Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “macrocycles”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 253 records · Page 14Linked to original sources
PubMed1997

Tsalen- and Tsalpn-Based Nickel Complexes with Two Aldehyde Functionalities as Potential Synthons for Thiophenolate-Containing Di- and Polynucleating Acyclic and Macrocyclic Ligands.

Tsalen- and tsalpn-based nickel complexes with aldehyde functionalities have been prepared (tsalen = N,N'-ethylenebis(thiosalicylideneaminato)(2-) and tsalpn = N,N'-propane-1,3-diyl(thiosalicylideneaminato)(2-)). One of the complexes has been structurally characterized: Ni(pftp) (pftp = N,N-ethylene(6-formyl-4-methyl-2-methyliminatothiophenolato)(2-)) crystallizes in the monoclinic space group C2/c with a = 28.761(7), b = 8.582(2), c = 7.841(4) Å; beta = 98.92(3) degrees, and Z = 4. Ni(pftp) and Ni(eftp) (efpt = N,N-ethylene(6-formyl-4-methyl-2-methyliminatothiophenolato)(2-)) were used as synthons for acyclic and macrocyclic complexes and a prototype of each has been structurally characterized. The Schiff base derivative of Ni(pftp) and 2-(2-aminoethyl)pyridine gives the acyclic complex, Ni(peptp) (peptp =N,N-propane-1,3-diyl(6-(N-(2-ethylpyridyl)iminomethyl)-4-methyl-2-methyliminatothiophenolato)(-)) with the two ethylpyridyl arms furnishing an "open site", which in this complex is vacant, and a "closed site", in which the Ni(2+) is located. Ni(peptp) crystallizes in the monoclinic space group P2(1)/n with a = 10.247(7), b = 21.886(8), c = 15.662(9) Å; beta = 92.58(6) degrees, and Z = 4. Schiff base condensation of Ni(pftp) with diaminopropane gave two different macrocyclic dinickel complexes [L(1)Ni(2)](ClO(4))(2) and L(2)Ni(2). L(1) and L(2) are the 2 + 2 and 4 + 4 macrocycles, respectively, comprising two propylenediamine and two thiocresol units and four propylenediamine and four thiocresol units, respectively. Crystals of L(2)Ni(2) (L(2) = (10,23,36,49-tetramethyl-13,26,39,52-tetramercapto-2,6,15,19,28,32,41,45-octaaza-1,7,14,20,27,33,40,46-octaene[7.7.7.7]metacyclophane) are of poor quality and crystallize in the C2/c space group with a = 31.517(14), b =8.980(2), c = 26.822(12) Å; beta = 117.17(2) degrees, and Z = 4.

Journal Article↗
PubMed1998

Effect of Mixed Pendent Groups on the Solution and Catalytic Properties of Europium(III) Macrocyclic Complexes: Bifunctional and Monofunctional Amide and Alcohol Pendents in Septadentate or Octadentate Ligands.

