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PubMed2002

Conformationally constrained macrocycles that mimic tripeptide beta-strands in water and aprotic solvents.

The beta-strand conformation is unknown for short peptides in aqueous solution, yet it is a fundamental building block in proteins and the crucial recognition motif for proteolytic enzymes that enable formation and turnover of all proteins. To create a generalized scaffold as a peptidomimetic that is pre-organized in a beta-strand, we individually synthesized a series of 15-22-membered macrocyclic analogues of tripeptides and analyzed their structures. Each cycle is highly constrained by two trans amide bonds and a planar aromatic ring with a short nonpeptidic linker between them. A measure of this ring strain is the restricted rotation of the component tyrosinyl aromatic ring (DeltaG(rot) 76.7 kJ mol(-1) (16-membered ring), 46.1 kJ mol(-1) (17-membered ring)) evidenced by variable temperature proton NMR spectra (DMF-d(7), 200-400 K). Unusually large amide coupling constants ((3)J(NH-CHalpha) 9-10 Hz) corresponding to large dihedral angles were detected in both protic and aprotic solvents for these macrocycles, consistent with a high degree of structure in solution. The temperature dependence of all amide NH chemical shifts (Deltadelta/T 7-12 ppb/deg) precluded the presence of transannular hydrogen bonds that define alternative turn structures. Whereas similar sized conventional cyclic peptides usually exist in solution as an equilibrium mixture of multiple conformers, these macrocycles adopt a well-defined beta-strand structure even in water as revealed by 2-D NMR spectral data and by a structure calculation for the smallest (15-membered) and most constrained macrocycle. Macrocycles that are sufficiently constrained to exclusively adopt a beta-strand-mimicking structure in water may be useful pre-organized and generic templates for the design of compounds that interfere with beta-strand recognition in biology.

Carboxylic Acids↗

PubMed2001

Effect of progressive benzyl substitution on the conformations of aminocaproic acid-cyclized dipeptides.

The constraint of dipeptides into a beta-turn conformation can be accomplished by linking the two ends of a standard dipeptide with a linker derived from aminocaproic acid (Aca). To elucidate the possibility of using substituted Aca linkers in peptidomimetic design, a series of five macrocycles composed of a monobenzylated Aca linker (containing the benzyl group on each of the five methylene groups of the parent linker) and Gly-Gly were synthesized. The requisite linkers were made by regiochemically controlled ring expansion techniques (for substitution on Aca positions C-3, C-4, or C-5), an Evans alkylation route (for C-2), or by chain extension of L-phenylalanal (for C-6). The solution-phase conformations of the macrocycles were examined by NMR and CD techniques; in addition, crystal structures of the C-4- and C-6-benzyl-substituted linkers were obtained. Four out of the five macrocycles were found to exist with the dipeptide portion taking up either a type II or II' beta-turn conformation, but the Gly-Gly unit in the compound derived from 4-benzyl-Aca did not correspond to one of the standard beta-turn types.

Aminocaproic Acid↗

PubMed2002

The formation of a cyclic diacetal of methyl alpha-D-mannopyranoside with a 16-membered macrocyclic loop.

The X-ray structure of a diacetal with a 16-membered macrocyclic loop, which was obtained as a product of the condensation of methyl alpha-D-mannopyranoside and 1,4-bis(2-formylphenoxy)butane is presented together with polymeric compounds resulting from polycondensation; a similar polymer was formed in the reaction of methyl 2,3:4,6-di-O-salicylidene-alpha-D-mannopyranoside with 1,4-dibromobutane.

Carbohydrate Sequence↗

PubMed1980

Photophysical properties of zinc and magnesium tris(pyrochlorophyllide a) 1,1,1-tris(hydroxymethyl)ethane triesters.

The zinc and magnesium tris(pyrochlorophyllide a) 1,1,1-tris(hydroxymethyl)ethane triesters have properties that are very similar to those exhibited by pairs of pyrochlorophyll a or chlorophyll a linked by ethylene glycol through their propionic acid side chains. In the open configuration, the fluorescence lifetimes and emission spectra of the triesters resemble those of chlorophyll a monomers. However, the triesters have a mechanism for energy dissipation not present in monomeric chlorophyll a, which prevents the build-up of significant concentrations of molecules in S(1) states. Optical pumping of these compounds in their folded configuration results in the formation of high concentrations of molecules in S(1) states and in laser light emission, which originates from the two folded macrocycles. The optical data indicate that efficient energy transfer occurs from the open to the folded configurations.

