ISMSC 2007 - Università degli Studi di Pavia

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.