Five new Eu(III) macrocyclic complexes have been prepared and their solution and catalytic properties studied. The Eu(III) complexes with septadentate ligands TRED and NB-TRED dissociate rapidly at pH 7.4, 37 degrees C (TRED = 1,4,7-tris(hydroxyethyl)-1,4,7,10-tetraazacyclododecane, NB-TRED = 1-(nitrobenzyl)-4,7,10-tris(hydroxyethyl)-1,4,7,10-tetraazacyclododecane). Dissociation rates as determined in the presence and absence of strongly binding competing ligands suggest that under most conditions the Eu(III) complexes of ATHC, ABHC, and CNPHC are more kinetically inert to dissociation than is the Eu(III) complex containing all hydroxyethyl groups (ATHC = 1-(carbamoylmethyl)-4,7,10-tris(hydroxyethyl)-1,4,7,10-tetraazacyclododecane, ABHC = 1,7-bis(carbamoylmethyl)-4,10-bis(hydroxyethyl)-1,4,7,10-tetraazacyclododecane, CNPHC = 1-(1-carboxamido-3-(4-nitrophenyl)propyl)-4,7,10-tris(2-hydroxyethyl)-1,4,7,10-tetraazacyclododecane). Laser-induced luminescence excitation spectra of Eu(III) complexes of ABHC, ATHC, CNPHC, THED, and S-THP suggest that there is a single major species in solution at pH 6.3 and a second species that appears at more basic pH values (THED = 1,4,7,10-tetrakis(hydroxyethyl)-1,4,7,10-tetraazacyclododecane, S-THP = 1S,4S,7S,10S-tetrakis(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane). The species present at basic pH is proposed to be an alkoxide or hydroxide complex; pK(a) values as determined by potentiometric titrations are 7.5 and 8.1 for Eu(CNPHC)(3+) and Eu(ABHC)(3+), respectively. Eu(CNPHC)(3+), Eu(ATHC)(3+), and Eu(ABHC)(3+) promote transesterification of the hydroxypropyl ester of 4-nitrophenyl phosphate with pseudo-first-order rate constants at pH 7.3, 37 degrees C, and 1.00 mM complex of 1.4 x 10(-)(5), 9.3 x 10(-)(6), and 1.0 x 10(-)(6) s(-)(1), respectively. Both Eu(CNPHC)(3+)and Eu(ABHC)(3+) promote attack of an hydroxyethyl group of the macrocycle on bis(4-nitrophenyl) phosphate with pseudo-first-order rate constants at pH 7.3, 37 degrees C, and 1.00 mM complex of 1.5 x 10(-)(4) and 3.5 x 10(-)(5) s(-)(1), respectively. In general, an increase in the number of amide groups on the macrocycle of the Eu(III) complex decreases the rate of both intramolecular or intermolecular phosphate diester transesterification reactions.

Journal Article↗
PubMed1998

Macrocyclic Heterodinuclear Zn(II)Pb(II) Complexes: Synthesis, Structures, and Hydrolytic Function toward Tris(p-nitrophenyl) Phosphate.

A heterodinuclear Zn(II)Pb(II) complex ZnPb(L)(ClO(4))(2).2H(2)O (1) has been obtained where (L)(2)(-) is an unsymmetric macrocycle derived from the 2:1:1 condensation of 2,6-diformyl-4-methylphenol, ethylenediamine and diethylenetriamine and has the "salen"- and "saldien"-like metal-binding sites sharing the phenolic moiety. Its DMF adduct, ZnPb(L)(ClO(4))(2).MeOH.2DMF (1'), crystallizes in the triclinic space group P&onemacr; with a = 14.457(4) Å, b = 14.795(6) Å, c = 10.307(9) Å, alpha = 109.04(5) degrees, beta = 96.24(5) degrees, gamma = 102.56(3) degrees, V = 1995(2) Å(3), and Z = 2. The refinement converges with R = 0.058 and R(w) = 0.060 for 3532 reflections with |F(0)| > 3sigma(|F(0)|). It has a discrete heterodinuclear core with the Zn(II) in the "salen" site and the Pb(II) in the "saldien" site of the macrocycle (L)(2)(-). The Zn has a square-pyramidal geometry together with a methanol oxygen, and the Pb has a seven-coordinate geometry together with one DMF oxygen and one perchlorate oxygen. The complex 1 is converted into [ZnPb(L)(OH)ClO(4)]H(2)O (2) under a weak alkaline condition. Its anhydrous form, [ZnPb(L)(OH)]ClO(4) (2), crystallizes in the monoclinic space group C2/c with a = 25.835(4) Å, b = 13.190(6) Å, c = 16.553 Å, beta = 106.31(2) degrees, V = 5413(2) Å(3), and Z = 8. The refinement converges with R = 0.038 and R(w) = 0.029 for 3944 reflections with |F(0)| > 3sigma(|F(0)|). It has a dimer structure of a dinuclear {ZnPb(L)(OH)}(+) unit having the Zn(II) in the "salen" site and the Pb(II) in the "saldien" site of the macrocycle. The hydroxide is bound to the Zn(II) to afford a square-pyramidal geometry about the metal. The dimeric core [ZnPb(L)(OH)](2)(2+) is formed by the bridge of the hydroxide oxygen to the Pb of the adjacent molecule and vice versa. The geometry about the Pb in the dimer structure is a pentagonal pyramid showing a distortion to "umbrella-like" structure, with the bridging hydroxide oxygen at the apex. In a DMSO solution, an equilibrium exists between the dimeric and monomeric species: [{ZnPb(L)(OH)}(2)](2+) right harpoon over left harpoon 2[ZnPb(L)(OH)](+). On the basis of (31)P NMR and visible spectra, 2 is shown to hydrolyze tris(p-nitorophenyl) phosphate (TNP) into bis(p-nitrophenyl) phosphate (BNP) in DMSO. 1 also exhibits a low activity to hydrolyze TNP into BNP due to the equilibrium [ZnPb(L)(H(2)O)](2+) right harpoon over left harpoon [ZnPb(L)(OH)](+) + H(+). From the reaction mixture with 2, a BNP complex [ZnPb(L)(BNP)]ClO(4) (3) has been isolated. 3 crystallizes in the triclinic space group P&onemacr; with a = 13.494(9) Å, b = 13.88(1) Å, c = 12.765(8) Å, alpha = 94.71(6) degrees, beta = 97.02(6) degrees, gamma = 61.68(5) degrees, V = 2088(2) Å(3), Z = 2. The refinement converges with R = 0.044 and R(w) = 0.056 for 6070 reflections with |F(0)| > 3sigma(|F(0)|). The BNP(-) group bridges the pair of metal ions through its two oxygens, together with two phenolic oxygens of (L)(2)(-). On the basis of the above findings, a mechanistic scheme for the TNP hydrolysis by 2 is proposed; a TNP molecule is bound to the Pb center, and the hydroxide on the adjacent Zn ion attacks the phosphorus nucleus of TNP, leading to the formation of the BNP complex 3.

