Calixarene tubes as cation receptors

Details Calixarene tubes as cation receptors Calixarene tubes as cation receptors

2000-06-30

2001-12-04

Owens, Amelia (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C549S348000, C502S150000, C502S172000, C204S416000

Reexamination Certificate

active

06326394

ABSTRACT:

The present invention relates to molecules which are specific for certain cations, such as potassium or caesium, to their preparation and their uses for example as reagents in reactions requiring a cation scavenging agent. The molecules of the invention which are specific for potassium ions may also be regarded as mimicing potassium ion channels
Potassium channel proteins have been the subject of an intense investigation this last decade and a great deal of information about their structure/function relationships has been elucidated (e.g: C. Miller,
Science
1991, 252, 10921096 (re-view), J. O. Dolly, et al., J. Bioenerg. Biomembr. 1996, 28, 231-253; Q Lüet al., Science 1995, 268, 304-307; P. Hidalgo et al., Science 1995,268, 307-310; J. Aiyar, et al., Neuron 1995, 15, 1169-1181; M. Stocker et al., Proc. Natl. Acad. Sci. USA 1994, 91, 9509-9513; J. C. Bradley et al., Protein Eng. 1993, 7, 859-862). A very exciting aspect, still controversial, focuses on how these proteins transport potassium through the cell membrane, with high rates and almost perfect selectivity (K+ transported 1000 times more efficiently than Na+) (G. Yellen, J. Gen. Physiol. 1984, 84, 157; J. Neyton et al. J. Gen. Physiol. 1988, 92, 569).
The channel pore region responsible for the crucial alkali-metal selection, termed the selection filter, contains a square planar array of four converging tyrosine residues (e.g. R. Ranganathan et al., Neuron 1996, 16, 131-139; L. Heginbotham et al., Biophys. J. 1994, 66, 1061-1067; S. Bogusz et al., Protein Eng. 1992, 5, 285-293). A proposed selection mechanism, supported by experimental and ab initio studies, suggests that an en face cation-&pgr; interaction between the potassium and the aromatic surfaces of the tyrosines could be determinant for such a unique selectivity pattern (D. A. Dougherty,
Science
1996, 271, 163-168; C. Miller, Science 1993, 261, 1692-1693; L. Heginbotham, et al., Neuron 1992, 8, 483-491; J. Sunner et al., J. Phys. Chem. 1981, 85, 1814-1820).
Despite the involvement of numerous research groups in the development of synthetic channels (reviewed by G. W. Gokel et al., Acc. Chem. Res. 1996, 29, 425-432; K. S. Akerfeldt et al., Acc. Chem. Res. 1993. 26, 191-197, a biomimetic approach focusing in particular on the alkali-metal selection process has not previously been fully investigated. In an effort to accredit the cation-&pgr; hypothesis, a novel biomimetic calix[4]arene based tubular receptor whose access to metal cations may be controlled by filtering gates based on a square planar array of aromatic surfaces was designed.
According to the present invention, there is provided a cyclic compound of formula (I)
wherein R
x
groups which may be the same or different are selected from
—O—(CH
2
)
n
—O— or —O—(CH
2
CH
2
O)
n
— where n is an integer of from 2-6:
R
y
and R
z
groups which may be the same or different are independently selected from hydrogen, halogen or an optionally substituted hydrocarbyl group;
R
a
together with R
b
of the adjacent phenyl ring and R
c
together with R
d
of the adjacent phenyl ring form a group of formula —(CH
2
)
m
— or —O—(CH
2
)
p
—O— where m and p are integers of from 1-5, and each group R
a
-R
b
and R
c
-R
d
may be the same or different; and
x is an integer of 4 or more.
Suitably x is an integer of from 4-8. The precise number of x will depend upon the ion which the compound of formula (I) is intended to be specific for. In the case of potassium, x is suitably 4, but for caesium a higher value, for example 5 may be preferred.
Thus in a preferred embodiment, the invention provides a compound of formula (II)
where R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
,and R
8
are independently selected from hydrogen, halogen, or an optionally substituted hydrocarbyl group;
R
9
, R
10
, R
11
and R
12
are independently selected from —O—(CH
2
)
n
—O— where n is an integer of from 2-6;
