Syntheses of macrocyclic enzyme models. Part 3. Preparation and properties of water-soluble azaparacyclophanes.
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Aza Compounds↗
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Cyclic semipeptoids: peptoid-organic hybrid macrocycles.
[structure: see text] Cyclic semipeptoids 1 and 2 represent constrained, secondary structure mimics where the R(1) and R(2) side chains correspond to those of amino acids. Solid-phase syntheses and conformational analyses of these compounds are described.
Amino Acids↗
Cell wall active antifungal compounds produced by the marine fungus hypoxylon oceanicum LL-15G256. I. Taxonomy and fermentation.
The cell wall targeted antifungal activity of Hypoxylon oceanicum LL-15G256 extracts resulted from the production of novel lipodepsipeptides and previously reported macrocyclic polylactones. In an optimized medium, titers of the lipodepsipeptide and the polylactones reached approximately 200-400 mg/liter and 25-50 mg/liter, respectively. The optimum fermentation temperature for production of 15G256 gamma was 28 degrees C. Seawater appeared to have an inhibitory effect on metabolite accumulation at lower fermentation temperatures.
Antifungal Agents↗
Synthesis and Properties of 5-Chloro-8-hydroxyquinoline-Substituted Azacrown Ethers: A New Family of Highly Metal Ion-Selective Lariat Ethers.
New 5-chloro-8-hydroxyquinoline (CHQ)-substituted aza-18-crown-6 (4), diaza-18-crown-6 (1), diaza-21-crown-7 (2), and diaza-24-crown-8 (3) ligands, where CHQ was attached through the 7-position, and aza-18-crown-6 (11) and diaza-18-crown-6 (10) macrocycles, where CHQ was attached through the 2-position, were prepared. Thermodynamic quantities for complexation of these CHQ-substituted macrocycles with alkali, alkaline earth, and transition metal ions were determined in absolute methanol at 25.0 degrees C by calorimetric titration. Two isomers, 1 and 10, which are different only in the attachment positions of the CHQ to the parent macroring, exhibit remarkable differences in their affinities toward the metal ions. Compound 1 forms very stable complexes with Mg(2+), Ca(2+), Cu(2+), and Ni(2+) (log K = 6.82, 5.31, 10.1, and 11.4, respectively), but not with the alkali metal ions. Ligand 10 displays strong complexation with K(+) and Ba(2+) (log K = 6.61 and 12.2, respectively) but not with Mg(2+) or Cu(2+). The new macrocycles and their complexes have been characterized by means of UV-visible and (1)H NMR spectra and X-ray crystallography. New peaks in the UV spectrum of the Mg(2+)-1 complex could allow an analytical determination of Mg(2+) in very dilute solutions in the presence of other alkali and alkaline earth metal cations. (1)H NMR spectral and X-ray crystallographic studies indicate that ligand 10 forms a cryptate-like structure when coordinated with K(+) and Ba(2+), which induces an efficient overlap of the two hydroxyquinoline rings. Such overlapping forms a pseudo second macroring that results in a significant increase in both complex stability and cation selectivity.
Journal Article↗
Assessment of a liposomal formulation of ivermectin in rabbit after a single subcutaneous administration.
Ivermectin is a member of the macrocyclic lactone family widely used in livestock, pets, and humans as a potent parasiticide. Slight differences in formulation may change the plasma kinetics and efficacy of these compounds. The aim of the study is to evaluate the ability of a liposomal formulation of ivermectin to generate an efficient exposure of the animal to the drug. Ten rabbits were subcutaneously administered with 0.3 mg kg(-1) of ivermectin using Ivomec (n=5) or a liposomal formulation (n=5). The areas under serum concentration-time curve were similar after both treatments, indicating the same bioavailability for the two formulations. However, the liposomal formulation gave a higher C(max) value (33.33 ng ml(-1)) compared with Ivomec (20.82 ng ml(-1)) and a significantly faster absorption as indicated by the T(max) of 0.23 days compared with 1.13 days for the Ivomec formulation. The use of liposomal formulation shows promise as this system improves the efficacy of ivermectin and related drugs.
Animals↗
C-substituted macrocycles as candidates for radioimmunotherapy.
