ISMSC 2007 - Università degli Studi di Pavia
ISMSC 2007 - Università degli Studi di Pavia
ISMSC 2007 - Università degli Studi di Pavia
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Crown Ether Functionalized Texaphyrins: Approaches to Improved<br />
Biolocalization Properties.<br />
Jonathan L. Sessler a , Andreas Hirsch b , Darren Magda c , Christian Preihs a,b<br />
a University of Texas at Austin, 1 University Station A5300, Austin, TX 78712<br />
b University of Erlangen-Nuremberg, Institute of Organic Chemistry II, Henkestrasse 42, 91054<br />
Erlangen, Germany<br />
c Pharmacyclics, Inc., 995 East Arques Avenue, Sunnyvale, California, 94085.<br />
Irrespective of the mode of drug administration, drugs principally have to pass through cell<br />
membranes to become active in vivo. Therefore, a wide range of functional groups have been<br />
explored in an effort to improve the uptake properties of known or experimental pharmaceutical<br />
agents. One such functional group that has attracted attention is the crown ether. Crown<br />
ethers offer the opportunity to vary the overall polarity, and hence potentially improve the<br />
biolocalization properties of a putative active agent through coor<strong>di</strong>nation of alkali ions and<br />
tertiary amines. [1], [2] In this presentation the synthesis of motexafin gadolinium (MGd; Xcytrin ® )<br />
analogues containing 18-crown-6 moieties will be described. MGd has recently completed<br />
Phase III clinical testing as an agent for treating brain metastases from non-small cell lung<br />
cancer (NSCLC) in conjunction with whole brain ra<strong>di</strong>ation therapy and is currently in Phase II<br />
clinical trials as a single agent for the treatment of recurrent NSCLC and this is provi<strong>di</strong>ng an<br />
incentive to make and study analogues whose cellular uptake could be modulated via, e.g.,<br />
changes in external con<strong>di</strong>tions. Within the context of this broad conceptual goal the crown ether<br />
functionalized texaphyrin monomer and <strong>di</strong>mer shown below were prepared. Their syntheses,<br />
as well as those of related analogues, will be summarized in this presentation, as will be<br />
preliminary analyses of their in vitro anticancer activity.<br />
AcO<br />
AcO<br />
OH<br />
N<br />
N Gd<br />
OH<br />
N<br />
N<br />
N<br />
O<br />
O<br />
O<br />
K +<br />
O<br />
Figure 1: Crown-ether functionalized texaphyrins (see also [3])<br />
O<br />
O<br />
[1] Borrel, M. N.; Fiallo, M.; Veress, I.; Garnier-Suillerot, A.; Biochem. Pharmacol. 1995, 50,<br />
2069-2076.<br />
[2] Garnier-Suillerot, A.; Marbeuf-Gueye, C.; Salerno, M.; Loetchu-Tinat, C.; Fokt, I.; Krawczyk,<br />
M.; Kowalczyk, T.; Priebe, W.; Curr. Med. Chem. 2001, 8, 51-64.<br />
[3] Sessler, J. L.; Mody, T. D.; Ramasamy, R.; Sherry, A. D. New. J. Chem. 1992, 16, 541-544.<br />
N<br />
OH<br />
OH<br />
N<br />
Gd<br />
N<br />
N<br />
N<br />
OAc<br />
OAc<br />
O<br />
O<br />
O<br />
K +<br />
O<br />
O<br />
O<br />
AcO<br />
AcO<br />
N<br />
N<br />
N<br />
Gd<br />
N<br />
HO<br />
HO<br />
N<br />
PSB 43<br />
PSB 44<br />
Double-threa<strong>di</strong>ng of two strings through a ring: use of an octahedral metal<br />
as template<br />
Fabien Durola, Alexander I. Prikhod’ko (Oleksandr Prykhodko), Jean-Pierre Sauvage<br />
Laboratoire de Chimie Organo-Minérale, Institut de Chimie, Université Louis Pasteur-<br />
CNRS/UMR 7177, 4, rue Blaise Pascal, 67070 STRASBOURG-CEDEX, France<br />
Investigation of interme<strong>di</strong>ate [3]pseudorotaxane complexes is an essential step towards metalion<br />
assisted syntheses of novel mechanically interlocked molecular systems. The<br />
[3]pseudorotaxane complexes were obtained employing the recently reported biisoquinoline<br />
chelate (dabiiq) [1,2] , the biisoquinoline-based macrocycle (mb-41) [3] and iron(II)- or cobalt(II)-<br />
hexa-aqua ions. Following oxidation of the cobalt(II) complex led to the stable <strong>di</strong>amagnetic<br />
cobalt(III)-[3]pseudorotaxane. Formation of the heteroleptic species [Fe(dabiiq)2mb-41] 2+ and<br />
[Co(dabiiq)2mb-41] 3+ was evidenced by means of mass-spectrometry. Both cobalt(III)- and<br />
iron(II)-[3]pseudorotaxanes were characterised in solution by means of NMR-techniques and<br />
compared to the correspon<strong>di</strong>ng homoleptic complexes [M(dabiiq)3] n+ (M = Fe 2+ or Co 3+ ) and<br />
related mixed-ligand complexes such as [Fe(bipy)2mb-41] 2+ (bipy = 2,2’-bipyri<strong>di</strong>ne). -<br />
Stacking between aromatic fragments and hindered rotation of the aromatic rings as well as<br />
flexibility of the oxo<strong>di</strong>ethylene chains belonging to the macrocycle clearly evidence the doublethreaded<br />
structure of the complexes.<br />
[1] F. Durola, J.-P. Sauvage and O. S. Wenger, Chem. Comm., 2006, 171-173<br />
[2] F. Durola, D. Hanss, P. Roesel, J.-P. Sauvage and O. S. Wenger, Eur. J. Org. Chem., <strong>2007</strong>,<br />
125–135<br />
[3] F. Durola, J.-P. Sauvage and O. S. Wenger, Helv. Chim. Acta, in press.