J Bioenerg Biomembr
Introduction
A conserved tyrosine residue (tyrosine-343) in the carboxyl
terminus of the P2X7R, when phosphorylated can affect the
function of this receptor (Kim et al. 2001). Taking this infor-
mation into account, Wiley and co-workers evaluated the in-
P2X family takes part in the purinergic signaling network
where ATP (adenosine 5′-triphosphate), other nucleotides
and nucleosides are the extracellular signaling molecules
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6
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fluence of 18 protein tyrosine kinase inhibitors on the Rb
(
Bartlett et al. 2014). Together with P2Y family, P2X recep-
efflux mediated by the human P2X7R. A phthalazinamine
derivative (compound P), which inhibits the vascular endothe-
lial growth factor receptor kinase, was found to be the most
potent compound, blocking the ATP-induced cation efflux by
76% in human B-lymphocytes and by 66% in erythrocytes in
a dose-dependent manner (half-maximum inhibitory concen-
tration - IC ≅ 5 μM) in both cells. The authors suggested that
compounds targeting the ATP-binding sites of kinases would
be potential blockers of the P2X7R (Shemon et al. 2006).
An important class of inhibitors of tyrosine kinases is the
tyrphostin group which is benzylidene malononitriles mole-
cules that can inhibit the cell-signaling transduction by de-
creasing tyrosine phosphorylation. Tyrphostins are tyrosine
kinase (TYK) inhibitors enzymes that play critical roles in
the inflammation process. Therefore, tyrphostins molecules
are bioactive compounds which have been shown a promising
anti-inflammatory activity (Fig. 1) (Dimitrova and Ivanovska
2013; Gyurkovska et al. 2014).
tors are involved in the cellular response to extracellular ATP
molecules (Baas 2012). P2X receptors are trimeric ligand-
gated cation channels whose family consists of seven mem-
bers of receptors (P2X1–7). Comparatively, the monomeric
unit of the P2X7 receptor (P2X7R) is the highest among mem-
bers of the P2X family. This subtype also differs from the
others because it has a large number of amino acids residues
in the intracellular C terminus (Baas 2012; Burnstock and
Knight 2018). P2X7R is present in many cell types including
hematopoietic lineages, epithelial and endothelial cells, fibro-
blasts, osteoblasts, astrocytes, Schwann cells, some popula-
tions of neurons, and cells from microglia, among others
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0
(
Bartlett et al. 2014).
Differently from the other members of the P2X family,
P2X7R when activated for micromolar ATP concentrations
leads to the opening of the channels for the flux of small
cations (Na , K or Ca ) through the plasma membrane.
When P2X7R is stimulated for high ATP concentrations
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+
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Recently, the effect of introducing the boronic acid group
(
mM range) and, after prolonged or repeated stimulation, thus
B(OH) in arylcyanovinyl compounds, that can be classified
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a larger permeability state is reached forming or inducing a
large conductance ionic channel (Faria et al. 2017; North
as tyrphostins compounds was investigated in their anticancer
properties by our research group. A series of boronic acid
derivatives were synthesized, generating the compounds of
NO series (Fig. 2). From this boronic acid analogs series,
the compound NO-12 displayed high antiproliferative activity
against GH3 cell lines from rat pituitary tumor (0.14 ±
0.09 μM), whereas compound NO-13 has shown antiprolifer-
ative potential against the human leukemic monocyte lympho-
ma cell line U937 (9.83 ± 1.07 μM) (Hiller et al. 2018).
In addition to compounds in the NO series, there are other
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002). Molecules with a mass of up 900 Da can permeate
the membrane by these large pores, which makes possible
the liberation of inflammatory cytokines (Young and
Górecki 2018). Activation of P2X7R gives rise to a sequence
of signaling events, which are reliant on the cell type express-
ing this receptor, the ATP extracellular concentration and oth-
er conditions of the extracellular medium (Bartlett et al. 2014).
According to the cell type, P2X7R activation modulates
different signaling pathways leading to the activation of the
caspase-1-containing inflammasome NLRP3, release of pro-
inflammatory molecules; such as interleukin 1β (IL-1β),
interleukin-18 (IL-18) and interleukin-36α (IL-36α); activa-
tion of metalloproteases and other proteases, the formation of
reactive oxygen species (ROS) and other events. There are
many evidences which support that the P2X7R is an essential
target to be investigated for the treatment of a variety of dis-
eases (Bartlett et al. 2014; Chen et al. 2018; Gorodeski 2012;
Savio et al. 2018; Skaper 2011; Sugiyama 2014; Tsuda et al.
studies showing the introduction of the B(OH) unit into the
2
aromatic ring of known anticancer compounds resulting in better
activities or bioavailability or modifying the performance profile
of these compounds (Ahmed et al. 2006; Asano et al. 2004; Ban
et al. 2009; Bradke et al. 2008; Kumar et al. 2003; LeBeau et al.
2008; Modzelewska et al. 2006; Nakamura et al. 2006; Shimizu
et al. 2010). Bortezomib, for example, is proteasome inhibitor
current in use in multiple myeloma therapy (Buac et al. 2013;
Diaz and Yudin 2017; Dou and Zonder 2014). Due to their
empty p orbital, boronic acids can coordinate to the heteroatoms
present in enzymes and receptors in a reversible covalent mech-
anism. These characteristics are responsible for the recent grow-
ing interest both in the industry and in the academy for the
development of new boron-based drugs (Baker et al. 2009;
Ban and Nakamura 2015; Das et al. 2013, 2013).
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010). Several diseases states are associated with P2X7R sin-
gle nucleotide polymorphisms (SNPs) (Volonté et al. 2012)
and other related to the role that P2X7R exerts in disorders
such as the inflammatory and immune response, for instance
(
Baudelet et al. 2015; Rech et al. 2016). Therefore, the devel-
opment of P2X7R inhibitors may be a relevant strategy for the
discovery of new drugs for the treatment of inflammatory
conditions such as rheumatoid arthritis (Mehta et al. 2014).
Since arylboronic acids derivatives can show different phar-
macological activities, in the present work, the action of NO
series compounds was evaluated on the P2X7R. This study was