The reaction between aryl aldehydes, the macrocyclic ligand 6-methyl-1,4,8,11-tetraazacyclotetradecane-6-amine (L1), and NaBH3CN produces the corresponding benzyl-substituted ligands in good yield. Copper(II) complexes of the ligands derived from salicylaldehyde (L2), p-hydroxybenzaldehyde (L4), and p-carboxybenzaldehyde (L5) were structurally characterized: [CuL2](ClO4)2.3H2O (monoclinic, P2(1)/c, a = 11.915(6) A, b = 13.861(2) A, c = 17.065(8) A, beta = 102.14(2) degrees, Z = 4); [CuL4](ClO4)2 (monoclinic, P2(1)/n, a = 9.550(3) A, b = 17.977(2) A, c = 14.612(4) A, beta 96.76(1) degrees, Z = 4), and [CuL4](ClO4)2 (monoclinic, P2(1)/n, a = 9.286(2) A, b = 11.294(1) A, c = 23.609(8) A, beta 93.68(1) degrees, Z = 4). Conjugation of several CuII complexes to a protein (bovine serum albumin) has been pursued with a view to the application of these macrocycles as bifunctional chelating agents in radioimmunotherapy.
Crystallography, X-Ray↗
In vitro anticancer activities and optical imaging of novel intercalative non-cisplatin conjugates.
The first pi-conjugated macrocyclic diimine and triaza DNA-binding intercalators and their platinum(II) conjugates have been synthesized by direct Schiff base cyclocondensation. The in vitro anticancer activities of compounds 3, 4, and 5 were tested on five cancer cell lines: MCF-7, A549, P388, A2780, and A2780cisR. Ovarian tumors were included specifically to evaluate the new conjugates' ability to circumvent A2780cisR resistance. Antitumor effects of the newly conjugated compounds were compared to those of cisplatin. The data clearly indicate that improved drug efficiencies are achieved as a result of the intercalative moieties. The luminescent probe that was integrated in complexes 8-10 made it possible to monitor drug penetration using optical imaging. Enhanced targeting of tumor nuclei by the study compounds was confirmed by confocal microscopy. This paper describes a new class of platinum-based antitumorals differing from cisplatin in several critical aspects with the potential for significantly improving clinical outcomes in cancer patients.
Antineoplastic Agents↗
Selective synthesis of the para-quinone region of geldanamycin.
[structure: see text] The quinone portion of the ansamycin geldanamycin was made with complete selectivity from the 1,4-dihydroquinone generated from a 1,4-bis-methoxymethyl (MOM) ether intermediate. Palladium catalysis with air gave the desired product in 98% isolated yield. The structure was established using NMR, UV, and X-ray analysis with comparisons to geldanamycin, ortho-quino-geldanamycin and a model compound.
Benzoquinones↗
First total synthesis of antimitotic compound, (+)-phomopsidin.
[reaction: see text] The first total synthesis of (+)-phomopsidin has been achieved via a diastereoselective transannular Diels-Alder (TADA) reaction. Key steps in the synthesis include diastereoselective ynone reduction with (-)-alpha-pinene and 9-BBN, macrocyclization by E-selective intramolecular Horner-Wadsworth-Emmons (HWE) reaction, as well as carbometalation under Wipf's conditions, followed by HWE reaction at low temperature to selectively construct the (E)-1-methylpropenyl and (1E,2E)-4-carboxy-1,3-butadienyl substituents.
Antineoplastic Agents↗
Total synthesis and biological evaluation of a C(10)/C(12)-phenylene-bridged analog of epothilone D.
The total synthesis of compound 8, a conformationally constrained analog of epothilone D (2), has been achieved through a convergent strategy based on three key fragments comprising C(1)-C(6) (26), C(7)-C(12) (16), and C(13)-O(16) (19) of the macrocyclic framework. Construction of the C(12)-C(13) bond involved Pd(0)-mediated B-alkyl Suzuki coupling between aryl bromide 16 and olefin 19, and proceeded in excellent yield, while formation of the C(6)-C(7) bond through aldol reaction was somewhat less efficient. Surprisingly, macrolactonization was rather low-yielding and gave protected 8 only in 39% yield. Although 8 had been suggested by pharmacophore modeling to adopt a conformation similar to the bioactive conformation of epothilone B, the compound was devoid of any significant antiproliferative activity.
