Self-Assembled Micellar Glutaminase Allosteric Inhibitor for Effective Therapeutic Intervention

Abstract

Introduction: Kidney-type glutaminase (KGA) has been an important anti-tumor drug target, and KGA allosteric inhibitors attracted much interest for their superior enzymatic specificity with good drug safety profiles. For glutaminase allosteric inhibitors such as BPTES, CB-839 and Selen derivatives, the low solubility remains as the main factor that limits in vivo efficacy. The 1,3,4-Selenadiazole compound CPD 23 showed improved in vivo efficacy but worse solubility; however, the graft polymer polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (PVCap-PVA-PEG), Soluplus ® (SOL) stood out as an excellent delivery carrier for CPD 23. Methods: The CPD 23@SOL micelles were prepared, optimized and evaluated through on the basis of solubility improvement and loading capacity. Characterizations of particle size and Zeta potential by dynamic light scattering, morphology by transmission electron microscopy and solid state by X-ray powder diffraction were closely conducted. The biological studies included the tumor cell growth inhibition, blood and liver microsomal stability, in vivo pharmacokinetics and tissue biodistribution. Results: At 1:20 ratio of CPD 23:SOL, CPD 23@SOL micelles were well-dispersed, spherical and stable, with size less than 200 nm with encapsulation efficiency of more than 90%. This SOL micellar system significantly increased the aqueous solubility of CPD 23 by 15,000 folds. Particularly, CPD 23@SOL micelles demonstrated higher stability in blood and liver microsomes, showing approximately 86% remaining at 2 h incubation and about 66% at 4 h, respectively. In addition, with or without micellar formulation, CPD 23 maintained essentially the same inhibitory activity in tumor cells. Interestingly, CPD 23@SOL micelles significantly improved the pharmacokinetic exposure, prolonged the in vivo circulation and dramatically changed tissue biodistributions of CPD 23. Conclusion:The current work provided an encouraging and practical delivery system for novel Selenadiazoles and glutaminase allosteric inhibitors whose poor water-soluble characteristic has been a bottleneck for the field.

First Exclusive Stereo‐ and Regioselective Preparation of 5‐Arylimino‐1,3,4‐Selenadiazole Derivatives: Synthesis, NMR analysis, and Computational Studies

“…As such, the unsubstituted isoselenocyanate 27 a produced the product 43 in an improved yield of 60%, meanwhile the stronger + M 4-methoxylated derivative 27 h generated the product 37 in highest yield (90%). Introduction of a methoxy group into the meta position of the isoselenocyanate (27 i) reduced product yield to 78% (38) and to 70% (39) when two methoxy substituents were placed in the meta positions of the substrate (27 j). The reduced yields of 1,3benzodioxole 40 (78%) and 1,4-dioxane 41 (76%) compared to the para-methoxylated analog 37 also support the detrimental role of alkoxy in the meta position.…”

“…To highlight the versatile pharmacology of selenadiazoles, several bioactive species performing various biological and chemical roles are summarized in Figure 1 (1–6). These include insecticidal, [2] antifungal, [37] antiglutaminase, [38–40] antibacterial, [41] anticancer, [42] and antioxidant functions [43] …”

“…[2][3][4][5][6][7][8][9][10][11][12] To highlight the versatile pharmacology of selenadiazoles, several bioactive species performing various biological and chemical roles are summarized in Figure 1 (1-6). These include insecticidal, [2] antifungal, [37] antiglutaminase, [38][39][40] antibacterial, [41] anticancer, [42] and antioxidant functions. [43] Compared to the chemistry and biological properties of 1,2,3-selenadiazole, [2][3][4][5][6] 1,2,4-selenadiazole, [7,8] 1,2,5-selenadiazole and 1,3,4-thiadiazole, [44] those of 1,3,4-selenadiazole remain much less known.…”