R
13
, R
14
, R
15
, R
16
, R
17
, R
8
, R
19
and R
20
are independently selected from —(CH
2
)
m
— or —O—(CH
2
)
p
—O— where m and p are integers of from 1-5.
Suitable hydrocarbyl groups for R
y
, R
z
, R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
and R
8
include hydrocarbyl groups containing from 1 to 20 carbon atoms including straight or branched alkyl, alkenyl or alkynyl groups, cycloalkyl, aryl groups or aralkyl groups. As used herein, the term ‘aryl’ includes phenyl and naphthyl groups. The term “aralkyl” includes C
1-6
alkylaryl such as benzyl. Suitable optional substitutents for hydrocarbyl groups include functional groups such as ether or ester groups, in particular alkyl ether or ester groups.
Preferably R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
and R
8
are the same group, in particular C
1-6
alkyl groups such as methyl, ethyl, propyl or n- or tert-butyl, most preferably tert-butyl.
Suitably R
9
, R
10
, R
11
and R
12
are the same and n is 2.
Suitably R
13
R
14
, R
15
, R , R
16
, R
17
, R
18
, R
19
and R
20
are the same group, in particular an alkylene group where m is 1.
Preferably p is 1.
Compounds of formula (I) are suitably prepared by reacting a compound of formula (III)
where R
y
, R
a
, R
b
and x are as defined in relation to formula (I), and and R
21
groups are the same or different and are selected from —O—(CH
2
)
n
—O—R
22
where R
22
is a leaving group such as tosylate or mesylate;
with a compound of formula (IV)
 where R
z
, R
c
, R
d
and x are as defined in relation to formula (I); in the presence of a base.
Suitable bases include weak bases such as carbonates, in particular alkali metal carbonates such as potassium carbonate.
Suitably the reaction is effected in the presence of an organic solvent such as acetonitrile.
Compounds of formula (III) and (IV) are either known compounds or they can be prepared from known compounds by conventional methods.
For example, the template-driven condensation of p-tert-butyl-calix[4]arene (VI) with a per-tosylated derivative of formula (V) in acetonitrile, in presence of potassium carbonate, furnished the novel calix[4]tube (VII) in fairly good yields (51% isolated yields, Scheme 1).
Compounds of formula (I) combine several appealing features that make them a suitable model system of relevance for the design of new selective ion channels in particular potassium selective ion channels as illustrated hereinafter. They may be utilised in an in vitro screen, where compounds which have an effect on potassium ion channels would be of assistance. In addition, the effects on cell membranes may mean that compounds of formula (I) display antibiotic properties.
Moreover, the amazing potassium selectivity displayed by compound VI, allied with the biomimetic design of its cation-accessing gates, tend to accredit the cation filtering role occupied by the fourfold symmetrical array of aromatic residues at the narrower portion of naturally occurring channels. The distance separating the two cofacial phenyl rings in compound VI (5.88 Å) is very close to the corresponding distance, predicted by ab initio calculations, in a hypothetical cation-&pgr; complex -(bis-&eegr;
6
-arene) made of two benzene rings and a potassium ion (5. 84 Å) (R. A. Kumpf, D. A. Dougherty,
Science
1993, 261, 1708-1710). This raises the question as to whether such a transient species between compound VII and K+, may be responsible for the very original binding behaviour observed.
These properties mean that the compounds of the invention may also be utilised as ion selective electrodes which select specifically particular ions such as potassium ions. Such electrodes form a further aspect of the invention.
In addition, the compounds of formula (I) can be used as a reagent in chemical reactions and processes where cation scavenging is required. Such reactions include the purification of analar salts of alkali and alkaline earth metals. For instance, contact of sodium, lithium and caesium salts with compound of formula (II) will result in the removal of contaminating potassium ions.
Furthermore, compounds of formula (I) may act as phase transfer catalysts

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