Journal Article↗

PubMed1978

Tumor-promoting phorbol esters inhibit binding of epidermal growth factor to cellular receptors.

Tumor-promoting phorbol esters and related plant macrocyclic diterpenes inhibit the binding of epidermal growth factor to its receptors on HeLa cells. This effect shows marked structural specificity and correlates with other biological effects of these compounds on mouse skin and in cell culture systems. The active compounds inhibited binding of 125I-labeled epidermal growth factor with a 50 per-cent effective dose in the range of 10(-8) to 10(-9) M. Inhibition appears to be due to a decrease in the number of available epidermal growth factor receptors rather than a change in receptor affinity. These results suggest that certain biologic effects of tumor promoters may result from alterations in the function of cell surface receptors involved in growth regulation.

Binding, Competitive↗

PubMed1975

Studies on the biosynthesis of basic 16-membered macrolide antibiotics, platenomycins. III. Production, isolation and structures of platenolides I and II.

Two neutral macrocyclic lactones designated platenolides I and II have been isolated as the major products from the fermentation broth of the blocked mutants of Streptomyces platensis subsp. malvinus. These two compounds were isolated by solvent extraction and purified by column chromatography. Both platenolides [PL-I: C20H32O6, PL-II: C20H34O6] are closely related to the platenomycin aglycone.

Anti-Bacterial Agents↗

PubMed2006

Synthesis of iso-epoxy-amphidinolide N and des-epoxy-caribenolide I structures. Initial forays.

Two strategies for the projected total synthesis of the phenomenally potent antitumour macrolides amphidinolide N (1) and caribenolide I (2) are described. The title compounds are introduced as challenging and unique targets for chemical synthesis, and their retrosynthetic analysis is presented. The synthesis of the four defined key building blocks (10, 39, 67 and 72), required for the construction of amphidinolide N (1), in their enantiomerically pure forms, is described, followed by the coupling of 10, 39 and 72 through hydrazone alkylation processes to generate the complete C6-C29 carbon framework of the target compound (1). Fusion of the remaining C1-C5 sector (72) onto the molecule by metathesis-based methods was unsuccessful, resulting in the adoption of a second-generation strategy which called for the employment of one of the array of palladium-catalysed cross-coupling reactions to generate the C5-C6 carbon-carbon bond. Vinyl bromide 125, representing the C6-C29 skeleton of caribenolide I (2), was prepared through the sequential alkylation of hydrazone 10 with bromide 116 and iodide 55, but failed to engage in the appropriate cross-coupling reaction with a variety of C1-C4 partners. Despite these setbacks, the information gleaned from these endeavours was to prove invaluable in laying the foundation for the eventual successful approach to the macrocyclic structures of amphidinolide N (1) and caribenolide I (2).

Antineoplastic Agents↗

PubMed2006

Speciation of selenium compounds by open tubular capillary electrochromatography-inductively coupled plasma mass spectrometry.

We introduce a T-type interface and a crossflow nebulizer to find ways to combine CEC with inductively coupled plasma MS (ICP-MS) detection for selenium speciation. For CEC separation, we employed a macrocyclic polyamine-bonded phase capillary as the separation column and a bare fused-silica capillary filled with the make-up liquid (0.05 M HNO3). The effect of nebulizer gas flow rate, make-up liquid flow, type, concentration and pH of the mobile phase on the separation have been studied. Tris buffer of 50 mM at pH 8.50 gave the best performance for selenium speciation. The reproducibility of the retention time indicated that sample injection by electrokinetic and nebulizer gas flow was better than that by self-aspiration alone. The detection limits for selenate, selenite, selenocystine and selenomethionine were found to be 2.40, 3.53, 12.86 and 11.25 ng/mL, respectively. Due to the high sensitivity and element-specific detection, as well as the high selectivity of the bonded phase, quantitative analysis of selenium speciation in urine was also achieved.

