The Rhodadyns, a new class of small molecule inhibitors of dynamin gtpase activity

Article abstract of DOI:10.1021/ml200284s

Six focused rhodanine-based libraries, 60 compounds in total, were synthesized and evaluated as potential dynamin I GTPase inhibitors. Twenty-six were more potent than the lead compound with 13 returning IC₅₀ values ≤10 μM, making the Rhodadyn

Full text of DOI:10.1021/ml200284s

Letter
pubs.acs.org/acsmedchemlett
The Rhodadyns, a New Class of Small Molecule Inhibitors of Dynamin
GTPase Activity
Mark J. Robertson,† Gordana Hadzic,† Joseph Ambrus,† D. Yuri Pome,†,∥ Emily Hyde,† Ainslie Whiting,‡
̀
Anna Mariana,‡ Lisa von Kleist,§ Ngoc Chau,‡ Volker Haucke,§ Phillip J. Robinson,‡
and Adam McCluskey*,†
†Chemistry, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia
‡Cell Signalling Unit, Children's Medical Research Institute, The University of Sydney, Sydney, NSW 2145, Australia
§Leibniz Institut fur Molekulare Pharmakologie & Freie Universitat Berlin, 13125 Berlin, Germany
̈
̈
S
* Supporting Information
ABSTRACT: Six focused rhodanine-based libraries, 60 compounds in total, were synthesized and evaluated as potential
dynamin I GTPase inhibitors. Twenty-six were more potent than the lead compound with 13 returning IC50 values ≤10 μM,
making the Rhodadyn series among the most active dynamin inhibitors reported. Two analogues were highly effective at blocking
receptor-mediated endocytosis: C10 and D10 with IC50(RME) = 7.0 2.2 and 5.9 1.0 μM, respectively. These compounds are
equipotent with the best reported in-cell dynamin inhibitors.
KEYWORDS: dynamin inhibition, Knoevengal condensation, rhodanine
ynamin is a 100kD GTPase,1 with three closely related
D
mammalian isoforms: dynamin I (dynI),2,3 dynamin II
(dynII),4 and dynamin III (dynIII).5 Each isoform has a
different number of spliced variants: dynI has eight, dynII has
four, and dynIII has thirteen.6 Each may have different
regulatory mechanisms at distinct locations within the cell or
be involved in the cellular localization of dynamin.7,8
The best-characterized superfamily member is dynI,
exclusively expressed in brain and neuronal tissue. DynI is a
key component of the synaptic vesicle (SV) recycling, which in
turn is essential for the maintenance of neurotransmission,
serving to retrieve empty SVs for refilling and reuse.6,9,10 SV
recycling is a specialized, rapid local endocytic recycling, con-
sidered to be a specialized form of receptor-mediated
endocytosis (RME).6−8
Dynamin is also involved in clathrin-independent endocy-
tosis, phagocytosis, and caveolae internalization. It has been
implicated in cellular processes such as vesicle trafficking, Golgi
function, organelle division, and mitochondria and chloroplast
biogenesis.7,8,11 Dynamin facilitates cell migration and invasion
and potentially plays an important role in cell growth, cell
spreading, and neurite outgrowth.12
Figure 1. Chemical structure of the lead Rhodadyn A1.
a
Scheme 1
a
Reagents and conditions: (i) EtOH, MW irradiation, 120 °C, 55 min
or EtOH, piperidine, reflux, 18 h.
port process has been linked to over 100 diseases involving
endocytosis and intracellular trafficking defects.16,17 In humans,
dynamin has been implicated in Charcot-Marie-Tooth
disease,18 centronuclear myopathy,19 dominant optic atro-
phy,20,21 and HIV entry.22
Targeting endocytosis and trafficking defects through the
dynamin inhibition represents a novel strategy for the treat-
ment of many diseases such as neurological (e.g., epilepsy),
viral, and bacterial (which enter cells via clathrin-medicated
endocytosis) infections.13−15 Disruption of the cellular trans-
Received: December 7, 2011
Accepted: March 26, 2012
Published: March 26, 2012
© 2012 American Chemical Society
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ACS Medicinal Chemistry Letters
Letter
a
We have reported the MiTMAB,23,24 Bis-T,25,26 RTILs,27
Dynole,28 Iminodyn,29 and Pthaladyn series of compounds as
novel dynamin inhibitors.30 Each series thus far has targeted
many of dynamin's four domains: the pleckstrin homology, the
assembly domain, the proline-rich domain, and the GTP
binding domain. Other reported dynamin inhibitors include
dynasore, antipsychotics, and selective serotonin reuptake
inhibitors.31−33 As part of our ongoing studies, we identified
(Z)-3-benzyl-5-(4-bromobenzylidene)-2-thioxothiazolidin-4-
one (A1) (Figure 1) as a dynI inhibitor, IC50 = 134 μM.
