Macrocyclic Fragments Research Articles

Synthesis of Two Macrocyclic Fragments of Manadomanzamine Alkaloids

Abstract The synthesis of two macrocyclic fragments in the manadomanzamine alkaloids based on a strategy using reductive nucleophilic addition to macrolactams is reported. The sequence through the Wittig coupling and macrolactamization gives quick access to both eleven-membered and ten-membered macrolactams. The iridium-catalyzed reductive Strecker reaction of the ten-membered macrolactam takes place via the corresponding unstable imine intermediate.

Conjugates of Pyropheophorbide a with 17-Substituted Steroidal Androgens. Synthesis, Molecular Modeling, Interaction with Some Cancer Cells

Five new bifunctional conjugates of pyropheophorbide a with 17-substituted testosterone, dihydrotestosterone and epitestosterone differing in the length of linker (1 � 5) and two new complex conjugates 6 and 7 (containing three functional units: pyropheophorbide a, 17?-substituted testosterone, and lipophylic hexadecyl chain, connected with L-lysine joining block) were synthesized. Mutual influence of steroidal and macrocyclic fragments in conjugates (1 � 7) was established by analysis of 1H NMR spectra and molecular models of conjugates. Studies of interaction of conjugates 1 � 5 with prostate carcinoma cells revealed that their uptake and internalization were dependent on the structure of conjugates, particularly on the stereochemical configuration of 17-hydroxyl group in steroidal moiety, and the length of linker connecting pyropheophorbide a with steroid fragments. Conjugates 1 � 5 significantly decreased the growth and proliferation of LNCaP and PC-3 cells. The highest anti-proliferative activity demonstrated by epitestosterone derivative 3, comprising short linker. Irradiation of labeled cells with light (? = 660 nm) was significantly increased cytotoxicity. Trifunctional conjugates 6 and 7 easily formed mixed micells with phosphatidyl choline and pluronic F68; these mixed micelles efficiently internalized by human hepatocarcinoma Hep G2 cells. The binding of conjugates 6 and 7 in the form of mixed micelles to Hep G2 cells depended on the conjugate structure, rather than on the method of solubilization.

Modification of Oligo- and Polylactides With Macrocyclic Fragments: Synthesis and Properties.

Products of lactic acid polycondensation (poly- and oligolactic acids) are widely used as packaging materials, drug delivery agents, implants etc. Variety of their applications is caused by a number of practically important properties, e.g., biocompatibility and biodegradability, non-toxicity, and mechanical durability. Modification of these polymers with different additives allows improving their properties and extending future applications. In this manner, stability toward degradation, recognition of some substrates, extended thermal stability etc. can be improved. Macrocyclic compounds are promising candidates as modifiers. They are able to provide polymer materials with additional binding sites, impart certain orientation to spatial arrangement of polymer chains, change hydrophilic-lipophilic balance, and redox properties. The latter one can be used for assembling various electrochemical sensors and biosensors that combine steric discrimination of the analytes caused by oligolactides and highly sensitive response to their quantities caused by redox labels introduced. Different composite materials based on oligolactides as matrices for such redox labels were described in the assemblies of biosensors for drugs, pesticides, and antioxidants detection. In this mini-review, methods for the synthesis of the lactic acid oligomers and those modified with the macrocyclic fragments (porphyrin, cyclodextrin, and cyclophane) have been described. The effects of modifiers on complexation, thermal, and aggregation properties of materials are described. Analytical performance of oligolactide based sensors and biosensors has been considered with particular emphasis to the mechanism of signal generation.

Synthesis of Bisthiacalix[4]arene: Reaction of Piperazine with Monoacrylamide Derivative of p-tert-Butylthiacalix[4]arene

The reaction of acryloyl chloride with the monoamine derivative of p-tert-butylthiacalix[4]arene was used to synthesize p-tert-butylthiacalix[4]arene monoacrylamide in the 1,3-alternate conformation. The effect of the nature of the amine on the result of its Michael reaction with the synthesized p-tert-butylthiacalix[4]arene monoacrylamide was studied. The latter was reacted with piperazine to obtain bisthiacalix[4]arene with the macrocyclic fragments in the 1,3-alternate conformation.