Journal Article↗
PubMed1999

Structural Analysis of All the Nickel 14-Membered Tetraaza Macrocycles in the Cambridge Structural Database.

One hundred and thirty-nine nickel complexes containing the 1,4,8,11-tetraazacyclotetradecane backbone were found in the Cambridge Structural Database. Cluster analysis was used to separate the structures according to their macrocyclic configurations, using their conformations as a separation criteria. The most commonly found configuration was the trans III configuration. The amount of trans I macrocycles relative to trans III macrocycles was found to be higher for square-planar complexes than octahedral ones. Molecular mechanical conformational searches were done for select structures found in the Cambridge Structural Database.

Journal Article↗
PubMed2000

Interactions between divalent metal ions and an octacoordinate macrocyclic ligand.

A dinucleating hexaazadiphenol macrocyclic ligand, 15,31-dimethyl-3,11,19,27,33,35-hexaazapentacyclo[27.3.1.1.(5,9)1.(13,17)1. (21,25)]hexatriaconta-5,7,9(33),13,15,17(34),21,23,25(35),29,31,1(36)- dodecaene-34,36-diol (H2L), forms a number of protonated, neutral, and/or hydroxo mononuclear, homodinuclear, and heterodinuclear complexes with the divalent metal ions Cu2+, Cd2+, Mn2+, and Zn2+, controlled by the stoichiometry of the metal ion and ligand as well as the pH values of the solution. Their stability constants and species distribution as a function of p[H] are determined. The pH potentiometric studies show that the dinuclear complexes are formed via the mononuclear chelates in which two kinds of coordination patterns are observed. One is that the metal ions are complexed by exactly half of coordination sites of the dinucleating macrocycle (N3O-), and the other is that the metal ions occupy salen-like sites of the macrocycle (N3O(2)2-). In the 2:1 systems (2:1 molar ratio of metal ion to ligand), the mononuclear species predominate in acidic solutions while the dinuclear species predominate in basic solutions, except for the case of copper. The protonated mononuclear complex [H2LZn](NO3)(2).5H2O forms triclinic crystals, of space group P1, with a = 10.7797(12) A, b = 10.9047(12) A, c = 17.0176(15) A, alpha = 106.857(9) degrees, beta = 95.822(8) degrees, gamma = 100.191(9) degrees, and Z = 2; the neutral heterodinuclear complex [LZnCdCl2].6H2O forms monoclinic crystals, of space group C2/c, with a = 16.234(5) A, b = 15.976(9) A, c = 29.829(11) A, alpha = 90 degrees, beta = 90.28(2) degrees, gamma = 90 degrees, and Z = 8.

