Synthesis and structure-activity relationships of open D-Ring galanthamine analogues

Article abstract of DOI:10.1016/S0960-894X(03)00397-4

Open D-ring galanthamine analogues were prepared using ring-opening reactions of the quaternarized urethane or oxazolidine functions and were evaluated for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition potency.

Full text of DOI:10.1016/S0960-894X(03)00397-4

Bioorganic & Medicinal Chemistry Letters 13 (2003) 2389–2391
Synthesis and Structure–Activity Relationships of Open D-Ring
Galanthamine Analogues
Denyse Herlem, Marie-Therese Martin, Claude Thal and Catherine Guillou*
´ `
Institut de Chimie des Substances Naturelles, C.N.R.S., 91198 Gif-sur-Yvette Cedex, France
Received 3 January 2003; revised 1 April 2003; accepted 9 April 2003
Abstract—Open D-ring galanthamine analogues were prepared using ring-opening reactions of the quaternarized urethane or
oxazolidine functions and were evaluated for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition
potency.
#
2003 Elsevier Science Ltd. All rights reserved.
1
(
À)-Galanthamine 1, a tertiary alkaloid isolated from
Treatment of galanthamine 1 with ethyl chloroformate
at room temperature afforded 5 and 6 as an inseparable
mixture (80/20, respectively) in 80% yield together with
the o-chloromethyl substituted tertiary urethane 7 (5%).
Amaryllidaceae, is a centrally acting, competitive and
reversible inhibitor of acetylcholinesterase that enhances
cognitive functions in Alzheimer’s patients. This drug
is commercially available in Austria, and is the most
recently approved acetylcholinesterase inhibitor for use
in the United States and Europe.
2
À
Compound 7 results from a nucleophilic attack of Cl
at the benzylic position of the quaternary urethane 5.
Subsequent heating of the 5/6 mixture in water and
acetone yielded 8 (50%) and 6 (23%) (Scheme 1).
A variety of synthetic galanthamine derivatives has been
3
previously described including C-ring and D-ring deri-
4
The second route to access open D-ring galanthamine
analogues was based on degradation of the oxazocine
10 with ethyl chloroformate.
5
vatives, quaternary ammonium derivatives, esters and
5
carbamates of 6-O-demethylgalanthamine and bis-
6
interacting ligands.
In continuation of our work in the galanthamine series,
we report the synthesis of new optically pure open D-
ring galanthamine analogues 2 and 3 which could also
be the starting compounds for the synthesis of new bis-
interacting ligands of type 4 (Fig. 1). Furthermore,
galanthamine being also a nicotinic allosteric potentiat-
ing ligand, open D-ring galanthamine analogues will be
7
tested for this other activity.
Cleavage of the C9N10bond of galanthamine 1 was
based on D-ring opening reactions of galanthamine or
oxazocine 10 with ethyl chloroformate. The benzylic
cleavage of phthalidisoquinoline alkaloids by ethyl
8
chloroformate has been previously described.
*Corresponding author. fax: +33-1-6907-7247; e-mail: guillou@icsn.
cnrs-gif.fr
Figure 1.
0
960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00397-4

2390
D. Herlem et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2389–2391
group is a oriented. In addition, there is a strong inter-
action between H1 and H12a, which hinders the a face
of the molecule, where the nitrogen atom is localized
(
Fig. 2).
Biological Evaluation and Discussion
Newly synthesized compounds were assayed for AChE
Electrophorus electricus) and BChE (Human serum)
(
1
1
inhibition potency by the Ellman method. The results
are summarized in Table 1.
As shown in Table 1, replacement of the N-methyl
group of galanthamine 1 by a CO Et group (i.e., com-
2
pound 6) decreases the AChE inhibition. This could be
explained by the loss of a non-conventional hydrogen
bond between the N-methyl group of galanthamine and
1
2
aspartate 72 of AChE.
The potency of acetylcholinesterase inhibition decreases
when the size of the D-ring increases (i.e., 10) as well as
when the D-ring is opened (i.e., 7, 8 and 11). The pre-
sence of an electron withdrawing group on the A-ring of
galanthamine enhances the BChE inhibition potency
Scheme 1.
(i.e., 11) compared to the other analogues.
Galanthamine 1 was quantitatively converted into its N-
oxide 9 by oxidation with m-chloroperbenzoic acid in
The marked BChE/AChE selectivity of compounds 8,
10, 11 could be explained by the fact BChE seems to be
better able than AChE to accommodate steric bulk
around the catalytic site.
9
dichloromethane at room temperature. The heating of
N-oxide 9 at 170 C in N,N-dimethylacetamide afforded
ꢀ
the corresponding undescribed Meisenheimer rearran-
1
0
gement product 10. It was not possible to cleave the
N–O bond of 10 by reduction (under the following
.
conditions: Na/NH ; NiCl 6H O; NaBH ; TiCl etha-
3
2
2
4
3
nol; Li/EtNH ; SmI , Zn/Ac O) or by quaternization
2
2
2
with dimethyl sulfate in satisfactory yield. However,
reaction of 10 with ethyl chloroformate during 11 days
afforded 11 in 58% yield (Scheme 2).
This reactivity may be explained by the structure of 10,
in which the nitrogen atom is not easily accessible. In
particular it was found in the NMR spectrum (C D )
6
6
that the N-methyl group showed strong NOE inter-
actions with H9 and H12a suggesting that the methyl
Figure 2. Principal observed NOESY correlations.
Table 1. In vitro inhibition of acetylcholinesterase (AChE) and
butyrylcholinesterase (BChE)
Compd
AChEa
BChEb
Selectivityc
AChE BChE
IC50 (mM)
IC50 (mM)
6
7
8
67Æ8
30 Æ104.5 0
Æ401.2
650Æ30790
580Æ50216
9900Æ100
1000Æ400
0,35
Æ302.7
1
1
1
0
960Æ3010
155Æ3
1
6.5
18,6
0 .9Æ0.01 nM
53
Tacrine
16Æ2 nM
17.7
a
The source of AChE was Electrophorus electricus.
The source of BChE was Human serum.
b
c
The selectivity is defined as: selectivity for AChE=IC50(BChE)/
IC50(AChE), and selectivity for BChE=IC50(AChE)/IC50(BChE).
Scheme 2.

D. Herlem et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2389–2391
2391
In summary, open D-ring galanthamine analogues 7, 8,
1 have been prepared. These compounds are less active
E. J.; Forloni, G.; Coyle, J. T.; Davis, B. M.; Joullie
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1
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compounds could perhaps help prevent the formation
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1
3
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