Conjugates of 17-substituted testosterone and epitestosterone with pyropheophorbide a differing in the length of linkers

Conjugates of 17α-substituted testosterone (1 and 2) and 17β-substituted epitestosterone (3 and 4) with pyropheophorbide a were synthesized. The scheme consisted of synthesis of 17α-hydroxy-3-oxopregn-4-en-21-oic and 17β-hydroxy-3-oxopregn-4-en-21-oic acids, and their coupling with pyropheophorbide a by means of either ethylene diamine, or 1,5-diamino pentane linkers. Mutual influence of steroidal and macrocyclic fragments in conjugates molecules was dependent on configuration of C17 and length of linker, that was established by analysis of 1H NMR spectra and molecular models of conjugates. Studies of interaction of conjugates with prostate carcinoma cells revealed that their uptake and internalization were independent on the androgen receptor activity, but dependent on the structure of conjugates, decreasing in the following row: 3 > 4 ≥ 1 > 2. Conjugates significantly decreased the LNCaP and PC-3 cells growth at 96 h incubation. Epitestosterone derivatives 3 and 4 also showed superior anti-proliferative activity versus testosterone ones. Conformationally more rigid conjugates 1 and 3, comprising short linkers, were more active than those with long linkers; conjugate 3 was the most potent.

Tetranuclear complexes composed of dinickel(II) macrocyclic fragments bridged by 5,5′-(1,3-phenylene)bis-1H-tetrazolato and N,N-bis(tetrazol-5-ato)amine coligands: Synthesis, structures and magnetic properties

The dinuclear nickel(II) complex [Ni2LCl]+, where L2− represents a 24-membered macrocyclic hexamine-dithiophenolate ligand, reacts with 5,5′-(1,3-phenylene)bis-1H-tetrazole and N,N-bis(tetrazol-5-yl)amine to give the tetranuclear complexes [(Ni2L)2(N4C–X–CN4)]+, where X=1,3-C6H4 (1) and NH (2). The new complexes were both isolated as perchlorate or tetraphenylborate salts and characterized by elemental analysis, UV/Vis, IR spectroscopy, and X-ray analysis. The crystal structures of the tetraphenylborate salts show bridging bistetrazolato moieties joining two dinuclear [Ni2L]2+ fragments through their ring N2 and N3 atoms. Temperature-dependent magnetic susceptibility measurements reveal the presence of weak ferromagnetic exchange interactions between the NiII ions in the binuclear [Ni2L]2+ subunits with magnetic exchange coupling constant values of J1=16.6cm−1 for 1[BPh4]2, and J1=16.8cm−1 for 2[BPh4]2 (H=–2JS1S2). The exchange coupling constant J2 across the bistetrazolato bridge in both compounds is less than 0.1cm−1, which suggests that no significant interdimer coupling occurs across the linking tetrazolato moieties.

Passing Two Strings through the Same Ring Using an Octahedral Metal Center as Template: A New Synthesis of [3]Rotaxanes

Octahedral transition metal centers such as Fe(II), Co(II), and Co(III) have been used as templates in the construction of [3]pseudorotaxanes and [3]rotaxanes from various acyclic and macrocyclic fragments. The species obtained consist of a ring threaded by two string-like compounds. Such systems are relatively uncommon in the [3]rotaxane family, the most usual form being made up of a single axis threaded through two rings. The key structural feature of the present systems is the coordinating unit incorporated in the various organic fragments and used in conjunction with the metal to gather and thread the two filaments through the ring. This bidentate chelate is derived from 8,8'-diphenyl-3,3'-bi-isoquinoline, a very rare example of an endotopic but nonsterically hindering ligand. The stoppered [3]rotaxanes were obtained by using an open-chain fragment bearing azide groups as end functions, followed by click chemistry using a propargyl ether attached to a very bulky group. A particularly attractive X-ray structure was obtained for a cobalt(III)-complexed [3]pseudorotaxane consisting of a 41-membered ring and two crescent-shaped threaded components. The Fe(II) and Co(III) complexes were characterized by (1)H NMR and ES-MS. By taking advantage of the markedly different kinetic properties of the two oxidation states, Co(II) and Co(III), it was possible to proceed to fast coordination or decoordination reactions (for the divalent state) or, when needed, to "freeze" the complexes due to the kinetic inertness of the trivalent state and to study them by (1)H NMR. Finally, demetalation of the two stoppered compounds prepared was performed. This demetalation reaction was fast for the Co(II)-complexed [3]rotaxane, whereas decomplexation of the Fe(II) equivalent required harsh conditions which were not compatible with the stability of the metal-free rotaxane. Interestingly, the thermal stability of the free [3]rotaxane toward unthreading and formation of its constitutive elements was only limited. (1)H NMR measurements showed that the half-life of the rotaxane is about one week at room temperature in dichloromethane. A variable-temperature study revealed that the unthreading reaction leading to dissociation of the [3]rotaxane has a remarkably high entropy of activation, in agreement with the intuitive view that the unthreading process involves a highly ordered transition state.

