Proceedings of MatricesFor IITTEP – ICoMaNSEd 2015
ISBN: 978-602-74204-0-3
Chemistry Page 134
The most potent dynamin inhibitor from this library is compound 20 with IC
50
= 3.33 ± 0.75 µM. The removal of the C2 methyl group in this compound resulted an increase of 3-fold in
potency for dynamin I inhibition compound 21, Figure 4 with IC
50
= 1.30 ± 0.30 µM. This by far is the most potent dynamin inhibitors, two times more potent that Bis-T analogues and
fifteen times more potent than dynasore.
3.5. Phthalamide Analogues
From the virtual library screening used homology representations hDyn1-2 and hDyn1-7 and the ICM flexible ligand-grid receptor algorithm, resulted in 520 hits Odel,
et al
, 2010. Of these, 175 were obtained from the vendors for biological evaluation. From the initial
biological assay, 7 compounds were found to be moderate IC
50
= 50 – 170 µM to good IC
50
50 µM inhibitors of dynamin 1 GTPase activity Table 2. One of the active compound is compound 22 Figure 5, the phthalimde derivative IC
50
~ 170 µM.
N N
H O
O
O Cl
O HO
Figure 5. Structure Phthalamide derivative 22
Compound 22 contains a 2-biphenyl group and a 4-chlorobenzoic acid moiety, which connects to the phthalimide through an amide bond. The biological assay for compound 30
has shown it to be a moderate inhibitor of dynamin with IC
50
~ 170 µM, and from the binding mode evaluation it appears to fit well withing the binding site showing several hydrogen
bonding, ionic and van der Waals interactions with the active site residues. This compound is not commercially available, so it was synthesized via two straightforward condensation
reactions utilizing available precursors.
Two libraries were developed from this compound, namely Library A and Library B. Synthesis of library A explores the 1-amido-2-benzoic acid moiety, while the synthesis of
library B examines the effect of altering the biaryl moiety.
The compounds synthesized in libraries A and B, including compound 22, were submitted for biological evaluation. The results are presented in Table 2.
It can be seen that the analogues displayed weak i.e. 26; IC
50
= 266 ± 53 µM to moderate 36 and 38; IC
50
= 63 ± 32 µM and 66 ± 18 µM respectively inhibitor activity. These results show by altering the biaryl moiety can increase the potency of the compound to inhibit
dynamin’s GTPase activity.
Proceedings of MatricesFor IITTEP – ICoMaNSEd 2015
ISBN: 978-602-74204-0-3
Chemistry Page 135
Table 2: Inhibition of Dynamin 1 GTPase activity by Phthalimides libraries A nd B
R
2
R
3
R
1
N H
O N
O
O
Library A
No R
1
R
2
R
3
IC
50
µM
23 COOH
H Cl
400
24 H
H Cl
-
25 COOH
H H
-
26
COOH I
H
266 ± 53
27
H H
H
-
Cl
HO O
N H
O
N O
O R
3
R
1
R
2
Library B No
R
1
R
2
R
3
IC
50
µM 28
H H
H -
29 H
NO
2
H -
30 H
H NO
2
-
31 OH
H H
-
32
H OH
H -
33 H
H OH
400
34 CH
2
OH H
H -
35 H
CH
2
OH H
-
36 H
H CH
2
OH 66 ± 18
37
COOH H
H 184 ± 84
38 H
H COOH
63 ± 32
39 NH
2
H H
311 ± 28
40 H
NH
2
H 400
41
H H
NH
2
191 ± 48 -; No activity observed at 400 µ M. 400; 50 inhibition noted at 400 µ M. IC
50
’s were conducted in
triplicate.
Proceedings of MatricesFor IITTEP – ICoMaNSEd 2015
ISBN: 978-602-74204-0-3
Chemistry Page 136
4. Conclusion
