Structural analogs of tetrapyrrole macrocycles and their biological properties

The review summarizes data on the synthesis and properties of analogs of ABBB-and ABAB-type tetrapyrrole macrocycles and their metal complexes. The structural features of these compounds are discussed. Data on aromaticity and biological properties are considered. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 663–679, April, 2007.     

Synthesis and design of supramolecular systems on the basis of tetrapyrrole macrocycles

Three new cyclophane-like calixarene-bis-porphyrins were synthesized, and their spectral properties were studied. Zinc complex of meso-(aminophenyl)-substituted calixarene-bis-porphyrin was found to form a stable 1:1 complex with dimethyl maleate in toluene. Its stability constant was determined by spectrophotometric titration.     

Dynamic combinatorial libraries of macrocycles derived from phthalic aldehydes and α,ω-diamines

Dynamic combinatorial chemistry methodology was used to obtain eleven new polyazamacrocycles derived from isophthalic and terephthalic aldehyde and α,ω-diamines. Simple templates, such as alkali metal salts, were found to amplify large macrocycles: 45-membered [3+3]hexaazacrown and 60-membered [4+4]octaazacrown. Parent imine libraries were converted into corresponding secondary libraries of amines using a fast reduction protocol. Methyl carbamate protection of amine group allowed convenient isolation of polyazamacrocycles in very good yields.     

Electron transfer from the S1 and S2 states of pentacoordinated tetrapyrrole macrocycles to pyromellitic diimide as an axial ligand

Electron transfer (ET) reactions from the S(1) and S(2) states of some porphyrins and phthalocyanines to the axial ligand have been investigated by means of femtosecond laser flash photolysis. As the axial ligand, which acts as an acceptor, we synthesized an asymmetric pyromellitic diimide (PI) compound that has an alkyl chain and a pyridine ring on N and N' atoms, respectively. The pyridine ring of PI can coordinate to Zn of tetrapyrrole macrocycles. The coordination was confirmed by UV-vis and (1)H NMR spectra. ET from the S(1) state of Zn tetraphenylporphyrin (ZnTPP), Zn octaethylporphyrin (ZnOEP), Zn phthalocyanine (ZnPc), and Zn naphthalocyanine (ZnNc) to PI was confirmed with transient absorption spectroscopy by observing PI*-. ET from the S1 state occurred at the rate constant of (8.6 ps)(-1) - (78 ps)(-1), and the yield was almost unity. Furthermore, ET from the S(2) state of ZnTPP and ZnPc to PI was confirmed. ET from the S(2) state of ZnPc was observed for the first time. The ET rate from the S(2) state was faster than that from the S(1) state. In the case of ZnOEP-PI and ZnNc-PI complexes, ET from the S(2) state was not observed.     

Synthesis, structure and electrochemistry of ferrocene-peptide macrocycles

Redox active cyclopeptides Fc[CSA]2 (5), Fc[Gly-CSA]2 (6), Fc[Ala-CSA]2 (7), Fc[Val-CSA](2) and Fc[Leu-CSA]2 (9) (CSA = cysteamine) which are formed by the reaction of ferrocenedicarboxylic acid with peptide cystamines at high dilutions. These systems exhibit H-bonding involving the amide NH in solution as shown by their temperature dependent NMR spectra. With the exception of 5, the ferrocene macrocycles display intramolecular N...O cross-ring H-bonding in the solid state involving the amino acids proximal to the ferrocene.     

Evaluation of HX (X = Cl,Br, O) product distributions from chemiluminescence. I. H atom reactions

The HX product state distributions from the H+Cl₂, Br₂, NO₂Cl, PCl₃, and NO₂ reactions have been studied by the infrared chemiluminescence technique in two different laboratories with two types of reactors; a fast-flow system with = 1 Torr of Ar buffer gas and a low-pressure, cold-wall system (usually called the cold-wall arrested-relaxation method). The same Einstein coefficients were used in both laboratories to convert intensities to populations and emphasis is placed upon evaluation of the reliability of the resulting vibrational-rotational HX distributions. Good agreement was found between the HX distributions from the cold-wall reactors from the two laboratories and for both types of reactors for all of the reactions, except PCl₃. For the H+Cl₂, Br₂ and NO₂ reactions, our general results are in good accord with presently accepted data; but, our experiments provide somewhat more detail than in the literature. The NO₂Cl results are new and <f_v(HCl) > = 0.40 and <f_R(HCl) > = 0.01. The H+PCl₃ reaction appears to proceed by two channels and the HCl chemiluminescence cannot be assigned only to HCl formation via direct Cl atom abstraction.     

