Exploration of a Series of 5-Arylidene-2-thioxoimidazolidin-4-ones as Inhibitors of the Cytolytic Protein Perforin

Abstract

A series of novel 5-arylidene-2-thioxoimidazolidin-4-ones were investigated as inhibitors of the lymphocyte-expressed pore-forming protein perforin. Structure–activity relationships were explored through variation of an isoindolinone or 3,4-dihydroisoquinolinone subunit on a fixed 2-thioxoimidazolidin-4-one/thiophene core. The ability of the resulting compounds to inhibit the lytic activity of both isolated perforin protein and perforin delivered in situ by natural killer cells was determined. A number of compounds showed excellent activity at concentrations that were nontoxic to the killer cells, and several were a significant improvement on previous classes of inhibitors, being substantially more potent and soluble. Representative examples showed rapid and reversible binding to immobilized mouse perforin at low concentrations (≤2.5 μM) by surface plasmon resonance and prevented formation of perforin pores in target cells despite effective target cell engagement, as determined by calcium influx studies. Mouse PK studies of two analogues showed T1/2 values of 1.1–1.2 h (dose of 5 mg/kg iv) and MTDs of 60–80 mg/kg (ip).

Design, synthesis, molecular docking and cytotoxicity evaluation of some novel 5-arylidene-3-(substituted phenyl)-2-(p-tolylamino)-4-imidazolones

“…Also, (MJ238, VI) exhibited a docking score (-32.0139 Kcal/mol) with 2 hydrogen bonds, (Figure 7). Compound (9b) formed a bi-dentate hydrogen bond between 4-oxo and NH 2 of Arg 364 and this hydrogen bond was reported to be essential for all human topo I inhibitors (Staker et al, 2005) and this hydrogen bond is similar to that formed by compounds(I) and (VI). Also, hydrophobic interactions between both tolyl and benzylidene with adenine were found similar to compound (I) and (MJ238, VI).…”

“…In addition, C and D-rings of MJ 238 stacks on the intact DNA strand similar to rings A and B of camptothecin. The interaction with Arg 364 is common between all three different classes of topo I inhibitors representing the sole interaction on the minor groove (Staker et al, 2005). Also, it was reported that Asn 722 is important for subnuclear dynamics and stabilization of camptothecin-induced topo I cleavage complexes (Das et al, 2016).…”

“…In rapidly proliferated cells the replication fork of DNA is thought to collide with the trapped topo I-DNA complex leading to double strand breaks and apoptotic cell death (Topcu, 2001;Staker et al, 2005;Alonso et al, 2016;Beck et al, 2016;Jeon et al, 2016;Park et al, 2017).…”

The preclinical pharmacokinetic disposition of a series of perforin-inhibitors as potential immunosuppressive agents

“…were synthesised in-house at the Auckland Cancer Society Research Centre, The University of Auckland (Auckland, New Zealand) (Spicer et al 2012(Spicer et al , 2013. The structures of the compounds analysed are also described in Table 1.…”

“…More recently a series of novel compounds has been developed that show improved perforin-inhibitory activity in vitro (Spicer et al 2013). The series includes a promising lead compound which significantly inhibits perforin activity in a functional immune synapse.…”