Drug Evaluation, Preclinical↗
Photodynamic properties of amphiphilic derivatives of aluminum tetrasulfophthalocyanine.
Photodynamic therapy (PDT) is a promising treatment modality that has recently been accepted in clinics as a curative or palliative therapy for cancer and other nonmalignant conditions. Phthalocyanines (Pc) are attractive photosensitizers for PDT because of their enhanced photophysical and photochemical properties. The overall charge and solubility of Pc play a major role in their potential usefulness for PDT. A series of amphiphilic derivatives of tetrasulfonated aluminum Pc (AlPcS4) was prepared by substituting one of the four sulfonate groups with aliphatic side chains of 4, 8, 12 and 16 carbon atoms. The photodynamic properties of the derivatives were compared with those of AlPcS4 and the adjacent disulfonated aluminum Pc. Parameters studied included reversed-phase high-performance liquid chromatography (HPLC) retention times, capacity to generate singlet oxygen (1O2), in vitro cell uptake and phototoxicity, as well as PDT response of transplantable EMT-6 tumors in mice. The monomerized AlPcS4 derivatives showed similar or higher capacities to generate 1O2 as compared with the parent AlPcS4 as measured from relative L-tryptophan photooxidation yields. A549 cell uptake of the AlPcS4 derivatives decreased in the following order: AlPcS4(C16) > AlPcS4(C12) > AlPcS4(C8) > AlPcS4(C4). Human low-density lipoprotein at high concentrations (40 micrograms/mL) completely prevented uptake, whereas at 4 micrograms/mL uptake was decreased for the more lipophilic compounds and yet remained unaffected for the more hydrophilic dyes. Using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, A549 cell survival was assessed; it showed that photocytotoxic activity varied directly with the HPLC retention times, i.e. more hydrophilic compounds were less phototoxic. As 1O2 yields were similar for the four substituted AlPcS4 derivatives, it was postulated that the increased cytotoxic activity was caused by enhanced subcellular localization as a result of the long aliphatic side chains. These amphiphilic compounds proved to be photodynamically potent against the EMT-6 mouse mammary tumor model implanted in Balb/c mice. At dye doses of 0.2 mumol/kg and a fluence of 400 J/cm2 complete tumor regression was observed with no morbidity. The substitution of AlPcS4 with long aliphatic chains on the macrocycle greatly enhances its photodynamic efficacy both in vitro and in vivo.
Animals↗
Bi-, Tri-, and Tetranuclear Metallomacrocycles Constructed by Metal-Directed Reactions Involving Resorcinol or Hydroquinone or by Addition of Octahedral Metal Centers to Tetrahexylcalix[4]resorcinarene: X-ray Crystal Structure of syn,syn-[Mo{HB(3,5-Me(2)C(3)HN(2))(3)}(NO)(1,4-O(2)C(6)H(4))](3).