Bis‐ and Tris(tetraazamacrocyclic) Copper Complexes with Disulfide Linkers

AbstractDi‐ and trinuclear title complexes, 2Cu and 3Cu, containing, respectively, two and three macrocyclic fragments bound by aliphatic linkers with the ‐S–S‐ moieties have been synthesized by using cystamine dihydrochloride in the presence of triethylamine. The structure of the 2Cu complex in the solid state was confirmed by X‐ray analysis. Two macrocyclic rings of 2Cu form a rectangular cavity of size 17.18 Å [S19···S19 (1 – x, –y, –z)] × 3.62 Å. The shorter dimension of the cavity is the shortest observed in bis(macrocycle)s studied by us. The bis(macrocyclic) molecules in the crystal lattice are surrounded by PF6– ions and water molecules. Redox properties of the new compounds were determined by applying various voltammetric techniques. The macrocyclic architectures remained stable in nonaqueous solutions. For the bis‐ and tris(macrocyclic) compounds, the exchange of one electron takes place almost independently at each of the copper centers. The complexes were self‐ assembled at the gold surface to produce stable monolayer‐modified electrodes. The immobilization of these highly charged cations on the electrode required the application of appropriate negative potentials during the self‐assembly process.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

X-ray diffraction study of benzothiacrown compounds and their complexes with heavy metal cations

The structures of a series of substituted benzothiacrown compounds containing the dithia-15-crown-5, dithia-18-crown-6, or monothia-15-crown-5 fragment and their complexes with Ag+ and Pb2+ ions were studied by X-ray diffraction. In free benzothiacrown compounds, the sulfur atoms are preferably located outside the macrocyclic cavity, and their lone electron pairs (LEPs) point away from the center of the macrocycle, which is unfavorable for the formation of inclusion complexes. Flexible macrocyclic fragments can change their conformations in accord with the coordination requirements of heavy metal cations. As a result, benzothiacrown compounds involved in complexes adopt a crown conformation, in which LEPs of all hetero-atoms point toward the cation. The sulfur atoms are involved in coordination of Ag+ to a greater degree than the oxygen atoms due to high affinity of soft sulfur atoms for silver cations. On the contrary, the sulfur and oxygen atoms are involved to approximately the same degree in coordination of Pb2+ ions.

Structure of M(18-crown-6) + (M=T1, NH 4) oximate complexes: effective control of the molecular geometry employing a crystal engineering approach

The synthesis and structural characterization of one-dimensional coordination/H-bonded polymers M(18-crown-6) [H{ONC(CN)C(O)C 6H 5} 2] (M=NH 4, Tl) is reported. The hydrogen oximate anion is formed by means of strong hydrogen bonding O-H-O between two nitroso groups, it possesses a centrosymmetric structure and bridges two macrocyclic fragments. In both the structures these fragments M(18-crown-6) adopt unusual geometry with the large cations being situated exactly in the center of the crown ether cavity.