Journal Article↗
PubMed2001

Dopamine interaction in the absence and in the presence of Cu2+ ions with macrocyclic and macrobicyclic polyamines containing pyrazole units. Crystal structures of [Cu2(L1)(H2O)2](ClO4)4 and [Cu2(H-1L3)](ClO4)3*2H2O.

The interaction with Cu2+ and dopamine of three polyazacyclophanes containing pyrazole fragments as spacers is described. Formation of mixed complexes Cu2+-macrocycle-dopamine has been studied by potentiometric methods in aqueous solution. The crystal structures of the complexes [Cu2(L1)(H2O)2](ClO4)4*2H2O (4) (L1 = 13,26-dibenzyl-3,6,9,12,13,16,19,22,25,26-decaazatricyclo[22.2.1.1(11,14)]octacosa-1(27),11,14(28),24-tetraene) and [Cu2(H-1L3)](HClO4)(ClO4)2*2H2O (6) (L3 = 1,4,7,8,11,14,17,20,21,24,29,32,33,36-tetradecaazapentacyclo[12.12.12.1(6,9).1(19,22).1(31,34)]hentetraconta-6,9(41),19(40),21,31,34(39)-hexaene) are presented. In the first one (4), each Cu2+ coordination site is made up by the three nitrogens of the polyamine bridge, a sp2 pyrazole nitrogen and one water molecule that occupies the axial position of a square pyramid. The distance between the copper ions is 6.788(2) A. In the crystal structure of 6, the coordination geometry around each Cu2+ is square pyramidal with its base being formed by two secondary nitrogens of the bridge and two nitrogen atoms of two different pyrazolate units which act as exobidentate ligands. The axial positions are occupied by the bridgehead nitrogen atoms; the elongation is more pronounced in one of the two sites [Cu(1)-N(1), 2.29(2) A; Cu(2)-N(6), 2.40(1) A]. The Cu-N distances involving the deprotonated pyrazole moieties are significantly shorter than those of the secondary nitrogens. The Cu(1)...Cu(2) distance is 3.960(3) A. The pyrazole in the noncoordinating bridge does not deprotonate and lies to one side of the macrocyclic cavity. One of the aliphatic nitrogens of this bridge is protonated and hydrogen bonded to a water molecule, which is further connected to the sp2 nitrogen of the pyrazole moiety through a hydrogen bond. The solution studies reveal a ready deprotonation of the pyrazole units induced by coordination to Cu2+. In the case of L2 (L2 = 3,6,9,12,13,16,19,22,25,26-decaazatricyclo[22.2.1.1(11,14)]octacosa-1(27),11,14(28),24-tetraene), deprotonation of both pyrazole subunits is already observed at pH ca. 4 for 2:1 Cu2+:L2 molar ratios. All three free receptors interact with dopamine in aqueous solution. L3 is a receptor particularly interesting with respect to the values of the interaction constants over five logarithmic units at neutral pH, which might suggest an encapsulation of dopamine in the macrocyclic cage. All three receptors form mixed complexes Cu2+-L-dopamine. The affinity for the formation of ternary dopamine complexes is particularly high in the case of the binuclear Cu2+ complexes of the 1-benzyl derivative L1.

Cations, Divalent↗
PubMed2002

Is the corrolate macrocycle innocent or noninnocent? Magnetic susceptibility, Mössbauer, 1H NMR, and DFT investigations of chloro- and phenyliron corrolates.

