framework (MOF) involving meso‐L ligands, which can be regarded as (4,6)‐connected nets with vertex symbol (4⁵.6)(4⁷.6⁸). Complexes 4 and 5 contain 2D racemic layers and (6,3)‐honeycomb layers, respectively, both of which are combined into 3D supramolecular structures through π–π packing interactions of 2,2′‐bpy. The structure of complex 6 is a 2D network formed by 4,4′‐bpy bridging 1D tubes, which consist of metal atoms and enantiomers of L. These layers are connected through hydrogen bonds to give the final 3D porous supramolecular framework of 6 . Complex 7 is a 3D MOF with novel (3,4,5)‐connected (6³)(4².6⁴)(4².6⁶.8²) topology. The thermal stability of these compounds was also investigated.     

Salt forms of the pharmaceutical amide dihydrocarbamazepine

Carbamazepine (CBZ) is well known as a model active pharmaceutical ingredient used in the study of polymorphism and the generation and comparison of cocrystal forms. The pharmaceutical amide dihydrocarbamazepine (DCBZ) is a less well known material and is largely of interest here as a structural congener of CBZ. Reaction of DCBZ with strong acids results in protonation of the amide functionality at the O atom and gives the salt forms dihydrocarbamazepine hydrochloride {systematic name: [(10,11‐dihydro‐5H‐dibenzo[b,f]azepin‐5‐yl)(hydroxy)methylidene]azanium chloride, C₁₅H₁₅N₂O⁺·Cl⁻}, dihydrocarbamazepine hydrochloride monohydrate {systematic name: [(10,11‐dihydro‐5H‐dibenzo[b,f]azepin‐5‐yl)(hydroxy)methylidene]azanium chloride monohydrate, C₁₅H₁₅N₂O⁺·Cl⁻·H₂O} and dihydrocarbamazepine hydrobromide monohydrate {systematic name: [(10,11‐dihydro‐5H‐dibenzo[b,f]azepin‐5‐yl)(hydroxy)methylidene]azanium bromide monohydrate, C₁₅H₁₅N₂O⁺·Br⁻·H₂O}. The anhydrous hydrochloride has a structure with two crystallographically independent ion pairs (Z′ = 2), wherein both cations adopt syn conformations, whilst the two hydrated species are mutually isostructural and have cations with anti conformations. Compared to neutral dihydrocarbamazepine structures, protonation of the amide group is shown to cause changes to both the molecular (C=O bond lengthening and C—N bond shortening) and the supramolecular structures. The amide‐to‐amide and dimeric hydrogen‐bonding motifs seen for neutral polymorphs and cocrystalline species are replaced here by one‐dimensional polymeric constructs with no direct amide‐to‐amide bonds. The structures are also compared with, and shown to be closely related to, those of the salt forms of the structurally similar pharmaceutical carbamazepine.     

Synthesis of 4-acetyl-5(3)-amino-3(5)-methylpyrazoles and pyrazolo[3,4-d]pyrimidines from diacetylketeneN,S-acetal

Isomeric 4-acetyl-5-amino-3-methyl- and 4-acetyl-3-amino-5-methylpyrazoles (2, 3) were formed in the reaction of hydrazines with 3-[amino(methylthio)methylene]pentan-2,4-dione (1) (diacetylketeneN,S-acetal). Pyrazolo[3,4-d]pyrimidines (5a,b) were synthesized by condensation of 4-acetyl-5-amino-1,3-dimethylpyrazole (2a) with amide dimethylacetals followed by treatment with ammonium acetate. The structures of the compounds obtained were confirmed by¹³C and¹⁵N NMR spectroscopy.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1429–1433, August, 1993.     

