Xinnuo Xiong

Novel poly(ADP-ribose) polymerase inhibitor veliparib: biophysical studies on its binding to calf thymus DNA

Veliparib (ABT-888), which can inhibit cancer growth by blocking DNA base excision repair, is one of several recently developed oral inhibitors of poly(ADP-ribose) polymerases, which are currently used in clinical trials. In this work, interaction of calf thymus DNA (ctDNA) with ABT-888 was first investigated following UV-visible absorption, nuclear magnetic resonance (NMR) spectroscopy, steady-state and time-resolved fluorescence, viscosity measurements, circular dichroism (CD), and Fourier transform infrared (FT-IR) spectroscopy coupled with molecular docking methods. UV-visible absorption indicated that ABT-888 was indeed bound to ctDNA. Broadening and upfield shift of the proton peaks of ABT-888 in the proton NMR spectrum indicated that ABT-888 interacted with ctDNA primarily by partial intercalation. Fluorescence quenching and time-resolved fluorescence spectroscopy studies showed that binding of ABT-888 with ctDNA occurred through a static quenching mechanism, resulting in the formation of a ctDNA–ABT-888 complex. Thermodynamic calculations revealed that interaction was an enthalpy-driven process caused by hydrogen bonds and van der Waals forces. Competitive fluorescence experiments coupled with viscosity, CD, and FT-IR studies revealed that ABT-888 intercalates partially and binds to the groove, phosphate group, and deoxyribose sugar of ctDNA and also induces conformational changes. Molecular docking showed that ABT-888 preferably binds to the DNA groove. However, other types of binding, including classic intercalation and partial intercalation, cannot be ruled out.

Investigation on the interaction of antibacterial drug moxifloxacin hydrochloride with human serum albumin using multi-spectroscopic approaches, molecular docking and dynamical simulation

The interaction between moxifloxacin hydrochloride (MOXH) and human serum albumin (HSA) was experimentally and simulatively investigated. Fluorescence quenching presented that MOXH bound to HSA via a static process, resulting in the formation of MOXH–HSA complex. This quenching mechanism was further verified by time-resolved fluorescence. Binding constants (Ka) of the complex were found to be 105 L mol−1 according to fluorescence data, and the calculated thermodynamic parameters indicated that hydrogen bonds and van der Waals force played key roles in the binding process. The UV-vis absorption, synchronous fluorescence, three-dimensional fluorescence, and circular dichroism spectra suggested that binding with MOXH induced the conformational changes on HSA; the hydrophobicity around tryptophan residues increased, the α-helix content increased, whereas the β-sheet and turn content of HSA decreased. Displacement experiments demonstrated that MOXH mainly bound to site I of HSA. Molecular docking results supported the active site and showed that the diazabicyclo of MOXH inserted into the hydrophobic pocket of HSA. Molecular dynamics simulation further ascertained that MOXH steadily bound to site I of HSA. In conclusion, hydrogen bonds and VDW force played major roles in stabilizing the MOXH–HSA complex, and hydrophobic force was also involved in the binding process.

Effect of hydroxypropyl-β-cyclodextrin on the bounding of salazosulfapyridine to human serum albumin

The supramolecular interaction between salazosulfapyridine (SASP) and hydroxypropyl-β-cyclodextrin (HP-β-CD), as well as the influence of HP-β-CD on SASPs binding to human serum albumin (HSA), were investigated. Phase-solubility studies indicate that the HP-β-CD/SASP inclusion complex was formed at a 1:1 host-guest stoichiometry with high stability constant. The HP-β-CD/SASP complex, which was characterized by various techniques, exhibited markedly improves aqueous solubility of SASP. The binding of SASP with HSA in the presence and absence of HP-β-CD were investigated. The Stern-Volmer quenching constant and binding constant of SASP with HSA were found to be smaller in the presence of HP-β-CD. The Förster distance between the donor and the acceptor is altered in the presence of HP-β-CD. These results exhibited that the HP-β-CD reduced the quenching and binding of SASP on HSA. Molecular modeling is used to optimize the sites and mode of binding of SASP with HSA.