In an attempt to determine the electron configuration of (anion)iron corrolates, i.e., whether they are S = 1 Fe(IV)-corrolate(3-) or S = 3/2 Fe(III)-corrolate(2-*), with antiferromagnetic coupling between the iron and macrocycle electrons to yield overall S = 1, two axial ligand complexes of an iron octaalkylcorrolate have been studied by temperature-dependent magnetic susceptibility, magnetic Mössbauer, and 1H NMR spectroscopy, and the results have been compared to those determined on the basis of spin-unrestricted DFT calculations. Magnetic susceptibility measurements indicate the presence of a noninnocent macrocycle (corrolate (2-*)) for the chloroiron corrolate, with strong antiferromagnetic coupling to the S = 3/2 Fe(III) center, while those for the phenyliron corrolate are not conclusive as to the electron configuration. Temperature- and field-dependent Mössbauer spectroscopic investigations of these two complexes yielded spectra that could be simulated with either electron configuration, except that the isomer shift of the phenyl-iron complex is -0.10 mm/s while that of the chloroiron complex is +0.21 mm/s, suggesting that the iron in the former is Fe(IV) while in the latter it is Fe(III). 1H NMR spectroscopic studies of both axial ligand complexes show large negative spin density at the meso carbons, with those of the chloroiron complex (Cai, S.; Walker, F. A.; Licoccia, S. Inorg. Chem. 2000, 39, 3466) being roughly four times larger than those of the phenyliron complex. The temperature dependence of the proton chemical shifts of the phenyliron complex is strictly linear. DFT calculations are consistent with the chloroiron complex being formulated as S1 = 3/2 Fe(III)-corrolate (2-*) S2 = 1/2, with negative spin density at all nitrogens and meso carbons, and a net spin density of -0.79 on the corrolate ring and positive spin density (+0.17) on the chloride ion and +2.58 on the iron. In contrast, the phenyliron complex is best formulated as S = 1 Fe(IV)-corrolate (3-), but again with negative spin density at all nitrogens and meso carbons of the macrocycle, yet with the net spin density on the corrolate ring being virtually zero; the phenyl carbanion carbon has relatively large negative spin density of -0.15 and the iron +2.05. On the basis of all of the results, we conclude that in both the chloroiron and phenyliron complexes the corrolate ring is noninnocent, in the chloroiron complex to a much larger extent than in the phenyliron complex.

Iron↗
PubMed2003

Sanglifehrin-cyclophilin interaction: degradation work, synthetic macrocyclic analogues, X-ray crystal structure, and binding data.

Sanglifehrin A (SFA) is a novel immunosuppressive natural product isolated from Streptomyces sp. A92-308110. SFA has a very strong affinity for cyclophilin A (IC(50) = 6.9 +/- 0.9 nM) but is structurally different from cyclosporin A (CsA) and exerts its immunosuppressive activity via a novel mechanism. SFA has a complex molecular structure consisting of a 22-membered macrocycle, bearing in position 23 a nine-carbon tether terminated by a highly substituted spirobicyclic moiety. Selective oxidative cleavage of the C(26)=C(27) exocyclic double bond affords the spirolactam containing fragment 1 and macrolide 2. The affinity of 2 for cyclophilin (IC(50) = 29 +/- 2.1 nM) is essentially identical to SFA, which indicates that the interaction between SFA and cyclophilin A is mediated exclusively by the macrocyclic portion of the molecule. This observation was confirmed by the X-ray crystal structure resolved at 2.1 A of cyclophilin A complexed to macrolide 16, a close analogue of 2. The X-ray crystal structure showed that macrolide 16 binds to the same deep hydrophobic pocket of cyclophilin A as CsA. Additional valuable details of the structure-activity relationship were obtained by two different chemical approaches: (1) degradation work on macrolide 2 or (2) synthesis of a library of macrolide analogues using the ring-closing metathesis reaction as the key step. Altogether, it appears that the complex macrocyclic fragment of SFA is a highly optimized combination of multiple functionalities including an (E,E)-diene, a short polypropionate fragment, and an unusual tripeptide unit, which together provide an extremely strong affinity for cyclophilin A.

Binding, Competitive↗
PubMed2003

Chemoenzymatic route to macrocyclic hybrid peptide/polyketide-like molecules.