Buffers↗

PubMed1993

Biological activities of phthalocyanines--XVI. Tetrahydroxy- and tetraalkylhydroxy zinc phthalocyanines. Effect of alkyl chain length on in vitro and in vivo photodynamic activities.

Zinc phthalocyanine substituted with four hydroxyl groups attached to the macrocycle, either directly or via spacer chains of three or six carbon atoms, were tested for their photodynamic ability to inactivate Chinese hamster lung fibroblasts (line V-79) in vitro, and to induce regression of EMT-6 tumours grown subcutaneously in Balb/c mice. Their potential to inflict direct cell killing during photodynamic therapy was investigated by examining vascular stasis immediately following photoirradiation using fluorescein as a marker, and also by an in vivo/in vitro EMT-6 cell survival assay. Both of the tetraalkylhydroxy substituted zinc phthalocyanines are effective photodynamic sensitisers in vivo with the tetrapropylhydroxy compound exhibiting about twice the activity of the tetrahexylhydroxy analogue. The differences in activities were accentuated in vitro, the tetrapropylhydroxy compound was two orders of magnitude more potent than the tetrahexylhydroxy analogue in photoinactivating V-79 cells. The tetrahydroxy compound lacking spacer chains failed to exhibit photodynamic activity in either system. Tumour response with the active compounds was preceded by vascular stasis immediate following irradiation which suggests, together with the absence of activity in the in vivo/in vitro assay, that tumour regression involves an indirect response to the photodynamic action rather than direct cell killing. These data demonstrate the importance of the spatial orientation of functional groups around the macrocycle of photosensitisers for their efficacy in the photodynamic therapy of cancer.

Animals↗

PubMed2000

mu-Oxo-bis[(2,3,12,13-tetrabromo-5,10,15, 20-tetraphenylporphyrinato)iron(III)] bis(dichloromethane) solvate.

The precise structure of the title compound, [Fe(2)O(C(44)H(24)Br(4)N(4))(2)].2CH(2)Cl(2), is reported. The Fe-N distances are non-equivalent in pairs because of the asymmetric peripheral substitution; the values are 2.098 A to the brominated rings and 2.041 A to the other two rings. The Fe-O bond distance is 1.7583 (4) A. The molecule has required twofold symmetry so that there is one unique porphyrin macrocycle and one Fe-O bond length in contrast to a previous report on the same species.

Crystallography, X-Ray↗

PubMed1995

Stachybotrys toxins. 1.

Cultures of several isolates of Stachybotrys chartarum have produced a series of cytotoxic macrocyclic trichothecenes including two newly characterized congeners: isosatratoxin G and S-isosatratoxin H. Nine immunosuppressant phenylspirodrimanes (1-9) were isolated and characterized, the majority of which are newly reported compounds.

Crystallography, X-Ray↗

PubMed2002

The art of acetylenic scaffolding: rings, rods, and switches.

Acetylenic scaffolding with derivatives of tetraethynylethene (TEE, 3,4-diethynylhex-3-ene-1,5-diyne) and (E)-1,2-diethynylethene (DEE, (E)-hex-3-ene-1,5-diyne) provides carbon-rich compounds with interesting physicochemical properties. Thus, these modules are building blocks for monodisperse, linearly pi-conjugated oligomers [polytri(acetylene)s, PTAs] extending in length beyond 10nm, and for large, macrocyclic, all-carbon cores (dehydroannulenes and expanded radialenes) exhibiting strong chromophoric properties. The advanced materials' properties were strongly influenced by the presence of electron-donating substituents at the lateral positions, decreasing the decreasing the (HOMO-LUMO) gap in both PTAs and expanded radialenes. Arylated TEEs were found to undergo photochemically induced cis-trans isomerization, paving the way for applications as light-driven molecular switches in optoelectronic devices. Derivatives of 1,3-diethynylallene are new modules that offer the prospect of scaffolding in an orthogonal manner; that is, they represent precursors for helical oligomers.

Journal Article↗

PubMed2002

Super/subcritical fluid chromatography chiral separations with macrocyclic glycopeptide stationary phases.