While A1 was only a moderately potent dynamin inhibitor, the
primary rhodanine core is readily available or easily assessed and
amenable to focused library development. Herein, we selected six
commercially available rhodanines (A−F) (Figure 2a). As we were
keen to explore new chemical space with the aldehyde moiety and
to introduce novel isosteres with enhanced druglike character than
we had previously reported,26,29 we restricted our aldehyde library
to a family of 10 aldehydes (1−10) (Figure 2b). The introduction
of the aldehyde headgroup requires only a simple condensation
reaction.26,27,29,34
The rhodanine core is a privileged scaffold in medicinal chem-
istry and one that has found promise among many therapeutic
applications.34,35 Using our selected rhodanines (A−F) and
aldehydes (1−10), we constructed six, 10-component, focused
Figure 2. (a) Rhodanines (A−F) and (b) aldehydes (1−10) used in
the synthesis of libraries A−F.
Table 1. Inhibition of dynI GTPase by Rhodadyn Libraries A−F
a
IC50 > 100 μM; −, not active up to 300 μM.
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ACS Medicinal Chemistry Letters
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Table 2. DynI IC50 Values and In-Cell RME IC50 Values in U2OS Cells of Rhodadyn Analogues A8−F8, A10, B4, C10, D10, E3,
and F3
a
IC50 > 100 μM; −, not active up to 300 μM.
libraries as potential dynI inhibitors. We call this the Rhodadyn
class of dynamin inhibitors.
libraries A and B, three times more potent than dynasore,33 but
less potent than Dynole 34-228 or Iminodyn compounds.36 Ten
of the nineteen new analogues in libraries A and B were
significantly more potent than the lead, A1.
From the libraries C (N-ethyl) and D (N-allyl) analogues
C1−D10 (Scheme 1 and Table 1), only C8−C10 and D8−
D10 displayed any dynI inhibition. The N-ethyl analogues C8−
C10 were the most potent with IC50 values of 3.0, 5.1, and
6.4 μM, respectively. Within library D, D10 was the most
potent (3.6 μM), with other library D members at best modest
dynI inhibitors: D8 (31 μM) and D9 (134 μM, equipotent with
A1). Notwithstanding this, C8−C10 and D8−D10 are up to a
50-fold more active than A1.
Libraries E (N-acetic acid) and F (N-propionic acid) afforded
high levels of dynI inhibition with E2, E3, E8, and E9 returning
IC50 values of 73, 12.3, 5.5, and 3.4 μM, respectively. Library F
contained seven dynI inhibitors with F1−F3, F6, and F8−F10
returning IC50 values of 9, 42, 48, 23.5, 4.3, 10, and 21.7 μM,
respectively.
Interestingly, the head groups (2 and 3) that saw an activity
loss in libraries C and D saw activity restored in libraries E and
F, for example, 12.3 μM for E3 vs inactive for C3/D3,
suggesting some binding in the tail region of the molecule.
Analogues derived from 8 and 9 were again the most active
with IC50 values of 3.4 (E9) and 4.3 μM (F8). These two head
groups are not only among the most active across all libraries
but are the only ones retaining activity across all libraries.
Library A examined the retention of the N-benzyl moiety,
while library B examined removal of the N-benzyl moiety from
the lead A1. All Rhodadyn libraries were synthesized as shown
in Scheme 1 (see the Supporting Information) and were solids
that remained stable over extended periods at room temper-
ature.
Libraries A and B were examined for their ability to inhibit
dynI, and these data are presented in Table 1.
Table 1 identified five library A analogues with noteworthy
dynI inhibition. Of the actives, A9 was the most potent, IC50
=
7.4 0.8 μM, a 20-fold increase in potency over A1. Of the
library A inactives, the most striking was A7, the sulfur isostere
of A5, a 53 μM dynI inhibitor.
Library B contained six dynI inhibitors ranging in potency
from 5.5 to 90 μM. Generally, there was a correlation between
the actives in libraries A and B, with library A actives also
displaying a level of activity in library B. Only B1 and B10 were
inactive when the library A equivalents displayed inhibition.
Interestingly, in both cases, the aldehydes used were relatively
simple aromatic systems. The potency trend differs between
libraries A and B. In library A, the most potent analogue was
A9 (7.4 μM), but in library B, B3, B5, and B8 are equipotent
(5.5−7.4 μM). There was an 8-fold increase in dynI inhibition
on removal of the benzyl moiety on going from A5 to B5.
Analogue B3 is marginally the most potent Rhodadyn from
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ACS Medicinal Chemistry Letters
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Chemically significant modifications of the tail group have limited
impact on dynI inhibition, for example, the change from an ethyl
(C8) to acetic acid (E8) resulted in only an IC50 change from 3.1
to 5.5 μM.
