Docking of THPDTPI: to explore P-selectin as a common target of anti-tumor, anti-thrombotic and anti-inflammatory agent

Abstract

The impact of soluble P-selectin on tumor growth, thrombosis and inflammation has been individually documented. Whether the down-regulation of P-selectin expression can simultaneously slow the tumor growth, inhibit the thrombosis and attenuate the inflammatory response remains unknown. In this context, (2′S,5′S)- tetrahydropyrazino[1’,2’:1,6]-di{2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole}-1’,4’-dione (THPDTPI) was designed as an inhibitor of P-selectin. The suitable docking of THPDTPI towards the active site of P-selectin, the significant down-regulation of THPDTPI to P-selectin expression, and the direct action of THPDTPI on P-selectin suggest that P-selectin could be a target of THPDTPI. In vivo THPDTPI possesses the anti-tumor activity, the anti-thrombotic activity and the anti-inflammatory activity. This implies that targeting P-selectin is of essential importance for this triple activity. The minimal effective doses of THPDTPI inhibiting the tumor growth, the rat arterial thrombosis and the mouse ear edema are 0.01 μmol/kg, 0.1 μmol/kg and 0.001 μmol/kg, respectively. Atomic force microscopy images and FT-MS spectra showed that the adhesion of THPDTPI onto the surfaces of the platelets may be the first step of P-selectin targeting. Besides, the dependence of the triple action of THPDTPI inhibiting the tumor growth, the thrombosis and the inflammation on the decrease of the soluble P-selectin led to the correlation of the soluble P-selectin with the serum TNF-α and serum IL-8.

Dimethyl 2,2&prime;-[2,2&prime;-(ethane-1,1-diyl)bis(1<em>H</em>-indole-3,2-diyl)]-diacetate: a small molecule capable of nano-scale assembly, inhibiting venous thrombosis and inducing no bleeding side effect

“…To visualize the nano-feature of DEBIC in solid state, in water and in rat plasma, the transmission electron microscopy (TEM), scanning electron microscopy (SEM) and atomic force microscopy (AFM) images were recorded, by using the methods in the literature. [35][36][37][38] For TEM (JSM-2100LV; JEOL, Tokyo, Japan), the solution (2.5×10 -2 , 2.5×10 -3 and 2.5×10 -4 μM) of DEBIC in pH 6.8 ultrapure water, or 2.5×10 -2 μM solution of DEBIC in ultrapure water of pH 5.8 and pH 2.0, or 2.5×10 -2 μM solution of DEBIC in pH 7.4 PBS was dripped onto a formvar-coated copper grid, air-dried and heated at 37°C for 14 days. In a random region, the feature and size of the nano-particles were identified by examining .100 species.…”

“…Nano-images from mesoscalesimulation [35][36][37][38] DEBIC was sketched using ChemDraw Ultra 10.0 (Cam-bridgeSoft) and converted into 3D structure with Materials Studio 3.2 (Accelrys, Inc., Bedminster, NJ, USA). The 3D structure was further optimized using MS Forcite module and geometry optimized until the convergence of maximum energy and force been 2×10 -5 kcal/mol and 1×10 -3 kcal/mol/Å, respectively.…”

“…The nano-property of aqueous DEBIC was represented with Faraday-Tyndall effect, particle size and zeta potential by following the methods in the literature. [35][36][37][38] In brief, 20 μM solutions of DEBIC in the ultrapure water of pH 2.0, pH 5.8 and pH 6.8 as well as in PBS of pH 7.4 were prepared. The ultrapure water of pH 2.0, pH 5.8 and pH 6.8 as well as PBS of pH 7.4 were used as the control.…”

“…To estimate the number of DEBIC molecule in a nanoparticle with certain size, the mesoscale simulation was performed by using the software and a four-step procedure of the literature. [35][36][37] Figure 6 shows that in a nano-particle of 144.4 nm in diameter there are 1,086 molecules of DEBIC. This enables us to optionally simulate a nano-particle and to estimate the molecular number of DEBIC involved in a nano-particle.…”

Design and development of ICCA as a dual inhibitor of GPIIb/IIIa and P-selectin receptors

“…In this context, the structural characteristics of the previously reported carbolines were analyzed. These carbolines inhibited arterial thrombosis; 19 targeted GPIIb/IIIa receptor thereby inhibited arterial thrombosis; 20 targeted P-selectin receptor thereby inhibited arterial thrombosis and venous thrombosis, 21 slowed down tumor growth, 22 , 25 , 26 or simultaneously inhibited thrombosis and slowed down tumor growth; 22 , 23 or targeted P-selectin receptor thereby simultaneously inhibited arterial thrombosis and slowed down tumor growth. 24 The findings led to 10 known carbolines been docked into the active pockets of P-selectin and GPIIb/IIIa receptors.…”