ISMSC 2007 - Università degli Studi di Pavia

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Crown Ether Functionalized Texaphyrins: Approaches to Improved Biolocalization Properties. Jonathan L. Sessler a , Andreas Hirsch b , Darren Magda c , Christian Preihs a,b a University of Texas at Austin, 1 University Station A5300, Austin, TX 78712 b University of Erlangen-Nuremberg, Institute of Organic Chemistry II, Henkestrasse 42, 91054 Erlangen, Germany c Pharmacyclics, Inc., 995 East Arques Avenue, Sunnyvale, California, 94085. Irrespective of the mode of drug administration, drugs principally have to pass through cell membranes to become active in vivo. Therefore, a wide range of functional groups have been explored in an effort to improve the uptake properties of known or experimental pharmaceutical agents. One such functional group that has attracted attention is the crown ether. Crown ethers offer the opportunity to vary the overall polarity, and hence potentially improve the biolocalization properties of a putative active agent through coordination of alkali ions and tertiary amines. [1], [2] In this presentation the synthesis of motexafin gadolinium (MGd; Xcytrin ® ) analogues containing 18-crown-6 moieties will be described. MGd has recently completed Phase III clinical testing as an agent for treating brain metastases from non-small cell lung cancer (NSCLC) in conjunction with whole brain radiation therapy and is currently in Phase II clinical trials as a single agent for the treatment of recurrent NSCLC and this is providing an incentive to make and study analogues whose cellular uptake could be modulated via, e.g., changes in external conditions. Within the context of this broad conceptual goal the crown ether functionalized texaphyrin monomer and dimer shown below were prepared. Their syntheses, as well as those of related analogues, will be summarized in this presentation, as will be preliminary analyses of their in vitro anticancer activity. AcO AcO OH N N Gd OH N N N O O O K + O Figure 1: Crown-ether functionalized texaphyrins (see also [3]) O O [1] Borrel, M. N.; Fiallo, M.; Veress, I.; Garnier-Suillerot, A.; Biochem. Pharmacol. 1995, 50, 2069-2076. [2] Garnier-Suillerot, A.; Marbeuf-Gueye, C.; Salerno, M.; Loetchu-Tinat, C.; Fokt, I.; Krawczyk, M.; Kowalczyk, T.; Priebe, W.; Curr. Med. Chem. 2001, 8, 51-64. [3] Sessler, J. L.; Mody, T. D.; Ramasamy, R.; Sherry, A. D. New. J. Chem. 1992, 16, 541-544. N OH OH N Gd N N N OAc OAc O O O K + O O O AcO AcO N N N Gd N HO HO N PSB 43 PSB 44 Double-threading of two strings through a ring: use of an octahedral metal as template Fabien Durola, Alexander I. Prikhod’ko (Oleksandr Prykhodko), Jean-Pierre Sauvage Laboratoire de Chimie Organo-Minérale, Institut de Chimie, Université Louis Pasteur- CNRS/UMR 7177, 4, rue Blaise Pascal, 67070 STRASBOURG-CEDEX, France Investigation of intermediate [3]pseudorotaxane complexes is an essential step towards metalion assisted syntheses of novel mechanically interlocked molecular systems. The [3]pseudorotaxane complexes were obtained employing the recently reported biisoquinoline chelate (dabiiq) [1,2] , the biisoquinoline-based macrocycle (mb-41) [3] and iron(II)- or cobalt(II)- hexa-aqua ions. Following oxidation of the cobalt(II) complex led to the stable diamagnetic cobalt(III)-[3]pseudorotaxane. Formation of the heteroleptic species [Fe(dabiiq)2mb-41] 2+ and [Co(dabiiq)2mb-41] 3+ was evidenced by means of mass-spectrometry. Both cobalt(III)- and iron(II)-[3]pseudorotaxanes were characterised in solution by means of NMR-techniques and compared to the corresponding homoleptic complexes [M(dabiiq)3] n+ (M = Fe 2+ or Co 3+ ) and related mixed-ligand complexes such as [Fe(bipy)2mb-41] 2+ (bipy = 2,2’-bipyridine). - Stacking between aromatic fragments and hindered rotation of the aromatic rings as well as flexibility of the oxodiethylene chains belonging to the macrocycle clearly evidence the doublethreaded structure of the complexes. [1] F. Durola, J.-P. Sauvage and O. S. Wenger, Chem. Comm., 2006, 171-173 [2] F. Durola, D. Hanss, P. Roesel, J.-P. Sauvage and O. S. Wenger, Eur. J. Org. Chem., 2007, 125–135 [3] F. Durola, J.-P. Sauvage and O. S. Wenger, Helv. Chim. Acta, in press.