AUTHOR INFORMATION
■
Corresponding Author
*Tel: +61249216486. Fax: +61249215472. E-mail: Adam.
McCluskey@newcastle.edu.au.
Given that dynamin GTPase activity is essential for endocytosis,
we examined the Rhodadyns for their potential inhibition of
another key endocytotic protein, clathrin. We view clathrin
inhibition as an undesirable off-target action.37,38 Gratifyingly, no
clathrin inhibition was observed at 100 μM Rhodadyn con-
centration. Second, two compound cohorts were then examined
for their ability to block in-cell endocytosis using our automated
quantitative RME assay based on endocytosis of Texas Red-
transferrin (TxR-Tf) into U2OS human osteosarcoma epithelial
cells (see the Supporting Information).28,36 The first cohort, A8−
F8, varied only the tail group (Figure 1 and Table 2).
Surprisingly, only B8 of the first cohort screened for RME
activity was in-cell active (Table 2). This may be due to poor cell
permeability or rapid compound efflux of the others. Further
evaluation of RME efficacy of selected Rhodadyn analogues
identified the N-ethyl C10 and N-allyl D10 as more potent RME
blockers with IC50 values of 7.0 and 5.9 μM, respectively (Table 2).
The N-benzyl A10 was inactive. As A10, C10, and D10 possess
the same headgroup, this suggests that differences in RME activity,
within this cohort, arise via the tail group with small alkyl groups
better tolerated than aromatic moieties. As expected, on the basis of
our observations in Table 2, analogues the carboxylate substituted
E3 and F3 as well as the hydrophilic B4 displayed no RME activity
presumably due to poor cell permeability or rapid cellular efflux.
cLog P calculations showed no direct correlation between
compound solubility and membrane permeability (Table 2).39
The Rhodadyn series are highly active dynI inhibitors, and
through the development of six focused compound libraries, a
50-fold increase in potency has been realized. Thirteen
Rhodadyn analogues returned IC50 ≤ 10 μM, and of these,
C8 (3.0 μM), E9 (3.4 μM), and D10 (3.6 μM) have activity
better than our reported Pthaladyn series (IC50 ∼ 4.6 μM),
although not equal to the Iminodyn (IC50 ∼ 0.26 μM) or
Dynole (IC50 ∼ 1.30 μM) series.28,30
The most active compound in each library (A9, B3, C8, D10,
E9, and F8) varied significantly in regards to requisite aldehyde
but varied little in actual activity (IC50 ∼ 7.4, 5.5, 3.0, 3.6, 3.4, and
4.3 μM respectively). Of the 10 head groups evaluated, only one
(7) failed to display any significant dynI inhibition. Clearly, our
findings offer considerable scope to further improve on the
potency of this new class of Rhodadyn compounds. The impact of
the tail groups remains less clear with only 3,5-dichlorobenzalde-
hyde (8) retaining activity across all six libraries.
Examination of selected Rhodadyn analogues in our whole
cell RME assay identified two, C10 and D10, with best
IC50(RME) values of 7.0 and 5.9 μM, respectively. This represents
almost the same activity as compared to their measured dynI
IC50 values and compares favorably to the decrease in activity
found in the Pthaladyn (inactive), Iminodyn (24-fold decrease),
and Dynole (4-fold decrease) series. C10 and D10 are among
the most potent RME inhibitors reported, only surpassed by
Dynole 34-2 (IC50(RME) ∼ 5.0 μM).28,30,36 The development of
the Rhodadyn series adds another chemical biology probe to
the expanding palette of dynamin inhibitors.
Present Address
∥Department of Pharmaceutical Science, University of Milan,
via Mangiagalli, 25-20133 Milan, Italy.
Funding
This work was supported by the National Medical & Health
Research Council (Australia), the Australian Research Council,
and the Deutsche Forschungsgemeinschaft (SFB765/B4;
HA2686/3-2).
Notes
The authors declare the following competing financial
interest(s):We have entered into a commercial agreement
with Abcam biochemicals (Bristol, UK) for the supply of our
dynamin inhibitors. This includes the compounds listed in this
paper.
ABBREVIATIONS
■
dynI, dynamin I; dynII, dynamin II; dynIII, dynamin III; SV,
synaptic vesicle; RME, receptor-mediated endocytosis
ADDITIONAL NOTE
■
a
Rhodadyn, MiTMAB, Bis-T, Dynole, Dynole 34-2, and
Iminodyn are trademarks of Children's Medical Research
Institute and Newcastle Innovation Ltd. Rhodadyn compounds
and most other dynamin inhibitors described in this paper are
available from Abcam Biochemicals Ltd. (Bristol, United
Kingdom).
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