2,7-萘二磺酸阴离子导向五元瓜环基超分子自组装体的制备及其荧光检测性能

通过引入2,7-萘二磺酸(2,7-NDA^2-)阴离子作为结构导向剂,与五元瓜环(Q[5])和过渡金属离子(Co²⁺、Ni²⁺、Zn²⁺、Cd²⁺)在水热条件下制备了4种新颖的Q[5]基超分子自组装体(Q[5]-SA),即{[M (H₂O)₄(Q[5])]·(NDA)}·xH₂O (M=Co (1)、Ni (2)、Zn (3))和{[Cd₂Cl₂(H₂O)₄(Q[5])]·(NDA)}·13H₂O (4)。单晶X射线衍射测试结果表明,自组装体1~3同构,其中Q[5]仅一端的部分端口羰基氧原子与金属离子配位形成简单配合物;而4中Q[5]的2个端口均与金属离子Cd²⁺配位形成了一维配位链。在自组装体1~4中,配体2,7-H₂NDA均全脱质子,形成2,7-NDA^2-阴离子平衡体系电荷,但均未能与金属离子配位,而在2,7-NDA^2-阴离子与Q[5]外壁之间的瓜环外壁作用下进一步形成三维超分子结构。此外,还研究了自组装体1和4的荧光传感性能,结果表明它们都能够作为抗生素诺氟沙星(NFX)的比率型荧光探针。     

2,7-萘二磺酸阴离子导向五元瓜环基超分子自组装体的制备及其荧光检测性能

通过引入2,7-萘二磺酸(2,7-NDA^2-)阴离子作为结构导向剂,与五元瓜环(Q[5])和过渡金属离子(Co²⁺、Ni²⁺、Zn²⁺、Cd²⁺)在水热条件下制备了4种新颖的Q[5]基超分子自组装体(Q[5]-SA),即{[M(H₂O)4(Q[5])]·(NDA)}·x H₂O(M=Co (1)、Ni (2)、Zn (3))和{[Cd2Cl2(H₂O)4(Q[5])]·(NDA)}·13H₂O (4)。单晶X射线衍射测试结果表明,自组装体1～3同构,其中Q[5]仅一端的部分端口羰基氧原子与金属离子配位形成简单配合物;而4中Q[5]的2个端口均与金属离子Cd²⁺配位形成了一维配位链。在自组装体1～4中,配体2,7-H2NDA均全脱质子,形成2,7-NDA2-阴离子平衡体系电荷,但均未能与金属离子配位,而在2,7-NDA2-阴离子与Q[5]外壁之间的瓜环外壁作用下进一步形成...     

Innerkomplexe mit Metallamidbindungen. II. Zink- und Chrom(II)-Komplexe des 2-[β-(Phenyl-amino)-äthyl]-pyridins

The preparation of uncharged complexes with metal amide bonds of type [MeN₄]^±0 (Me = Zn²⁺, Cr²⁺ is reported. These compounds are obtained by the interaction between Zn(C₆H₅)₂ or Cr(C₆H₅)₃ · 3 THF and 2-[β-(phenyl-amino)-ethyl]-pyridine (I). The same complexes are formed by the reaction between ZnCl₂ · 2 THF, CrBr₂ · 2 THF, or CrCl₃ · 3 THF and the lithium amide (II), which is prepared from (I) and phenyl lithium. The structure of the chromium(II) complex is discussed on the basis of magnetic and visible absorption measurements.     

The First Homoleptic Bis(trifluoromethanesulfonyl)amide Complex of Yttrium: [bmim][Y(Tf2N)4]

1‐Butyl‐3‐methylimidazolium tetrakis‐(bis(trifluoromethanesulfonyl)amide)yttrium(III), [bmim][Y(Tf₂N)₄], was obtained from the ionic liquid 1‐butyl‐3‐methylimidazoliumbis(trifluoromethanesulfonyl)amide, [bmim][Tf₂N] and yttrium(III)bis(trifluoromethanesulfonyl)amide, Y(Tf₂N)₃. The crystal structure [monoclinic, C2/c (no. 15), a = 2096.(1), b = 1451.5(1), c = 1608.55(9) pm, β = 109.669(6)°, V = 4608.1(5)·10⁶ pm³, Z = 4, R₁ for 3874 symmetry independent reflections with I₀>2σ(I₀): 0.0438] contains Y^III coordinated by four Tf₂N‐ligands which all adopt a transoid‐conformation with respect to their –CF₃ groups. The oxygen coordination polyhedron around Y^III can be best described as a trigonal dodecahedron.One 1‐butyl‐3‐methylimidazolium cation compensates for the charge of the complex [Y(Tf₂N)₄]^? anion.