1,8-Naphthalimide derivatives: New leads against dynamin I GTPase activity

Mohammed K. Abdel-Hamid, Kylie A. Macgregor, Luke R. Odell, Ngoc Chau, Anna Mariana, Ainslie Whiting, Phillip J Robinson and Adam McCluskey

 

Supplementary Data

1. Figure S1. Clustering of the 1,8-naphthalimide scaffold (stick representation) at the GTP binding pocket of dynI (ribbon representation) 2. Calculated Ligand Efficiencies and related physicochemical properties of key napthaladyn and other dynamin inhibitor compounds. 3. 1H and 13C NMR spectra of key analogues

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry.This journal is © The Royal Society of Chemistry 2015

 

Figure S1. Clustering of the 1,8-naphthalimide scaffold (stick representation) at the GTP binding pocket of dynI (ribbon representation)

Table S1. Calculated ligand efficiencies and related physicochemical properties of key napthaladyn and other dynamin inhibitor compounds. The values cLogP and PSA were calculated using the Osiris Molecular Property Explorer (http://www.organic-chemistry.org/prog/peo/).

Compound Class Structure MW HAC cLogP* PSA (Å2)

HBA HBD IC50 (µM)

Ligand Efficiency

Ref

Napthaladyn 23

388.39 25 -1.59 163.4 7 4 19.1 0.20 This work

Napthaladyn 29

464.49 31 0.18 163.4 7 4 18.5 0.16 This work

MiTMAB

336.39 19 2.79 - - - 3.1 0.31 1

Bis-T-22

464.45 35 1.47 186.7 8 6 1.7 0.16 2

Dynole 2-24

408.58 30 5.23 20.2 2 1 0.56 0.23 3

Dyngo-4a

338.31 25 3.01 122.3 6 5 0.35 0.26 4

NO O

NH2

SO3K

OH

O

NO O

SO3KNH2

CO2H

NBr

HO

HOCN

NH

O

NH

O

CN

OH

OH

NH2

N

NH

N

OH

NH

ON

OH

OHOH

Rhodadyn C10

350.0 23 1.89 90.17 5 0 7.0 0.22 5

Anti-psychotic - Trifluoperazine

407.50 28 4.93 35.02 3 0 2.6 0.20 6

SSRI - Seralin

306.23 20 4.2 12.03 1 1 7.3 0.26 7

* Calculated as the SO3H analogue;

References:

1. T. A. Hill, L. R. Odell, A. Quan, G. Ferguson, P. J. Robinson, A. McCluskey. Long chain amines and long chain ammonium salts as novel inhibitors of dynamin GTPase activity. Bioorg. Med. Chem. Lett., 2004, 14, 3275-3278

2. T. Hill, L. R. Odell, J. K. Edwards, M. E. Graham, A. B. McGeachie, J. Rusak, A. Quan, R. Abagyan, J. L. Scott, P. J. Robinson, A. McCluskey. Small molecule inhibitors of dynamin I GTPase activity: development of dimeric tyrphostins. J. Med. Chem., 2005, 48, 7781-7788

3. C. P. Gordon, B. Venn-Brown, M. J. Robertson, K. A. Young, N. Chau, A. Quan, P. J. Robinson, A. McCluskey. Development of second generation indole based dynamin GTPase inhibitors. J. Med. Chem., 2013, 56, 46-59.

4. A. McCluskey, J. A. Daniel, G. Hadzic, N. Chau, E. L. Clayton, A. Mariana, A. Whiting, J. Lloyd, A. Quan, L. Moshkanbaryans, S. Perera, M. Chircop, A. B. McGeachie, M. T. Howes, R. G. Parton, M. Campbell, J. A. Sakoff, X. Wang, J. –Y. Sun, M. J. Robertson, F. M. Deane, T. H. Nguyen, F. A. Meunier, M. A. Cousin, P. J. Robinson. Building a better dynasore: The dyngos potently inhibit dynamin and endocytosis. Traffic 2013, 14, 1272-1289

5. M. J. Robertson, G. Hadzic, J. Ambrus, D. Y. Pome, E. Hyde, A. Whiting, A. Mariana, L. von Kleist, N. Chau, V. Haucke, P. J. Robinson, A. McCluskey. The rhodadynsTM – novel inhibitors of dynamin GTPase. ACS Med. Chem. Lett., 2012, 3, 352-356

ONS

N

O

S

N

S

N

N

F3C

HN

ClCl

6. J. A. Daniel, N. Ngoc Chau, A. Whiting, L. von Kleist, P. Maamary, M. K. Abdel-Hamid, V. Haucke, A. McCluskey, P. J. Robinson. Phenothiazine-derived antipsychotic drugs inhibit dynamin and clathrin-mediated endocytosis. Traffic, 2015, 14, 1272-1289.

7. M. Otomo, K. Takahashi, H. Miyoshi, K. Osada, H. Nakashima, N. Yamagichi. Some Selective Serotonin Reuptake Inhibitors Inhibit Dynamin I Guanosine Triphosphatase (GTPase), Biol. Pharm. Bull. 2008, 31, 1489-1495.