Hybrid peptide-polyketides are a class of medically and biologically important natural products characterized by stereochemical and functional diversity. In their biosynthesis, hybrids are often macrocyclized to achieve rigid structures that populate bioactive conformations. We herein present a chemoenzymatic strategy to access the stereochemical and functional diversity found in macrocyclic hybrid natural products in a manner amenable to efficient library synthesis. Our method makes use of small building blocks in the form of Fmoc-protected epsilon-amino acids containing embedded polyketide functionality. The building block approach allows for combinatorial synthesis of linear molecules that can be activated as soluble thioesters or tethered to a solid-phase resin. We demonstrate that these linear molecules are substrates for macrocyclization by a tolerant catalyst, TycC TE, derived from a nonribosomal peptide synthetase. The method should allow for access to diverse structures with hybrid peptide-polyketide character that can be screened for improved or novel activities.

Amides↗
PubMed2004

Shape-persistent macrocycles with intraannular polar groups: synthesis, liquid crystallinity, and 2D organization.

The synthesis of macrocycles with intraannular polar ester groups and extraannular oligo-alkyl groups is described. The compounds exhibit stable liquid crystalline phases showing fan-shaped textures under the polarizing microscope, typical for a columnar order of the molecules. X-ray powder diffraction data of the LC phase indicate that the unit cell contains two symmetry-related units, a feature pointing most probably to a restricted rotation of the macrocycles within a stack. The X-ray data were further supported by solid-state NMR experiments, showing that the rigid core of the compounds does not rotate with kHz or higher frequencies within the column in the LC phase. Apart from the organization of the molecules in the LC phase, the 2D organization of the macrocycles at the solvent-highly oriented pyrolytic graphite (HOPG) interface was investigated and showed that these compounds are capable of nanofunctionalizing the HOPG surface in the multinanometer regime.

Journal Article↗
PubMed2005

Total syntheses of amphidinolides T1 and T4 via catalytic, stereoselective, reductive macrocyclizations.

Described in this work are total syntheses of amphidinolides T1 and T4 using two nickel-catalyzed reductive coupling reactions of alkynes, with an epoxide in one case (intermolecular) and with an aldehyde in another (intramolecular). The latter was used to effect a macrocyclization, form a C-C bond, and install a stereogenic center with >10:1 selectivity in both natural product syntheses. Alternative approaches in which intermolecular alkyne-aldehyde reductive coupling reactions would serve to join key fragments were investigated and are also discussed; it was found that macrocyclization (i.e. intramolecular alkyne-aldehyde coupling) was superior in several respects (diastereoselectivity, yield, and length of syntheses). Alkyne-epoxide reductive couplings were instrumental in the construction of key fragments corresponding to approximately half of the molecule of both natural products. In one case (T4 series), the alkyne-epoxide coupling exhibited very high site selectivity in a coupling of a diyne. A model for the stereoselectivity observed in the macrocyclizations is also proposed.

Alkynes↗
PubMed2005

A new class of macrocyclic lanthanide complexes for cell labeling and magnetic resonance imaging applications.

Lanthanide complexes have wide applications in biochemical research and biomedical imaging. We have designed and synthesized a new class of macrocyclic lanthanide chelates, Ln/DTPA-PDA-C(n), for cell labeling and magnetic resonance imaging (MRI) applications. Two lipophilic Gd3+ complexes, Gd/DTPA-PDA-C(n) (n = 10, 12), labeled a number of cultured mammalian cells noninvasively at concentrations as low as a few micromolar. Cells took up these agents rapidly and showed robust intensity increases in T1-weighed MR images. Labeled cells showed normal morphology and doubling time as control cells. In addition to cultured cells, these agents also labeled primary cells in tissues such as dissected pancreatic islets. To study the mechanism of cellular uptake, we applied the technique of diffusion enhanced fluorescence resonance energy transfer (DEFRET) to determine the cellular localization of these lipophilic lanthanide complexes. After loading cells with a luminescent complex, Tb/DTPA-PDA-C10, we observed DEFRET between the Tb3+ complex and extracellular, but not intracellular, calcein. We concluded that these cyclic lanthanide complexes label cells by inserting two hydrophobic alkyl chains into cell membranes with the hydrophilic metal binding site facing the extracellular medium. As the first imaging application of these macrocyclic lanthanide chelates, we labeled insulin secreting beta-cells with Gd/DTPA-PDA-C12. Labeled cells were encapsulated in hollow fibers and were implanted in a nude mouse. MR imaging of implanted beta-cells showed that these cells could be followed in vivo for up to two weeks. The combined advantages of this new class of macrocyclic contrast agents ensure future imaging applications to track cell movement and localization in different biological systems.