Antitumor Properties of Actinocin-Based Crown Compounds

In recent years, considerable effort of researchers has been devoted to studying the cellular signal systems, that is, the pathways of information transfer inside the cell. A significant role in this process is played by the transport of K, Na, Ca, Mg and some other ions. In connection with this, it is interesting to study ionophores – compounds with a special molecular structure that renders them capable of carrying small ions through lipid barriers. Ionophores are stable both chemically and biologically. These compounds either contain macrocyclic structural fragments or are capable of forming such structures by means of hydrogen bonds. Macrocyclic ionophores of natural origin can be considered as prototypes of crown compounds [1]. As is known, actinomycin D forms complexes with Na analogous to those formed by crown compounds [2, 3]. The crown groups can be introduced into the structure of a DNA complexon [4], but the effect of such groups upon the antitumor activity of such complexes has not been systematically studied. It was suggested that the complexation of actinomycin D with Na is related to the properties of cyclopeptide groups of this antibiotic, which are composed predominantly of N-alkylamino acids [5, 6]. We suggested that introducing crown groups free of cationoid centers into the amide groups of actinocin amides would lead to new compounds with properties close to those of actinomycin D. In this context, we have synthesized actinocin derivatives containing benzo-15-crown-5 and benzo-18-crown-6 groups attached via amide bonds. We studied both compounds with the crown fragments introduced immediately in the amide groups of actinocin diamides [7] and those in which with the fragments were separated from the amide groups by amino acid residues (glycine, -alanine, and 6-aminocaproic acid) [8]. The compounds studied were synthesized as described previously [7, 8].

A 1:1.5 complex of 5,7-dioxo-1,4,8,11-tetraazacyclotetradecane and 2,6-dihydoxyanthraquinone

A complex of 5,7-dioxo-1,4,8,11-tetraazacyclotetradecane (dioxocyclam) and 2,6-dihydoxyanthraquinone (anthraflavic acid) has been obtained. The complex (crystals grown from water-ethanol solution) has a stoichiometry dioxocyclam-anthraflavic acid 1:1:5. C31H32N4O8, chemical formula weight 588.61, triclinic, P − 1, a = 10.542(3) A, b = 11.936(2) A, c = 12.206(2) A, α = 104.00(1)°, β = 92.68(2)°, γ = 103.64(2)°, V = 1439.4 (5) A3, Z = 2, Dx = 1.358 g cm−3. Only one of the two amine N-atoms of the macrocycle is protonated due to very weak acidic properties of 2,6-dihydoxyanthraquinone. Due to the rather poor quality of the crystals and structure refinement, reliable determination of H-bonds is complicated. Nevertheless, several types of H-bonding responsible for the formation of a developed supramolecular network can be suggested: between the protonated amino groups and macrocycle's C=O moieties; between non-protonated amino groups and macrocycle's C=O moieties; between protonated and non-protonated amino groups; between the amide NH and C=O groups of anthraflavic acid; and between protonated and deprotonated hydroxy groups of the acid. Two types of anthraflavic components can be distinguished in the lattice: those having a parallel orientation with respect to the macrocyclic fragments and forming hydrogen bonds with the latter, and those lying in an approximately perpendicular plane and not involved in H-bonding with the macrocycles.

Synthesis of “living” chains of polyvinylpyridine and their application to the construction of homo‐ and hybrid polymer with complex architecture

AbstractExperimental conditions ensuring the formation of living poly(2‐ and 4‐vinyl pyridine) chains in the vinyl pyridine ‐ allyl derivatives of chromium, molybdenum and tungsten systems are described. Variation of the reagents nature, polarity of the solvent permits to obtain polymers differing in their structural and molecular parameters. Synthesized polymers contain block and graft sequences, as well as macrocyclic fragments. Living chains under consideration were applied for polymerization of different monomers. Hybrid polymers obtained by this way were studied in detail by the same methods as the homopolymers.

Energy and electron transfer processes in self-organized porphyrin and chlorin triadic and pentadic complexes

Self-organized arrays stable at room temperature containing three or five macrocyclic fragments have been constructed using two-fold ligation of Zn-porphyrin and Zn-chlorin chemical dimers by di- or tetrapyridyl substituted porphyrins, chlorins or tetrahydroporphyrins. Spectral, photophysical and thermodynamic properties of the ensembles have been studied in the temperature range from 140 to 360 K. Kinetic behavior of the complexes upon optical excitation was investigated using a fluorescent picosecond laser setup (Δt≅30 ps) with 2-D (wavelength-lifetime) registration. Observed spectral properties are explained in terms of extra-ligation and excitonic coupling. Nonradiative forward and backward excitation energy transfer (ET), electron transfer andd-π interactions are discussed as the main paths of electronic excitation deactivation in the complexes.