The reaction between [Mo(NO)(Tp)I(2)] [Tp(-) = hydrotris(pyrazol-1-yl)borate] and tetrahexylcalix[4]resorcinarene (resH(8)) affords a mixture of metalated macrocycles from which [{Mo(NO)(Tp)}(2)(resH(4))], [{Mo(NO)(Tp)}(3)(resH(2))], and [{Mo(NO)(Tp)}(4)(res)] can be isolated. In the solid state the tetrametalated compound can act as a host for CH(2)Cl(2) which forms a weak hydrogen bond to the oxygen of a coordinated nitric oxide: H.O1 2.47 Å, angle C-H.O1 161 degrees. Direct reaction of [Mo(NO)(Tp)I(2)] [Tp(-) = hydrotris(3,5-dimethylpyrazol-1-yl)borate] with resorcinol itself offers a route to the related resorcinol-based tetrametallomacrocycle [Mo(NO)(Tp)(1,3-O(2)C(6)H(4))](4). This reaction also produces the cyclic trimer [Mo(NO)(Tp)(1,3-O(2)C(6)H(4))](3) together with some cyclic dimer. A similar reaction involving 1,4-dihydroxybenzene and [M(NO)(Tp)I(2)] (M = Mo, W) also affords cyclic trimers and cyclic tetramers, but in this case, cyclic dimers are not formed. It has been possible to separate the single isomers syn,syn-[Mo(NO)(Tp)(1,4-O(2)C(6)H(4))](3), anti,syn-[M(NO)(Tp)(1,4-O(2)C(6)H(4))](3) (M = Mo, W), anti,syn-[Mo(NO)(Tp)(1,3-O(2)C(6)H(4))](3), and anti,syn,syn-[Mo(NO)(Tp)(1,3-O(2)C(6)H(4))](4). The crystal structure of syn,syn-[Mo(NO)(Tp)(1,4-O(2)C(6)H(4))](3) has been determined: C(63)H(78)B(3)Mo(3)N(21)O(9); monoclinic space group P2(1)/a; a = 16.269(10), b = 35.31(3), c = 16.056(10) Å; beta = 97.59(2) degrees; Z = 4. The coordination geometry at the molybdenum atoms is essentially octahedral. The trimer does not show 3-fold symmetry, the triangle of molybdenum atoms having two long edges, 8.485(3) and 8.703(3) Å, and one short edge of 7.886(3) Å. These distances are paralleled by the corresponding distances between the nitrosyl oxygen atoms, 6.177(12), 6.526(12), and 3.729(12) Å, respectively. The electrochemical properties of the metallomacrocycles reveal differing patterns of redox potentials depending upon the number and geometric arrangement of metal centers in the macrocyclic structure.
Journal Article↗
Tetra-2,3-pyrazinoporphyrazines with externally appended pyridine rings. 4. UV-visible spectral and electrochemical evidence of the remarkable electron-deficient properties of the new tetrakis-2,3-[5,6-di{2-(N-methyl)pyridiniumyl}pyrazino]porphyrazinatometal octacations, [(2-Mepy)8TPyzPzM]8+ (M = MgII(H2O), CoII, CuII, ZnII).
Metal derivatives of the octacationic tetrakis-2,3-[5,6-di{2-(N-methyl)pyridiniumyl}pyrazino]porphyrazine macrocycle [(2-Mepy)(8)TPyzPzH(2)](8+) (2-Mepy = 2-(N-methyl)pyridiniumyl ring) isolated as water-soluble hydrated iodide salts of the general formula [(2-Mepy)(8)TPyzPzM](I(8)).xH(2)O, (M = Mg(II)(H(2)O), Co(II), Cu(II), Zn(II); x = 2-5) were prepared from the corresponding neutral complexes [Py(8)TPyzPzM].xH(2)O previously reported. Reaction of these complexes with CH(3)I in N,N-dimethylformamide under mild conditions led to full quaternization of all eight pyridine N atoms and formation of the octacations [(2-Mepy)(8)TPyzPzM](8+). Clathrated water molecules could be eliminated from the species [(2-Mepy)(8)TPyzPzM](I(8)).xH(2)O by mild heating ( Co(I) process, but the site of electron transfer is reversed and the final product upon a further one-electron reduction is formulated as a Co(II) dianion as opposed to a Co(I) pi-anion radical. This sequence is similar to what was earlier reported for reduction of the same compound in pyridine. Reversible one-electron oxidations are also observed for the unmethylated species [Py(8)TPyzPzM].xH(2)O where M = Co(II) and Mn(II) in DMSO. Remarkably, the octacationic macrocycles [(2-Mepy)(8)TPyzPzM](I(8)).xH(2)O, (M = Mg(II)(H(2)O), Co(II), Cu(II), and Zn(II); x = 2-5) are more easily reduced at any step of the reduction than the corresponding unquaternized species with the same metal ion. This indicates a higher tendency to stepwise electron uptake after the quaternization process, which enhances the charge redistribution capability within the species formed by the electroreduction.
Journal Article↗
The mechanism of formation of amide-based interlocked compounds: prediction of a new rotaxane-forming motif.
