Proceedings of MatricesFor IITTEP – ICoMaNSEd 2015
ISBN: 978-602-74204-0-3
Chemistry Page 131
Alzheimer’s disease Sung
et al
, 2001. Furthermore, these pathologies were found to be a direct consequence of α-synuclein endocytosis suggesting that endocytosis inhibitors may be
useful in the treatment of α-synuclein related disorders.
3. Structur-Activity Relationship SAR of Dynamin Endocytosis Inhibitors
Despite the possibility of numerous therapeutic applications, there are currently no dynamin inhibitors in clinical use. However, a number of dynamin inhibitors have been identified,
these include dynasore, which is claimed to have a role in endocytosis and act as dynamin inhibitor and Bis-T, myristyl trimethyl ammonium bromide MiTMAB series, the indole
analogues, and the phthalimide series.
3.1. Dynasore
OH N
H N
OH
OH O
Figure 1. Chemical Structure of Dynasore 1
Macia
et al
2006., screened about 16,000 small molecules and found dynasore Compound
1, Figure 1 which is interferes with dynamin I, dynamin II and Drp1
in vitro
. From this study, it was shown that dynasore is a non-competitive cell permeable inhibitor of the GTPase
activity of dynamin 1 and 2 Macia
et al
, 2006; Nankoe
et al
, 2016. Dynamin’s ability to oligomerize or bind lipids was not affected by dynasore. This means the inhibitory effects of
dynasore mediated through GTPase domain Thompson
et al
, 2006.
3.2. Bis-T
The Bis-T series contain some of the most potent inhibitors currently identified Hill
et al
, 2005; Hill
et al
, 2004. As illustrated in Table 1, trihydroxy subsititued aromatics affected the
activity whilst changes in length afforded equipotent analogues i.e compounds 3, 6, 9, and 12 with IC
50
of 1.7 ± 0.2, 1.7 ± 0.2, 2.1 ± 0.2, 1.7 ± 0.4 µM. Introduction of metoxy substituent
in C2 slightly reduced the activity compounds 4, 7, 10, and 13 with IC
50
of 9.0 ± 3.0, 5.0 ± 1.0, 8.0 ± 0.2, 8.0 ± 0.2 µM.
CN N
H O
R
4
R
3
N H
C N R
4
R
3
O
n
R
5
R
2
R
2
R
1
R
2
R
5
Lin ke r
Change s in l inking a toms possibl e
M ultipl e a roma ti c substitue nts poss ible
S pac er
var ia tions in si ze and t ype of linke r possible
Proceedings of MatricesFor IITTEP – ICoMaNSEd 2015
ISBN: 978-602-74204-0-3
Chemistry Page 132
Table 1. Symmetrically Substituted Analogues of Bis-T: Effect of Aromatic Ring Modifications Analogues on Dynamin 1 GTPase Activity
Compound R
1
R
2
R
3
R
4
R
5
n IC
50
µM
a
2 H
H OH
OH H
5.1 ± 0.6
3 H
OH OH
OH H
1.7 ± 0.2
4 H
OMe OH
OH H
9.0 ± 3.0
5 H
H OH
OH H
1 1.7 ± 0.2
6 H
OH OH
OH H
1 1.7 ± 0.2
7
H OMe
OH OH
H 1
5.0 ± 1.0
8 H
H OH
OH H
2 3.2 ± 1.0
9 H
OH OH
OH H
2 2.1 ± 0.2
10 H
OMe OH
OH H
2 8.0 ± 0.2
11
H H
OH OH
H 3
5.0 ± 1.4
12
H OH
OH OH
H 3
1.7 ± 0.4
13 H
OMe OH
OH H
3 8.0 ± 0.2
14 H
H OH
OH H
4 26 ± 2
15 H
OH OH
OH H
4 6.0 ± 2.0
16 H
OMe OH
OH H
4 80 ± 4
a
IC50 determinations conducted in triplicate; - 100 µM
This study reveals compound 5 IC
50
= 1.7 ± 0.2 µM which also known as BisT is the most potent and promising dynamin I GTPase inhibitor in this series. These analogues have been
shown to prevent dynamin self-assembly from a ring to a helix and also to block SVE in nerve terminals synaptosomes, cultured neurons, and chromaffin cells.
3.3. MiTMAB