Synthesis of mono- and dihydroxylated furanoses, pyranoses, and an oxepanose for the preparation of natural product analogue libraries

[structures: see text] Numerous biologically active natural products contain furanoses and pyranoses with mono- and dihydroxylated substituents. However, much of the structure-activity studies on such molecules is gathered on the aglycons without attention to the corresponding carbohydrate components. Consequently, there are few synthetic procedures that enable the rapid preparation of mono- and dihydroxyfuranoses and mono- and dihydroxypyranoses and no report for a 3,4-dihydroxyoxepanose. In this article we report the practical synthesis of orthogonally protected five-, six-, and seven-membered carbohydrate derivatives. The succinct manner in which these molecules were synthesized allows the rapid preparation of analogues aimed at discovering the role of ring size and individual hydroxyl moieties on the pyranose skeleton.     

Design and synthesis of screening libraries based on the muurolane natural product scaffold

The plant-derived natural product 14-hydroxy-6,12-muuroloadien-15-oic acid (1) was identified as a unique scaffold that could be chemically elaborated to generate novel lead- or drug-like screening libraries. Prior to synthesis a virtual library was generated and prioritised based on drug-like physicochemical parameters such as log P, log D(5.5), hydrogen bond donors/acceptors, and molecular weight. The natural product scaffold (1) was isolated from the endemic Australian plant Eremophila mitchellii and then utilised in the parallel solution-phase generation of two series of analogues. The first library consisted of six semi-synthetic amide derivatives, whilst the second contained six carbamate analogues. These libraries have been evaluated for antimalarial activity using a chloroquine-sensitive Plasmodium falciparum line (3D7) and several compounds displayed low to moderate activity with IC(50) values ranging from 14 to 33 μM.     

From data point timelines to a well curated data set, data mining of experimental data and chemical structure data from scientific articles, problems and possible solutions

The scientific literature is important source of experimental and chemical structure data. Very often this data has been harvested into smaller or bigger data collections leaving the data quality and curation issues on shoulders of users. The current research presents a systematic and reproducible workflow for collecting series of data points from scientific literature and assembling a database that is suitable for the purposes of high quality modelling and decision support. The quality assurance aspect of the workflow is concerned with the curation of both chemical structures and associated toxicity values at (1) single data point level and (2) collection of data points level. The assembly of a database employs a novel “timeline” approach. The workflow is implemented as a software solution and its applicability is demonstrated on the example of the Tetrahymena pyriformis acute aquatic toxicity endpoint. A literature collection of 86 primary publications for T. pyriformis was found to contain 2,072 chemical compounds and 2,498 unique toxicity values, which divide into 2,440 numerical and 58 textual values. Every chemical compound was assigned to a preferred toxicity value. Examples for most common chemical and toxicological data curation scenarios are discussed.     

Conjugated macrocycles related to the porphyrins. 21. Synthesis,spectroscopy, electrochemistry,and structural characterization of carbaporphyrins

The "3 + 1" variant of the MacDonald condensation has been shown to be an excellent methodology for synthesizing carbaporphyrins. In particular, 1,3-indenedicarbaldehyde condenses with tripyrranes in the presence of TFA to give, following oxidation with DDQ, a series of benzocarbaporphyrins in excellent yields. Triformylcyclopentadienes also afford carbaporphyrin products, albeit in low yields ranging from 5 to 8%. These hybrid bridged annulene structures have porphyrin-like electronic absorption spectra with strong Soret bands near 420 nm and a series of Q-bands through the visible region. The proton NMR spectrum confirms the presence of a strong diamagnetic ring current, and the meso-protons show up at 10 ppm, while the internal CH is shielded to approximately -7 ppm. Carbaporphyrins undergo reversible protonation with TFA. Initial addition of acid affords a monocation, although mixtures of protonated species are observed in the presence of moderate concentrations of TFA. However, in the presence of 50% TFA a C-protonated dication is generated. The dications relocate the pi-delocalization pathway through the benzo moiety of benzocarbaporphyrins, and these therefore represent bridged benzo[18]annulenes, although they nevertheless retain powerful macrocyclic ring currents. Carbaporphyrins with fused acenaphthylene and phenanthrene rings have been prepared, and the former demonstrated significantly larger bathochromic shifts in UV-vis spectroscopy that parallel previous observations for acenaphthoporphyrins. A diphenyl-substituted benzocarbaporphyrin 19b was also characterized by X-ray crystallography, and these data show that the macrocycle is reasonably planar although the indene subunit is tilted out of the mean macrocyclic plane by 15.5 degrees. The structural data indicates that the preferred tautomer in the solid state has the two NH's flanking the pyrrolene unit in agreement with previous spectroscopic and theoretical studies. Cyclic voltammetry for carbaporphyrin 19a was more complex than for true porphyrins, showing five anodic waves and two quasi-reversible reductive couples.     