Molecular modeling of four different reagent systems shows that the (free) energies of supramolecular interactions in the gas phase and in solution can explain the different reaction products (i.e., various sized macrocycles, catenanes, and linear oligomers) that are formed in classic amide-catenane-forming reactions. Self-assembly of the catenanes requires the formation of ordered intertwined chains and is driven by bifurcated hydrogen bonds, with pi stacking only playing a lesser role. The understanding gained from the computational study was used to predict the possibility of a new rotaxane-forming system that does not permit catenane formation. The predictions were confirmed by the successful synthesis and characterization (including X-ray crystallography) of two novel rotaxanes.
Journal Article↗
High-valent intermediates of heme proteins and model compounds.
Recent computational and experimental probes of high-valent intermediates in heme proteins and model compounds reveal a rich spectrum of chemical behavior that is dependent on the nature of the proximal ligand, metal center, distal- and proximal-binding site environment, porphyrin macrocycle architecture, and consequent electronic structure. The results of such studies reveal an underlying complexity, which is simply understood once one is cognizant of the 'chameleon'-like behavior of such intermediates is determined by the high-valent intermediate environment.
Catalase↗
Intermetallic interactions in face-to-face homo- and heterodinuclear bismacrocyclic complexes of copper(II) and nickel(II).
New face-to-face heterodinuclear complexes containing copper(II) and nickel(II) in identical tetraazamacrocyclic environments have been synthesized and characterized using ESI mass-spectrometry, X-ray diffraction, spectroscopic methods, and elemental analysis. These new bismacrocyclic systems were compared with the respective mono- and bismacrocyclic and [2]catenane homonuclear complexes. Interactions between the metal centers were monitored by magnetic and electrochemical measurements. Magnetic data indicate that all copper compounds studied behave as weakly interacting magnets. In the case of copper [2]catenane, the extent of magnetic interactions decreased when a benzocrown moiety was introduced between the macrocyclic units. On the basis of electrochemical data, the interactions between the metal centers were found to be substantially larger for the nickel complexes than for the corresponding copper ones. Interlocking of a benzocrown ether to form [2]catenane led to a nonequivalence of the metal centers and to the increase of donor abilities of the catenane compared to the respective bismacrocyclic complex. This is reflected by the shift of the first formal potential to less positive values. Intermetallic interactions for the heteronuclear nickel/copper complexes were found intermediary compared to the homonuclear ones. They were strengthened by shortening the spacer between the two tetraazamacrocyclic subunits which is a convenient way of fine-tuning the interactions. The increase of intermetallic interactions led to the increased stability of the intermediate mixed-valence states indicated by the higher values of comproportionation constants.
Journal Article↗
Synthesis and structural characterization of a nonplanar neutral [36]metallacrown-12 nickel compound [Ni(C13H9N3O2)(CH3OH)]12.
A nonplanar metallacrown [Ni-N-N]12 was achieved using a pentadente ligand, salicylaldehyde 2-pyridinecarboxylhydrazone (H2L) via a new modular self-assembly approach. The special bridging models of the ligand forced the macrocycle to form in a specific size with the wavelike conformation.
Journal Article↗
Crown-annelated oligothiophenes as model compounds for molecular actuation.
Crown-annelated quater- (4T) and sexithiophenes (6T) with oligooxyethylene chains of various lengths attached at the 3-positions of the terminal thiophene rings have been synthesized. Analysis of the cation-binding properties of the macrocycles by (1)H NMR and UV-vis spectroscopy reveals the formation of a 1:1 complex with Ba(2+), Sr(2+), or Pb(2+) and shows that cation complexation results in a conformational transition in the pi-conjugated system. Theoretical analysis of this process by density functional methods predicts that this conformational transition results in a narrowing of the highest occupied-lowest unoccupied molecular orbital gap of the conjugated system with a decrease of the redox potentials (E(0)(1) and E(0)(2)) associated with the formation of the 4T cation radical and dication. Cyclic voltammetry shows that, depending on the binding constant, the presence of metal cation produces a negative or a positive shift of E(0)(1) while E(0)(2) always shifts negatively. This unusual behavior is discussed in terms of interplay between electrostatic interactions and conformational changes associated with cation binding.
Journal Article↗