Reaction mechanism of NO with hydrolysates of NAMI-A: an MD simulation by combining the QM/MM(ABEEM) with the MD-FEP method

Nitrosylation reaction mechanisms of the hydrolysates of NAMI-A and hydrolysis reactions of ruthenium nitrosyl complexes were investigated in the triplet state and the singlet state. Activation free energies were calculated by combining the QM/MM(ABEEM) method with free energy perturbation theory, and the explicit solvent environment was simulated by an ABEEMσπ polarizable force field. Our results demonstrate that nitrosylation reactions of the hydrolysates of NAMI-A occur in both the triplet and the singlet states. The Ru-N-O angle of the triplet ruthenium nitrosyl complexes is in the range of 132.0°–138.2°. However, all the ruthenium nitrosyl complexes at the singlet state show an almost linear Ru-N-O angle. The nitrosylation reaction happens prior to the hydrolysis reaction for the first-step hydrolysates. The activation free energies of the nitrosylation reactions show that the H₂O-NO exchange reaction of [RuCl₄(Im)(H₂O)] in the singlet spin sate is the most likely one. Comparing with the activation free energies of the hydrolysis reactions of the ruthenium nitrosyl complexes, the results indicate that the rate of the DMSO–H₂O exchange reaction of [RuCl₃(NO)(Im)(DMSO)] is faster than that of [RuCl₃(H₂O)(Im)(DMSO)] in both the triplet spin state and the singlet spin state. © 2018 Wiley Periodicals, Inc.     

Influence of redox activation of NAMI-A on affinity to serum proteins: transferrin and albumin

Imidazolium trans-tetrachloridodimethylsulfoxideimidazoleruthenate(III), NAMI-A, is a ruthenium drug exhibiting unique properties under clinical studies such as ability to inhibit the process of metastases without exerting tumor toxicity. Its place of action is concentrated at the extracellular level, therefore, the transformation and fate of this drug upon injection is of great importance. This study focuses on evaluation of the reducing potency of blood stream on interaction with two serum proteins: albumin and transferrin. It was investigated by applying various simplified serum models preserving physiological concentration of proteins and the amount of Ru complex as found in patients. It was shown that ruthenation of albumin is slightly increased while transferrin decreased upon addition of reductant in blood stream (ascorbate, glutathione, and cysteine) at physiological concentration. Interestingly, in serum models comprising low-molecular-mass components the amount of the reductant in the solution had a pronounced effect on the Ru content, in particular in transferrin. Supplementation of serum models with glutathione at concentration enough for complete reduction of NAMI-A selectively enhanced the binding of Ru complex to transferrin while ruthenation of albumin was almost unchanged. Spectrofluorimetric studies revealed that reduction has a marginal effect on binding affinity, therefore, both Ru(III) and (II) derivatives equally can compete for binding to transferrin.     

Development of NAMI-A-loaded PLGA-mPEG Nanoparticles: Physicochemical Characterization,in vitro Drug Release and in vivo Antitumor Efficacy

NAMI-A has showed extraordinary activities against metastatic tumors. However, the hydrolysis of DMSO from NAMI-A could reduce anti-metastatic activity. To enhance the circulation time and the anti-metastatic effect of NAMI-A, we first synthesized the NAMI-A-loaded nanoparticles. NAMI-A-loaded nanoparticles were prepared by the double emulsion method and characterized by scanning electron microscopy for surface morphology, laser light scattering for size and zeta potential for surface charge. Controlled release of NAMI-A was observed in a sustained manner. Compared with free NAMI-A, NAMI-A -loaded nanoparticles exhibited superior antitumor effect by delaying tumor growth in T739 mice. PLGA-mPEG nanoparticles are promising for further studies as drug delivery carriers.     

应用QM与ABEEM/MM结合的方法研究NAMI-A的结构性质

应用量子力学(QM)与ABEEM浮动电荷力场(ABEEM/MM)相结合的方法研究了抗癌药物NAMI-A在水溶液中的结构性质. 所有的结构优化都是在DFT的B3LYP方法下采用6-31G(d,p)和LanL2DZ基组完成的, 没有加入任何限制性条件. 结果表明, 优化得到的NAMI-A构型受不同环境及方法的影响均有变化. 与气相中得到的构型相比, QM/MM迭代优化得到构型要比PCM的构型变化更明显. QM/MM (ABEEM/MM)迭代优化得到的NAMI-A构型比QM/MM (OPLS-AA)的变化要小. 总之, 溶剂通过极化效应对NAMI-A结构、电荷分布及径向分布函数等性质均有影响, 客观地处理极化效应才能正确地反映QM区的性质.