Virtual screening of organic molecule databases. Design of focused libraries of potential ligands of NMDA and AMPA receptors

A system of virtual screening of organic molecule databases is designed, which permits preprocessing of databases, molecular docking to a three-dimensional model of receptor, and post-processing of the results obtained. Using this screening system, it is possible to reproduce positions of the known ligands in the glutamate sites of the NMDA and AMPA receptors and in the glycine site of the NMDA receptor, to substantially enrich the database with potentially active compounds, and to distinguish between the agonistic and antagonistic character of the action of these compounds in the case of docking to the open and closed forms of the binding sites. Based on the results of screening of a database of low-molecular-weight organic compounds (total of 135,000 structures) using models of the open and closed forms of the glutamate and glycine sites of the NMDA receptor and of the glutamate site of the AMPA receptor, focused libraries of potential agonists and antagonists of these sites were designed.     

Self-assembly, binding, and dynamic properties of heterodimeric porphyrin macrocycles

A series of heterodimeric tetralactam macrocycles have been self-assembled using two kinetically labile zinc porphyrin-pyridine interactions. The stability constants have been determined by UV-vis titrations in CHCl3. The stability constants depend on the degree of preorganization of the linker units connecting the interacting groups. The ability of the self-assembled macrocycles to bind a terephthalamide guest was also investigated. One of the macrocycles was used for the construction of a [2]rotaxane. The dynamic properties of this system provide insight into the exchange mechanisms that operate in complex noncovalent assemblies.     

Synthesis and characterization of two isomeric, self-assembled arsenic-thiolate macrocycles

The use of labile As-S bond formation in the self-assembly of discrete supramolecular structures is extended. Macrocyclic structures of chemical formula As2L2Cl2 (H2L=alpha,alpha'-dimercapto-p-xylene) were prepared and characterized. Diastereomeric syn and anti isomers of these macrocycles were selectively crystallized and characterized in the solid state using single-crystal X-ray diffraction. Both the syn and anti macrocycles show close contacts between the arsenic(III) ions and the aromatic carbons, consistent with intramolecular arsenic-pi interactions. The dynamic behavior of the isomers in solution is also investigated. anti-As2L2Cl2.AsCl3 crystallizes in monoclinic space group P2(1)/c (No. 14) with a=10.6194(5) A, b=16.7780(9) A, c=8.5725(4) A, beta=100.6830(10) degrees, and Z=2. syn-As2L2Cl2 crystallizes in orthorhombic space group Pnma (No. 62) with a=10.8881(8) A, b=19.3511(14) A, c=9.9524(7) A, and Z=4.     

Boron macrocycles having a calix-like shape. Synthesis, characterization, X-ray analysis, and inclusion properties

The syntheses, structure, and inclusion properties of trinuclear boron compounds having a calix-like shape are described. The compounds have been obtained via self-assembly reactions between salicylaldehyde derivatives and 3-aminophenylboronic acid, whereby the formation of three N --> B coordination bonds favored the oligomerization. The products have high melting points (>370 degrees C), are stable to moisture, and have good solubility in organic solvents; the latter property is useful for host-guest recognition experiments. The structural analysis by X-ray diffraction revealed that diverse conformations are possible because of the presence of two different units of aromatic rims. A cone-cone (double-cone) conformation is observed for three of these compounds, while the remaining one has a cone-partial cone conformation. An analysis of the molecular packing showed that the molecules are stacked in columns in two different orientations in relation to the organization of the macrocycles when referred to the N-B bonds. The inclusion properties toward primary amines and ammonium chlorides were analyzed by titration experiments and monitored by UV spectroscopy, whereby association constants on the order of 10(2)-10(3) M(-1) were determined.     