Solvates and polymorphs of rebamipide: preparation, characterization, and physicochemical analysis

This study aimed to investigate the solid forms of the peptic ulcer agent rebamipide (RBM). Four RBM solvates, including dimethyl sulfoxide solvate (RBM/DMSO), dichloromethane solvate (RBM/CH2Cl2), hydrate (RBM/H2O), and hemiethanol hemihydrate, were prepared via solvent crystallization. Single crystals of RBM/DMSO and RBM/CH2Cl2 were successfully obtained at 4 °C. These solid forms were both monoclinic with the space group P21/c. Hirshfeld surface and 2D fingerprint plot analyses indicated that RBM/DMSO and RBM/CH2Cl2 showed similarities in hydrogen bonds but exhibited differences in subtle intermolecular interactions. RBM/CH2Cl2 transformed into a novel solid form (form 3) after solvent removal and transformed into another solid form (form 4) when heated at 220 °C. RBM/H2O was converted to form 5 after dehydration. Forms 3–5 were RBM polymorphs. The stability results indicated that RBM/H2O, form 3, and form 4 showed good stability at 40 °C and 75% relative humidity. Furthermore, the three solid forms displayed higher solubility than commercial RBM (form 1) in both water and phosphate buffer solution (PBS). Compared with form 1, RBM/H2O and form 4 showed a comparable and faster dissolution rate in water and PBS, respectively.

Solid-state amorphization of rebamipide and investigation on solubility and stability of the amorphous form

Abstract Solid-state amorphization of crystalline rebamipide (RBM) was realized by ball milling and spray drying. The amorphous content of samples milled for various time was quantified using X-ray powder diffraction. Crystalline RBM and three amorphous RBM obtained by milling and spray drying were characterized by morphological analysis, X-ray diffraction, thermal analysis and vibrational spectroscopy. The crystal structure of RBM was first determined by single-crystal X-ray diffraction. In addition, the solubility and dissolution rate of the RBM samples were investigated in different media. Results indicated that the solubility and the dissolution rates of spray-dried RBM-PVP in different media were highly improved compared with crystalline RBM. The physical stabilities of the three amorphous RBM were systematically investigated, and the stability orders under different storage temperatures and levels of relative humidity (RH) were both as follows: spray dried RBM < milled RBM < spray dried RBM-PVP. A direct glass-to-crystal transformation was induced under high RH, and the transformation rate rose with increasing RH. However, amorphous RBM could stay stable at RH levels lower than 57.6% (25 °C).

Binding modes of environmental endocrine disruptors to human serum albumin: insights from STD-NMR, ITC, spectroscopic and molecular docking studies

Given that bisphenols have an endocrine-disrupting effect on human bodies, thoroughly exposing their potential effects at the molecular level is important. Saturation transfer difference (STD) NMR-based binding studies were performed to investigate the binding potential of two bisphenol representatives, namely, bisphenol B (BPB) and bisphenol E (BPE), toward human serum albumin (HSA). The relative STD (%) suggested that BPB and BPE show similar binding modes and orientations, in which the phenolic rings were spatially close to HSA binding site. ITC analysis results showed that BPB and BPE were bound to HSA with moderately strong binding affinity through electrostatic interactions and hydrogen bonds. The order of binding affinity of HSA for two test bisphenols is as follows: BPE > BPB. The results of fluorescence competitive experiments using 5-dimethylaminonaphthalene-1-sulfonamide and dansylsarcosine as competitors, combined with molecular docking indicated that both bisphenols are prone to attach to the binding site II in HSA. Spectroscopic results (FT-IR, CD, synchronous and 3D fluorescence spectra) showed that BPB/BPE induces different degrees of microenvironmental and conformational changes to HSA.

Effects of Temperature and Solvent on the Solid-State Transformations of Pranlukast During Mechanical Milling

Four solid forms of pranlukast (PRS) were obtained during mechanical milling including neat milling (NM) and solvent-drop milling (SDM), which were characterized by various analytical techniques. The effect of milling conditions including 3 milling temperatures and 6 assist solvents on the solid-state transformations of commercial PRS (PRS HH) was systemically investigated. Milling temperature significantly influenced the NM process. A low milling temperature (5°C) led to a complete amorphization of PRS HH, whereas higher milling temperatures (15°C and 30°C) only induced a partial amorphization. The milling at 5°C was proven to be a progressive amorphization process, and the amorphous material showed an increasing stability with prolonged milling time. Amorphous PRS can stay stable under low temperature and relative humidity conditions and showed significantly higher solubilities and faster dissolution rates in both water and pH 6.8 phosphate buffer solution. A total of 6 solvents were used in the SDM experiments. N,N-dimethylformamide and dimethyl sulfoxide should be avoided in the manufacturing process of PRS because corresponding solvates of PRS can be easily generated by SDM of PRS HH with short milling time and small amount of solvents.