Simple Isophthalamide Derivatives As Transmembrane Cl - PSB 45 Transporters Paul V. Santacroce, † Jeffery T. Davis, † Mark E. Light, ‡ Philip A. Gale, ‡ José Carlos Iglesias- Sánchez, § Pilar Prados, § Roberto Quesada § † Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA, ‡ School of Chemistry, University of Southampton, Southampton, SO17 1BJ, United Kingdom, and § Departamento de Química Orgánica, Universidad Autónoma de Madrid, 28049 Madrid, Spain The control of ion transport across membranes is a key function in living cells. Chloride, the most abundant anion in physiological solutions, is usually transported by a variety of different anion transport proteins buried into the membranes, being the largest family of these the ClC proteins. Recently, numerous diseases have been associated with malfunction of anion channels, notably the cystic fibrosis, the most extended genetic disease among Caucasians. Development of molecules or synthetic systems capable of alternative transport might have therapeutic potential if a disease is due to malfunction of natural anion channels. Moreover, transport is expected to modify the concentration gradients across cell membranes, thus potentially inducing physiological effects. 1 We have synthesized a family of isophthalamide derivatives and studied their anion binding properties in solution and their chloride transport activity in model EYPC liposomes. 2 The presence of intramolecular hydrogen bonds in 4,6-dihydroxy-isophthalamides stabilizing a synsyn conformation of the amide groups resulted in an enhanced anion affinity and a remarkable transport activity. Noteworthy, this activity can be modulated as function of the pH. A detailed account of this work will be presented within this communication. [Cl - ] / mM 30 25 20 15 10 5 0 0 50 100 150 200 250 Time /sec pH = 6.4 pH = 7.8 pH = 7.4 pH = 8.0 pH = 9.1 Figure 1. Left: Representation of a 4,6-dihydroxy-N,N`-butylisophthalamide receptor transporting chloride anion through the lipidic membrane. Right: transport activity displayed by this compound as function of the pH. [1] For a recent review on synthetic anion transporters see: A. P. Davis, D. N. Sheppard, and B. D. Smith, Chem. Soc. Rev. 2007, 36, 348-357. [2] P. V. Santacroce, J. T. Davis, M. E. Light, P. A. Gale, J. C. Iglesias-Sánchez, P. Prados, and R. Quesada, J. Am. Chem. Soc. 2007; 129, 1886-1887. PSB 46 Diphosphonate-macrocycle Conjugates – Probe Complexes for a Sorption Investigation T. Vitha, V. Kubíek, I. eho, P. Hermann, Z. I. Kolar, H. T. Wolterbeek, J. A. Peters, I. Lukeš Department of Inorganic Chemistry, Faculty of Science, Charles University in Prague, Albertov 6, 12843, Prague, Czech Republic Geminal diphosphonates are strongly adsorbed on surfaces of many inorganic oxides and salts.[1,2] Their strong sorption on the surface of hydroxyapatite (HA) – a main inorganic component of bones predeterminates their most important application – treatment of diseases connected with disorder of calcium metabolism (osteoporosis, Paget disease and others). We have synthesized and studied three ligands, combining a diphosphonic acid group with a DOTA-core – BPAMD [3], BPAPD and BPPED. Presence of a DOTA core makes these compounds extremely suitable for radiochemical studies as radiolabeling proceeds via complexation. Radiolabeled Tb(III) complexes of the ligands were used for study of an interaction between bisphosphonate acid group and HA surface. Tb(III)-BPAPD complex has also been used as a probe for a study of the interaction between HA and a group of other diphosphonates via competitive sorption. To describe the competition of two diphosphonates during sorption, a physicochemical model based on the Langmuir and on the Langmuir–Freundlich adsorption isotherm was evaluated and successfully applied. HOOC N N O N PO3H2 PO3H2 HOOC N N O N PO3H2 PO3H2 HOOC N N O OH P PO3H2 PO3H2 HOOC N N COOH HOOC N N COOH HOOC N N COOH BPAMD BPAPD BPPED [1] H. Fleisch, Bisphosphonates in Bone Disease, 4th ed., Academic Press London, 2000 [2] R. L. Hilderbrand, The Role of Phosphonates in Living Systems, CRC Press, 1983 [3] V. Kubíek, J. Rudovský, J. Kotek, P. Hermann, L. Vander Elst, R. N. Muller, Z. I. Kolar, H. T. Wolterbeek, J. A. Peters, I. Lukeš, J. Am. Chem. Soc., 2005, 127, 16477–16485
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nd International Symposium on Macro
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Eric Anslyn University of Texas at
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1 Map of Salice Terme 7 5 6 3 9 2 8
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Symposium Program All sessions will
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11:40 - 12:00 Oral Presentation: V.