Synthesis, structure, and computational studies of soluble conjugated multidentate macrocycles

[Chemical reaction: See text] Conjugated, shape-persistent macrocycles based on [3 + 3] Schiff-base condensation are of interest for supramolecular materials. In an effort to develop new discotic liquid crystals based on these compounds, a series of macrocycles with peripheral alkoxy groups of varying length have been prepared. The synthesis and mechanism of formation have been probed by isolation of oligomeric intermediates. A single-crystal X-ray diffraction study of one macrocycle revealed a nonplanar, strongly hydrogen-bonded structure. To our surprise, even with very long substituents, the macrocycles were not liquid crystalline. This has been rationalized by ab initio calculations that indicate the macrocycles are undergoing rotation of the dihydroxydiiminobenzene rings that may not allow a stable discotic liquid crystalline phase. These results provide new insight into the formation and properties of these large macrocycles and may provide guidance to developing stable liquid crystalline materials in the future.     

Enediynes in 11-membered rings. Synthesis, structure, and reactivity of highly strained but unusually stable macrocycles.

The synthesis of two new aromatic cyclic enediynes 1a and 1b using a double Wittig condensation, followed by bromination and di-dehydrobromination, is reported. The structures were determined using X-ray crystallography. The observed C(1)-C(6) distances of the enediyne moiety in the oxygen- and sulfur-containing eleven-membered rings are quite short with 3.44 and 3.50 A, respectively, indicating the highly strained nature of these compounds. Isodesmic calculations at the B3LYP/6-31G level of theory indicate a strain energy of 8.2 and 5.8 kcal/mol, respectively. Despite the highly strained ring system, the compounds were found to be stable under thermal, photochemical, and electron-transfer conditions. Using BLYP/6-311+G/BLYP/6-31G calculations, the origin of this unusual stability was traced to the high energy of the 1,4 benzyne diradicals formed via Bergman cyclization. For the radical cation, both the C(1)-C(6) and the C(1)-C(5) cyclization mode previously reported for acyclic analogues of 1 were found to be energetically prohibitive.     

Giant macrocycles composed of thiophene, acetylene, and ethylene building blocks

Fully conjugated giant macrocyclic oligothiophenes with 60pi, 90pi,120pi, 150pi, and 180pi frames (1, 2, 3, 4 and 5) have been designed, and their butyl-substituted derivatives (1a, 2a, 3a, 4a, and 5a) have been synthesized using modified Sonogashira and McMurry coupling reactions as key steps. The 60-180pi systems 1-5 are circular with 1.8-6 nm inner cavities and 3.3-7.5 nm outside molecular diameters. Compound 1a containing ten 3,4-dibutyl-2,5-thienylene, eight ethynylene, and two vinylene units has been converted into macrocyclic oligo(3,4-dibutyl-2,5-thienylene-ethynylene) 6a using bromination/dehydrobromination procedure. Giant macrocycles 1a-6a exhibit a red shift of their absorption spectra and a fairly strong fluorescence with a large Stokes shift as compared to a linear conjugated counterpart having five thiophene rings. Compounds 1a-6a exhibit multistep reversible redox behaviors with fairly low first oxidation potentials, reflecting their cyclic conjugation. Furthermore, chemical oxidation of 1a-6a with FeCl3 shows drastic changes of spectroscopic properties due to intramolecular and intermolecular pi-pi interactions. Doping of 1a-3a with iodine forms semiconductor due to its pi-donor properties and pi-pi stacking ability. X-ray analysis of 1a confirmed a round, planar structure with nanoscale inner cavity, and revealed host ability for alkanes and unique packing structure. Interestingly, 2a and 3a self-aggregate in the solid state to form "molecular wires," which are about 200 nm thick and more than 1 mm long. The internal structures of fibrous aggregates have been investigated by optical microscope, scanning electron microscopy, atomic force microscopy, and X-ray diffraction analyses.     

Synthesis of chiral, amphiphilic, and water-soluble macrocycles via urea formation

A simple, efficient, and flexible procedure for the synthesis of chiral, amphiphilic, and water-soluble macrocycles is reported. Acylation of p-xylylenediamine with N^α-Fmoc-protected glycine, l-aspartic acid, l-glutamic acid, and l-arginine, followed by removal of Fmoc-groups, gave amino acid:p-xylylene conjugate diamines, which were converted to ten macrocycles via stepwise urea formation using p-nitrophenyl chloroformate. l-Aspartic acid-containing macrocyles proved to be soluble in aqueous buffers and a macrocycle containing four aspartate residues was found to recognize arginine and arginine esters with moderate affinity.