Blue moon ensemble simulation of aquation free energy profiles applied to mono and bifunctional platinum anticancer drugs

Aquation free energy profiles of neutral cisplatin and cationic monofunctional derivatives, including triaminochloroplatinum(II) and cis-diammine(pyridine)chloroplatinum(II), were computed using state of the art thermodynamic integration, for which temperature and solvent were accounted for explicitly using density functional theory based canonical molecular dynamics (DFT-MD). For all the systems the "inverse-hydration" where the metal center acts as an acceptor of hydrogen bond has been observed. This has motivated to consider the inversely bonded solvent molecule in the definition of the reaction coordinate required to initiate the constrained DFT-MD trajectories. We found that there exists little difference in free enthalpies of activations, such that these platinum-based anticancer drugs are likely to behave the same way in aqueous media. Detailed analysis of the microsolvation structure of the square-planar complexes, along with the key steps of the aquation mechanism are discussed

Myelin-like structures seen intracellularly in renal tubule cells subjected to ischemia.

Renal cortex was studied during experimentally induced ischemia. A transient increase in anerobic glycolysis occurred with concomitant swelling of both the Golgi apparatus and mitochondria. These intracytoplasmic organelles underwent marked changes in their intracellular positions. Infolding of cytoplasmic membrane at the basal side of proximal tubule cells increased in complexity and proceeded to enclose various intracytoplasmic microorganelles such as mitochondria and the Golgi apparatus. Piling up in layers was particularly marked around mitochondria. This piling up appeared as myelin-like structures on the free surface of, and within, proximal tubule cells, and followed disruption of the brush border at the free surface. Histological examination of thin sections showed that the fused portions of this brush border were actually brush border cytoplasmic membrane piled up in layers giving the appearance of myelin-like structures. After two hours of ischemia, parts of the membrane of these myelin-like structures were disrupted. Large vacuoles developed and these were thought to be related to the large vacuoles seen during cell degeneration

Endoscopic thoracic sympathectomy as a novel strategy for vasospastic angina refractory to medical treatments

SummaryAlthough vasospastic angina (VSA) is usually controlled by medications, refractory or lethal cases are occasionally encountered. We performed bilateral endoscopic thoracic sympathectomy (ETS) in 5 male patients with refractory VSA. Prior to ETS, stellate ganglion blockade was performed in 4 patients to reduce VSA attacks and to confirm the effect of sympathetic blockade. Under endoscopic guidance, the second to fourth thoracic sympathetic ganglia were ablated with a YAG-laser. No patient had complications after ETS, including major sweating abnormalities. In 4 of 5 patients, ETS relieved all VSA symptoms. ST-segment elevation often detected before ETS was absent on repeated ambulatory 24-h Holter monitoring after ETS. ETS is an effective strategy for the treatment of refractory VSA

First-Principles Molecular Dynamics Analysis of Ligand-Free Suzuki-Miyaura Cross-Coupling in Water: Transmetalation and Reductive Elimination

We investigated the transmetalation step of the Suzuki–Miyaura cross coupling reaction (SMR) catalyzed by ligand-free Pd atom or Pd-X- (X=Cl or Br) using first-principles molecular dynamics simulations with an explicit solvent model. When starting from the single Pd atom, the halogen anion bound to the Pd was not replaced by the organoboronate species and instead remained bound to the Pd throughout the transmetalation step. However, when starting from the Pd-X--catalyst, one of the two halogen anions was released from the first coordination sphere of the Pd during transmetalation. Therefore, the product after the transmetalation starting with either the single Pd atom or the Pd-X- were the same. We concluded that Pd-X- is the active species of the ligand-free Pd catalyst for the SMR. The overall activation free energies for transmetalation and reductive elimination were relatively low, estimated to be at most, 13.5 kcal/mol for both halogen species, leading to the efficient turnover of the SMR

First-Principles Molecular Dynamics Analysis of Ligand-Free Suzuki−Miyaura Cross-Coupling in Water Solvent: Oxidative Addition Step

We investigated the oxidative addition of PhX (X = Cl, Br) to a single Pd(0) atom or a PdX− complex in water using first-principles molecular dynamics simulations, with solvent H2O molecules explicitly included in the calculation models, to clarify the origin of the extremely high reactivity of a ligand-free Pd catalyst in an aqueous solution for the Suzuki−Miyaura reaction. The free-energy profiles are estimated using blue moon ensemble sampling to include the entropy effect in chemical reactions in a water solvent. The free energy barrier of the oxidative addition step is quite low for PhBr, whereas the barrier for PhCl is sizable, indicating that the reaction can proceed at room temperature with a high rate for PhBr but a rather low rate for PhCl. We also investigated the effect of the additional halogen anion on the Pd catalyst as a “supporting ligand”. The activation barrier of the oxidative addition step is not affected by the supporting halogen ligand, but the final state is significantly destabilized, which should be important for the following transmetalation step. The solvent effect has also been investigated and discussed

First-Principles Molecular Dynamics Analysis of Ligand-Free Suzuki–Miyaura Cross-Coupling in Water: Transmetalation and Reductive Elimination

We investigated the transmetalation step of the Suzuki–Miyaura cross coupling reaction (SMR) catalyzed by ligand-free Pd atom or Pd-X^– (X = Cl or Br) using first-principles molecular dynamics simulations with an explicit solvent model. When starting from the single Pd atom, the halogen anion bound to the Pd was not replaced by organoboronate species and instead remained bound to the Pd throughout the transmetalation step. However, when starting from the Pd-X^– catalyst, one of the two halogen anions was released from the first coordination sphere of the Pd during transmetalation. Therefore, the products after the transmetalation starting with either the single Pd atom or the Pd-X^– were the same. We concluded that Pd-X^– is the active species of the ligand-free Pd catalyst for the SMR. The overall activation free energies for transmetalation and reductive elimination were relatively low, estimated to be at most, 8.1 kcal/mol for X = Br and 8.4 kcal/mol for X = Cl, respectively, leading to the efficient turnover of the SMR. We ascribe the origin for the suppression of the catalytic reactivity of the ligand-free SMR for PhCl to the larger activation barrier in the oxidative addition step, which causes the aggregation of Pd catalysts