Animals↗
PubMed2006

Cationic shape-persistent macrocycles: the unexpected formation of a nano-size supramolecular dimer.

Shape-persistent macrocycles with a rigid pyridyl core and a flexible oligo-alkyl corona aggregate to some extent in nonpolar solvents to form large (tubular) aggregates. To increase the assembling tendency, the intraannular pyridyl groups of the macrocycles were alkylated. Unexpectedly, the quarternized macrocycles show no tendency at all to form tubular micellar-like structures but form well-defined dimers, as determined by X-ray and dynamic light scattering.

Journal Article↗
PubMed2006

2D supramolecular structures of a shape-persistent macrocycle and co-deposition with fullerene on HOPG.

Two 2D supramolecular structures of macrocycle 1 and 1/C60 have been obtained on HOPG by self-assembly under ambient conditions and investigated by high-resolution STM. The monolayers of 1 are characterized by structures with perfect ordering over relatively large areas. In the case of 1/C60, the size of the macrocycle 1 and the presence of two individual bithiophene units per ring lead in the final superstructure to a 1:2 stoichiometry. The fullerenes are not trapped at the graphite surface inside the macrocyclic holes but are located around the periphery of the bithiophene units. This clearly shows that the donor-acceptor interaction between C60 and the electron-rich units of the ring is the dominant factor for the structure formation.

Journal Article↗
PubMed2000

Synthesis, stability, antiviral activity, and protease-bound structures of substrate-mimicking constrained macrocyclic inhibitors of HIV-1 protease.

Three new peptidomimetics (1-3) have been developed with highly stable and conformationally constrained macrocyclic components that replace tripeptide segments of protease substrates. Each compound inhibits both HIV-1 protease and viral replication (HIV-1, HIV-2) at nanomolar concentrations without cytotoxicity to uninfected cells below 10 microM. Their activities against HIV-1 protease (K(i) 1.7 nM (1), 0.6 nM (2), 0.3 nM (3)) are 1-2 orders of magnitude greater than their antiviral potencies against HIV-1-infected primary peripheral blood mononuclear cells (IC(50) 45 nM (1), 56 nM (2), 95 nM (3)) or HIV-1-infected MT2 cells (IC(50) 90 nM (1), 60 nM (2)), suggesting suboptimal cellular uptake. However their antiviral potencies are similar to those of indinavir and amprenavir under identical conditions. There were significant differences in their capacities to inhibit the replication of HIV-1 and HIV-2 in infected MT2 cells, 1 being ineffective against HIV-2 while 2 was equally effective against both virus types. Evidence is presented that 1 and 2 inhibit cleavage of the HIV-1 structural protein precursor Pr55(gag) to p24 in virions derived from chronically infected cells, consistent with inhibition of the viral protease in cells. Crystal structures refined to 1.75 A (1) and 1.85 A (2) for two of the macrocyclic inhibitors bound to HIV-1 protease establish structural mimicry of the tripeptides that the cycles were designed to imitate. Structural comparisons between protease-bound macrocyclic inhibitors, VX478 (amprenavir), and L-735,524 (indinavir) show that their common acyclic components share the same space in the active site of the enzyme and make identical interactions with enzyme residues. This substrate-mimicking minimalist approach to drug design could have benefits in the context of viral resistance, since mutations which induce inhibitor resistance may also be those which prevent substrate processing.

Anti-HIV Agents↗
PubMed1991

Design and synthesis of P2-P1'-linked macrocyclic human renin inhibitors.

