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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.

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