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PSA 22 Anion Receptors Based On The
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PSA 72 Molecular Tectonics: STM Stu
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PSB 11 Dual binding properties of p
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PSB 57 Removal Of Heavy Metal Ions
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40 years of polyazamacrocycles. A p
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PL 5 Anion-Templated Assembly of In
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Exercising Demons: Synthetic Molecu
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Synthetic Strategies and Structural
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Anion binding as a conformational a
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Supramolecular control of a metal c
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OP 3 Control of molecular architect
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Catalyst discovery using dynamic co
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Cucurbit[n]uril Molecular Container
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OP 15 From non-mesomorphic nature t
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OP 19 Pyrrolic Tripodal Receptors f
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PSA 1 Efficient synthesis of pseudo
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Tetra-Cationic phthalocyanines Yasi
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PSA 9 Cell penetrating borosilica n
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PSA 13 Halide anion interactions wi
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Sensing with cavitands: Moving from
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Lead(II) complexation by calix[4]-h
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Functional [2×2] Grids Xiao-Yu Cao
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Neutral supramolecular systems inco
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PSA 33 Ratiometric Ion Sensors by R
Page 59 and 60: A photocontrollable receptor for Cu
Page 61 and 62: New emitters for mass spectrometric
Page 63 and 64: PSA 45 A fast-moving electrochemica
Page 65 and 66: Macrocyclic Porphyrin-Bidentate Che
Page 67 and 68: PSA 53 Electronic spectroscopy of e
Page 69 and 70: PSA 57 Self-assembly of calixarene/
Page 71 and 72: PSA 61 Piperazine Containing Polyam
Page 73 and 74: PSA 65 Synthesis of Self-Assembly S
Page 75 and 76: PSA 69 Assembly of Metallomacrocycl
Page 77 and 78: Supra-Biomolecular Tandem Assays -
Page 79 and 80: PSA 77 Synthesis and molecular reco
Page 81 and 82: PSA 81 Reaction of phthalic aldehyd
Page 83 and 84: Binding of perrhenate and pertechne
Page 85 and 86: PSA 89 Supramolecular assemblies of
Page 87 and 88: Polytopic Ligands for the Recovery
Page 89 and 90: PSB 1 Rosette Nanotubes as Scaffold
Page 91 and 92: PSB 5 Towards the development of ne
Page 93 and 94: PSB 9 A Quantitative [2]Rotaxane Sy
Page 95 and 96: Metal Complexes of the Polyether Io
Page 97 and 98: PSB 17 Metal controlled anion inter
Page 99 and 100: Crown Ether-tert-Ammonium Salt Comp
Page 101 and 102: PSB 25 A Minimalist Design for Self
Page 103 and 104: PSB 29 Control of Translation of th
Page 105 and 106: PSB 33 Multinuclear NMR, ESI MS and
Page 107 and 108: PSB 37 New Anthracene-based cycloph
Page 109: PSB 41 1,3,5-Tris(2-aminophenyl)ben
Page 113 and 114: PSB 49 On Sokolov’s approach to a
Page 115 and 116: PSB 53 New chromogenic sensors usin
Page 117 and 118: PSB 57 Removal of heavy metal ions
Page 119 and 120: PSB 61 Molecular Recognition of Ele
Page 121 and 122: PSB 65 Switching of Self to non-Sel
Page 123 and 124: Investigation of -cyclodextrin bind
Page 125 and 126: Novel ditopic probes for different
Page 127 and 128: PSB 77 Synthesis, supramolecular ar
Page 129 and 130: PSB 81 Tripodal polyamines as anion
Page 131 and 132: PSB 85 Templated Synthesis of Large
Page 133 and 134: PSB 89 Direct C-C coupling of 1,2,4
Page 135 and 136: PSB 93 The study of cytotoxicity ef
Page 137 and 138: PSB 97 Development of innovative so
Page 139 and 140: Campbell B. PSA 39 Campbell F. PSB
Page 141 and 142: Jensen L.G. PSA 82 Jeppesen J.O. IL
Page 143 and 144: Peters A.J. PSB 39 Peters A.J. PSB
Page 145 and 146: Sponsors of ISMSC 2007 The contribu
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