Characterization and In Vitro Evaluation of the Complexes of Posaconazole with β- and 2,6-di-O-methyl-β-cyclodextrin

Posaconazole is a triazole antifungal drug that with extremely poor aqueous solubility. Up to now, this drug can be administered via intravenous injection and oral suspension. However, its oral bioavailability is greatly limited by the dissolution rate of the drug. This study aimed to improve water solubility and dissolution of posaconazole through characterizing the inclusion complexes of posaconazole with β-cyclodextrin (β-CD) and 2,6-di-O-methyl-β-cyclodextrin (DM-β-CD). Phase solubility studies were performed to calculate the stability constants in solution. The results of FT-IR, PXRD, 1H and ROESY 2D NMR, and DSC all verified the formation of the complexes in solid state. The complexes showed remarkably improved water solubility and dissolution rate than pure posaconazole. Especially, the aqueous solubility of the DM-β-CD complex is nine times higher than that of the β-CD complex. Preliminary in vitro antifungal susceptibility tests showed that the two inclusion complexes maintained high antifungal activities. These results indicated that the DM-β-CD complexes have great potential for application in the delivery of poorly water-soluble antifungal agents, such as posaconazole.

Synthesis, structure, and calf-thymus DNA binding of ternary fleroxacin–Cu(II) complexes

Two mononuclear copper(II) (Cu(II)) complexes containing quinolone drug fleroxacin (flrx) were synthesized in the presence of 1,10-phenanthrolin (phen) and 2,2′-bipyridine (bipy). To fully characterize these two complexes, single-crystal X-ray diffraction study and other characterizations were employed. X-ray crystallography results showed that the deprotonated flrx coordinated with the central Cu(II) via one pyridone oxygen and one carboxylate oxygen. Intermolecular interactions including hydrogen bonding and π–π stacking stabilized these complexes. Moreover, interactions of [Cu(flrx)(bipy)Cl]·4H2O and [Cu(flrx)(phen)·H2O]·9.8H2O complexes with calf-thymus DNA (CT DNA) were investigated. Fluorescence measurements and fluorescence lifetime investigations indicated that CT DNA could effectively quench the fluorescence of the complexes and the interaction modes were static quenching. Isothermal titration calorimetry showed that the two complexes exhibited a similar moderate binding affinity to CT DNA, and their binding constants were basically consistent with the results of the fluorescence measurements. Thermodynamic parameters revealed that the bindings were driven by considerable enhancements in beneficial entropy and unfavorable increases in enthalpy, and the negative Gibbs energy values indicated that the interactions were spontaneous. Circular dichroism, interaction with denatured CT DNA, and iodide quenching studies suggested that the possible interaction modes between CT DNA and these two complexes are both in the intercalation mode.

Effect of milling conditions on solid-state amorphization of glipizide, and characterization and stability of solid forms

In this study, the amorphization of glipizide was systematically investigated through high-energy ball milling at different temperatures. The results of solid-state amorphization through milling indicated that glipizide underwent direct crystal-to-glass transformation at 15 and 25°C and crystal-to-glass-to-crystal conversion at 35°C; hence, milling time and temperature had significant effects on the amorphization of glipizide, which should be effectively controlled to obtain totally amorphous glipizide. Solid forms of glipizide were detailedly characterized through analyses of X-ray powder diffraction, morphology, thermal curves, vibrational spectra, and solid-state nuclear magnetic resonance. The physical stability of solid forms was investigated under different levels of relative humidity (RH) at 25°C. Forms I and III are kinetically stable and do not form any new solid-state forms at various RH levels. By contrast, Form II is kinetically unstable, undergoing direct glass-to-crystal transformation when RH levels higher than 32.8%. Therefore, stability investigation indicated that Form II should be stored under relatively dry conditions to prevent rapid crystallization. High temperatures can also induce the solid-state transformation of Form II; the conversion rate increased with increasing temperature.