The chiral recognition capabilities of three macrocyclic glycopeptide chiral selectors, namely teicoplanin (Chirobiotic T), its aglycone (Chirobiotic TAG) and ristocetin (Chirobiotic R), were evaluated with supercritical and subcritical fluid mobile phases. A set of 111 chiral compounds including heterocycles, analgesics (nonsteroidal antiinflamatory compounds), beta-blockers, sulfoxides, N-protected amino acids and native amino acids was separated on the three chiral stationary phases (CSPs). All separations were done with an outlet pressure regulated at 100 bar, 31 degrees C and at 4 ml/min. Various amounts of methanol ranging from 7 to 67% (v/v) were added to the carbon dioxide along with small amounts (0.1 to 0.5%, v/v) of triethylamine and/or trifluoroacetic acid. The Chirobiotic TAG CSP was the most effective closely followed by the Chirobiotic T column. Both columns were able to separate, partially or fully, 92% of the enantiomers of the compound set. The ristocetin chiral selector could partially or baseline resolve only 60% of the enantiomers tested. All separations were done in less than 15 min and 70% were done in less than 4 min. The speed of the separations is the main advantage of the use of SFC compared to normal-phase HPLC. In addition, SFC is advantageous for preparative separations with easy solute recovery and solvent disposal.

Chromatography, Liquid↗

PubMed2003

Core-modified porphyrin incorporating a phenolate donor. Characterization of Pd(II), Ni(II), Zn(II), Cd(II), and Fe(III) complexes.

Coordinating properties of acetoxybenziporphyrin, (TPBPOAc)H, have been investigated for a number of metal ions. Insertion of Ni, Pd, and Fe results in the cleavage of the acetoxy group leading to complexes (TPBPO)Ni(II), (TPBPO)Pd(II), and (TPBPO)Fe(III)X containing a M-O bond. No cleavage is observed with Zn(II) and Cd(II), which form complexes (TPBPOAc)M(II)Cl, where M = Zn, Cd. (TPBPO)Ni(II) can also be obtained from the dication of hydroxybenziporphyrin, [(TPBPOH)H(3)]Cl(2), which is prepared by acid hydrolysis of the acetoxy compound. The diamagnetic (TPBPO)Ni(II) can be transformed into the paramagnetic (TPBPOAc)Ni(II)Cl in a reaction with acetyl chloride. X-ray structures have been determined for (TPBPO)Pd(II) and (TPBPOAc)Zn(II)Cl. In the palladium species, the phenolate moiety forms a strong bond to the Pd ion and an unusual interaction geometry is observed, enforced by the macrocyclic environment. Association of a TFA molecule to the phenolic oxygen does not cause significant structural changes in the (TPBPO)Pd(II) molecule. In (TPBPOAc)Zn(II)Cl, the metal ion weakly interacts with the phenolic fragment. The paramagnetic Fe(III) complexes, (TPBPO)Fe(III)X, have been investigated with (1)H NMR spectroscopy. The observed spectral patterns are consistent with the presence of a high-spin Fe(III) center and pi delocalization of spin density onto the phenoxide fragment. Each of the compounds (TPBPO)Fe(III)X exists in solution as a mixture of two isomers, which for X = I are shown to remain in a temperature-dependent equilibrium. The observed isomerism results from two nonequivalent orientations of the axial halide with respect to the puckered macrocyclic ring.

Journal Article↗

PubMed1996

Formation and X-ray Structures of PCP Ligand Based Platinum(II) and Palladium(II) Macrocycles.

