No abstract

This paper reports large bathochromic shifts of up to 260 meV in both the excitonic absorption and emission peaks of oleylamine (OLA)-passivated molecule-like (CdSe) nanocrystals caused by postsynthetic treatment with the electron accepting Cd(OCPh) complex at room temperature. These shifts are found to be reversible upon removal of Cd(OCPh) by N,N,N',N'-tetramethylethylene-1,2-diamine. H NMR and FTIR characterizations of the nanocrystals demonstrate that the OLA remained attached to the surface of the nanocrystals during the reversible removal of Cd(OCPh). On the basis of surface ligand characterization, X-ray powder diffraction measurements, and additional control experiments, we propose that these peak red shifts are a consequence of the delocalization of confined exciton wave functions into the interfacial electronic states that are formed from interaction of the LUMO of the nanocrystals and the LUMO of Cd(OCPh), as opposed to originating from a change in size or reorganization of the inorganic core. Furthermore, attachment of Cd(OCPh) to the OLA-passivated (CdSe) nanocrystal surface increases the photoluminescence quantum yield from 5% to an unprecedentedly high 70% and causes a 3-fold increase of the photoluminescence lifetime, which are attributed to a combination of passivation of nonradiative surface trap states and relaxation of exciton confinement. Taken together, our work demonstrates the unique aspects of surface ligand chemistry in controlling the excitonic absorption and emission properties of ultrasmall (CdSe) nanocrystals, which could expedite their potential applications in solid-state device fabrication.

We have previously shown that a novel microtubule-modulating noscapinoid, EM011 (9-Br-Nos), displays potent anticancer activity by inhibition of cellular proliferation and induction of apoptosis in prostate cancer cells and preclinical mice models. However, physicochemical and cellular barriers encumber the development of viable formulations for future clinical translation. To circumvent these limitations, we have synthesized EM011-cyclodextrin inclusion complexes to improve solubility and enhance therapeutic index of EM011. Phase solubility analysis indicated that EM011 formed a 1:1 stoichiometric complex with β-CD and methyl-β-CD, with a stability constant (Kc) of 2.42 × 10−3 M and 4.85 × 10−3 M, respectively. Fourier transform infrared spectroscopy suggested the penetrance of either O-CH2 or OCH3-C6H4-OCH3 moiety of EM011 in the β-CD or methyl-β-CD cavity. In addition, multifarious techniques viz., differential scanning calorimetry, powder X-ray diffraction, scanning electron microscopy, NMR spectroscopy, and computational studies validated the cage complex of EM011 with β-CD and methyl-β-CD. Moreover, rotating frame overhauser enhancement spectroscopy showed that the Ha proton of OCH3-C6H4-OCH3 moiety was in close proximity with H3 proton of β-CD or methyl-β-CD cavity. Furthermore, we found that the solubility of EM011 in phosphate buffer saline (pH 7.4) was enhanced by ∼11 fold and ∼21 fold upon complexation with β-CD and methyl-β-CD, respectively. The enhanced dissolution of the drug CD-complexes in aqueous phase remarkably decreased their IC50 to 28.5 μM (9-Br-Nos-β-CD) and 12.5 μM (9-Br-Nos-methyl-β-CD) in PC-3 cells compared to free EM011 (∼200 μM). This is the first report to demonstrate the novel construction of cylcodextrin-based nanosupramolecular vehicles for enhanced delivery of EM011 that warrants in vivo evaluation for the superior management of prostate cancer.

First-principles determination of free energy profiles for condensed-phase chemical reactions is hampered by the daunting costs associated with configurational sampling on ab initio quantum mechanical/molecular mechanical (AI/MM) potential energy surfaces. Here, we report a new method that enables efficient AI/MM free energy simulations through mean force fitting. In this method, a free energy path in collective variables (CVs) is first determined on an efficient reactive aiding potential. Based on the configurations sampled along the free energy path, correcting forces to reproduce the AI/MM forces on the CVs are determined through force matching. The AI/MM free energy profile is then predicted from simulations on the aiding potential in conjunction with the correcting forces. Such cycles of correction−prediction are repeated until convergence is established. As the instantaneous forces on the CVs sampled in equilibrium ensembles along the free energy path are fitted, this procedure faithfully restores the target free energy profile by reproducing the free energy mean forces. Due to its close connection with the reaction path-force matching (RP-FM) framework recently introduced by us, we designate the new method as RP-FM in collective variables (RP-FM-CV). We demonstrate the effectiveness of this method on a type-II solution-phase SN 2 reaction, NH 3 + CH 3 Cl (the Menshutkin reaction), simulated with an explicit water solvent. To obtain the AI/MM free energy profiles, we employed the semiempirical AM1/MM Hamiltonian as the base level for determining the string minimum free energy pathway, along which the free energy mean forces are fitted to various target AI/MM levels using the Hartree−Fock (HF) theory, density functional theory (DFT), and the second-order Møller−Plesset perturbation (MP2) theory as the AI method. The forces on the bond-breaking and bond-forming CVs at both the base and target levels are obtained by force transformation from Cartesian to redundant internal coordinates under the Wilson B-matrix formalism, where the linearized FM is facilitated by the use of spline functions. For the Menshutkin reaction tested, our FM treatment greatly reduces the deviations on the CV forces, originally in the range of 12−33 to ∼2 kcal/mol/Å. Comparisons with the experimental and benchmark AI/MM results, tests of the new method under a variety of simulation protocols, and analyses of the solute−solvent radial distribution functions suggest that RP-FM-CV can be used as an efficient, accurate, and robust method for simulating solution-phase chemical reactions.

Background: Extracellular Ca 2ϩ alters mGluR1␣ activity but by an unknown mechanism. Results: Mutations in predicted Ca 2ϩ -binding sites modulated the potency of both orthosteric and allosteric modulators. Conclusion: Ca 2ϩ binding exerts multiple types of effects on mGluR1␣. Significance: Improved knowledge of the mechanisms underlying the actions of Ca 2ϩ on mGluR1␣ activity could facilitate development of isoform-selective drugs and/or suggest ways to tune the actions of available drugs.