Using a computer model of the active site of human renin developed at Merck, we designed a series of novel P2-P1'-linked, macrocyclic renin inhibitors 3-10. These unique inhibitors incorporate a transition-state isostere within a 13- or 14-membered ring. The three most active compounds in this family were 13-membered-ring glutamine-derived inhibitor 3, 14-membered-ring diaminopropionic acid derived inhibitor 6, and 13-membered-ring diol 9 (IC50 0.61, 0.59, 0.65 microM, respectively). Modification of inhibitor 3 at P4 led to 56 nM macrocyclic renin inhibitor 39. This study shows the viability of renin inhibitor designs which incorporate a scissile-bond replacement within a macrocycle.

Amino Acid Sequence↗
PubMed2001

Design, synthesis, and structure-activity relationships of macrocyclic hydroxamic acids that inhibit tumor necrosis factor alpha release in vitro and in vivo.

To search for TNF-alpha (tumor necrosis factor alpha) converting enzyme (TACE) inhibitors, we designed a new class of macrocyclic hydroxamic acids by linking the P1 and P2' residues of acyclic anti-succinate-based hydroxamic acids. A variety of residues including amide, carbamate, alkyl, sulfonamido, Boc-amino, and amino were found to be suitable P1-P2' linkers. With an N-methylamide at P3', the 13-16-membered macrocycles prepared exhibited low micromolar activities in the inhibition of TNF-alpha release from LPS-stimulated human whole blood. Further elaboration in the P3'-P4' area using the cyclophane and cyclic carbamate templates led to the identification of a number of potent analogues with IC(50) values of </=0.2 microM in whole blood assay (WBA). Although the P3' area can accommodate a broad array of structurally diversified functional groups including polar residues, hydrophobic residues, and amino and carboxylic acid moieties, in both the cyclophane series and the cyclic carbamate series, a glycine residue at P3' was identified as a critical structural component to achieve both good in vitro potency and good oral activity. With a glycine residue at P3', an N-methylamide at P4' provided the best cyclophane analogue, SL422 (WBA IC(50) = 0.22 microM, LPS-mouse ED(50) = 15 mg/kg, po), whereas a morpholinylamide at P4' afforded the most potent and most orally active cyclic carbamate analogue, SP057 (WBA IC(50) = 0.067 microM, LPS-mouse ED(50) = 2.3 mg/kg, po). Further profiling for SL422 and SP057 showed that these macrocyclic compounds are potent TACE inhibitors, with K(i) values of 12 and 4.2 nM in the porcine TACE assay, and are broad-spectrum MMP inhibitors. Pharmacokinetic studies in beagle dogs revealed that SL422 and SP057 are orally bioavailable, with oral bioavailabilities of 11% and 23%, respectively.

ADAM Proteins↗
PubMed2003

Macrocyclization in the design of Grb2 SH2 domain-binding ligands exhibiting high potency in whole-cell systems.

While most SH2 domains bind phosphotyrosyl (pTyr) containing peptides in extended fashion, the growth factor receptor-bound protein 2 (Grb2) SH2 domain preferentially binds ligands in bend conformations. Accordingly, incorporation of bend-inducing functionality into synthetic ligands could potentially enhance their affinity for this SH2 domain. A macrocyclic tripeptide mimetic that contains a simplified pTyr surrogate lacking an alpha-nitrogen has recently been shown to exhibit high Grb2 SH2 domain-binding affinity in extracellular ELISA-based assays. However, the same compound is largely ineffective in whole-cell assays. It is known that acidic functionality originating from the alpha-nitrogen of pTyr residues or from the alpha-position of P0 pTyr mimetics not only increases binding affinity of peptides to Grb2 SH2 domains in extracellular assays but also enhances potency in cell-based systems. Such functionality is absent from the previously reported macrocycle. Therefore, the current study was undertaken to examine the effects of introducing carboxylic functionality at the pTyr mimetic alpha-position of macrocyclic ligands. It was found that such a modification not only enhanced Grb2 SH2 domain binding in extracellular assays but also conferred high efficacy in whole-cell systems. The most potent compound of the current study exhibited an IC(50) value of 0.002 microM in an extracellular ELISA-based assay, and in MDA-MB-453 cells, it both inhibited the association of Grb2 with p185(erbB-2) and exhibited antimitogenic effects with submicromolar IC50 values.

Adaptor Proteins, Signal Transducing↗