The coordination behavior prior to C-M bond formation of the chelating aromatic PCP substrate DPPMH (3; DPPMH = 1,3-bis((diphenylphosphino)methylene)mesitylene) has been studied in order to determine the factors which control the complex formation of such ligands. Reacting 3 with (RCN)(2)MCl(2) (R = Me, Ph; M = Pd, Pt) and (COD)PtX(2) (X = Cl, Me; COD = 1,5-cyclooctadiene) resulted in the formation of several 8- and 16-membered mono- and binuclear palladium(II) and platinum(II) macrocycles: trans-[(DPPMH)PdCl(2)](2) (5), trans-[(DPPMH)PtCl(2)](2) (6), cis-(DPPMH)PtCl(2) (7), cis-(DPPMH)PtMe(2) (8), and cis-[(DPPMH)PtMe(2)](2) (9). Compounds 5-9 were fully characterized using NMR, FAB-MS, FD-MS, elemental analysis, and X-ray crystallography. Thermolysis of the bimetallic trans-[(DPPMH)PtCl(2)](2) (6) results in the formation of the monomeric cis-(DPPMH)PtCl(2) (7). The product formation depends on the neutral- (nitriles or COD) and anionic ligands (Cl and CH(3)) of the metal precursor. The molecular structures of trans-[(DPPMH)PdCl(2)](2) (5) and cis-[(DPPMH)PtMe(2)](2) (9) have been determined by complete single-crystal diffraction studies. Crystal data for 5: monoclinic, space group P2(1)/n with a = 14.547(3) Å, b = 17.431(4) Å, c = 27.839 (5) Å, beta = 99.56(2) degrees, V = 6961(3) Å(3), and Z = 4. The structure converged to R = 0.048 and R(w) = 0.049. Crystal data for 9: monoclinic, space group P2(1)/n with a = 19.187(4) Å, b = 19.189(4) Å c = 20.705(2) Å, beta = 103.41(3) degrees, V = 7415(3) Å(3), and Z = 4. The structure refinement converged to R = 0.0977 and R(w) = 0.2212.

Journal Article↗

PubMed1998

Bridged Aminotroponiminate Complexes of Lanthanum.

The reaction of the new ligand 1,3-di(2-(N-isopropylamino)troponimine)propane, H(2)[(iPr)TP], with KH affords K(2)[(iPr)TP]. The salt of this new ligand is a useful starting material for the preparation of the lanthanum compounds [[(iPr)TP](3)La(2)(THF)](2) and [[(iPr)TP]LaCl(THF)](2), respectively. These metal complexes were characterized by NMR and X-ray crystallography. In contrast to macrocyclic ligands the [(iPr)TP](2)(-) anion shows a higher flexibility upon coordination and features two different coordination modes. Further reaction of [[(iPr)TP]LaCl(THF)](2) with 2 equiv of LiCH(SiMe(3))(2) or KN(SiMe(3))(2) in toluene affords the alkyl or amide derivatives [[(iPr)TP](2)LaE(SiMe(3))(2)] (E = CH, N) in high yield. Crystal data: [[(iPr)TP](3)La(2)(THF)](2), space group P2(1)/c, a = 19.860(2) Å, b = 17.691(3) Å, c = 21.333(3) Å, beta = 102.211(8) degrees, Z = 4, V = 7325.8 Å(3); [[(iPr)TP]LaCl(THF)](2), space group P2(1)/n, a = 12.848(3) Å, b = 32.902(7) Å, c = 16.215(3) Å, beta = 110.38(3) degrees, Z = 4, V = 6425(2) Å(3).

Journal Article↗

PubMed2003

Total synthesis of dendroamide a: oxazole and thiazole construction using an oxodiphosphonium salt.

The total synthesis of dendroamide A (1), a multidrug-resistance reversing bistratamide-type peptide-derived macrocycle, has been accomplished in 19% yield. Fmoc-protected amino acids were condensed into appropriately protected dipeptides which were treated with bis(triphenyl)oxodiphosphonium trifluoromethanesulfonate to afford oxazoles and thiazolines (oxidized to thiazoles) with high chemo- and stereoselectivity. The convergent condensation of three heterocyclic amino acids followed by macrocyclization afforded the natural product.

Amino Acids↗

PubMed2004

Total synthesis of macrosphelides A, B, and E: first application of ring-closing metathesis for macrosphelide synthesis.

A new synthetic route for macrosphelides A, B, and E based on ring-closing metathesis (RCM) was established. The substrates for RCM could be synthesized starting from commercially available chiral materials, methyl (S)-lactate and methyl (S)- or (R)-3-hydroxybutyrate, in good overall yields. In the investigation of the key RCM step, it was found that the steric factor around the reaction site significantly affected the reaction rate of macrocyclization. A detailed account regarding this synthetic study is described herein.

Heterocyclic Compounds↗