Computer-Aided Search for 5-Arylideneimidazolone Anticancer Agents Able To Overcome ABCB1-Based Multidrug Resistance

ABCB1 modulation is an interesting strategy in the search for new anticancer agents that can overcome multidrug resistance (MDR). Hence, 17 new 5-arylideneimidazolones containing an amine moiety, as potential ABCB1 inhibitors, were designed, synthesized, and investigated. The series was tested in both parental (PAR) and multidrug-resistant (MDR) ABCB1-overexpressing T-lymphoma cancer cells using cytotoxicity assays. The ABCB1-modulating activity was examined in rhodamine 123 accumulation tests, followed by Pgp-Glo™ Assay to determine the influence of the most active compounds on ATPase activity. Lipophilic properties were assessed both, in silico and experimentally (RP-TLC). Pharmacophore-based molecular modelling toward ABCB1 modulation was performed. The studies allowed the identification of anticancer agents (p-fluorobenzylidene derivatives) more potent than doxorubicin, with highly selective action on MDR T-lymphoma cells (selectivity index >40). Most of the investigated compounds showed ABCB1-modulating action; in particular, two 5-benzyloxybenzylidene derivatives displayed activity nearly as strong as that of tariquidar.     

纳米CaCO3的表面改性研究

本文研究了纳米CaCO3表面改性的影响因素，确定了最优改性剂和改性条件，并运用沉降实验、透射电镜（TEM）等表征手段对粉体的改性效果进行了分析。结果表明：以月桂酸钠为改性剂，用量为10％，pH值为7，改性时间为1h时，改性后的纳米CaCO3的亲油化度达到85．1％，能较好地分散于环己烷和二甲苯中。     

N-(Anilinoethyl)amide Melatonergic Ligands with Improved Water Solubility and Metabolic Stability

The MT₂-selective melatonin receptor ligand UCM765 (N-(2-((3-methoxyphenyl)(phenyl)amino)ethyl)acetamide), showed interesting sleep inducing, analgesic and anxiolytic properties in rodents, but suffers from low water solubility and modest metabolic stability. To overcome these limitations, different strategies were investigated, including modification of metabolically liable sites, introduction of hydrophilic substituents and design of more basic derivatives. Thermodynamic solubility, microsomal stability and lipophilicity of new compounds were experimentally evaluated, together with their MT₁ and MT₂ binding affinities. Introduction of a m-hydroxymethyl substituent on the phenyl ring of UCM765 and replacement of the replacement of the N,N-diphenyl-amino scaffold with a N-methyl-N-phenyl-amino one led to highly soluble compounds with good microsomal stability and receptor binding affinity. Docking studies into the receptor crystal structure provided a rationale for their binding affinity. Pharmacokinetic characterization in rats highlighted higher plasma concentrations for the N-methyl-N-phenyl-amino derivative, consistent with its improved microsomal stability and makes this compound worthy of consideration for further pharmacological investigation.     

柚皮苷-卵磷脂包合物的制备及其理化性质研究

柚皮苷是一种天然抗氧化剂,具有多种生物活性,但是存在脂溶性差、口服吸收率低等问题。为了提高柚皮苷的脂溶性和生物利用度,本研究制备了柚皮苷-卵磷脂包合物,并采用紫外(UV),红外(IR),差示量热扫描(DSC),X-射线衍射(XRD)等波谱分析方法研究了该包合物的理化性质。研究结果表明,柚皮苷与卵磷脂并没有形成一种新的化合物,柚皮苷只是以一种无定形状态分散在卵磷脂中,二者是通过氢键、范德华力等非共价键形式相结合。同时对比了柚皮苷与柚皮苷-卵磷脂包合物中柚皮苷在正辛醇中的溶解性,结果表明,与卵磷脂形成包合物后,柚皮苷在正辛醇中的溶解度由3.28μg/m L增加至755.50μg/m L,脂溶性得到了显著的提高;亚油酸体系中抗氧化能力实验表明,柚皮苷与卵磷脂的包合可以显著提高柚皮苷在脂溶性体系中的抗氧化能力。     

Synthesis and in vivo bioactivity of lipophilic alendronate derivatives against osteoporosis

New lipophilic alendronate amidated derivatives 1a–1d anchored alkyl chains (C_nH_2n+1, n?=?12, 14, 16, 18) had been obtained through the reaction of alendronate with carboxylic acid under anhydrous condition. The physicochemical parameters, such as the solubility and partition coefficient P_o/w in n-octanol/water, were determined through calculation by performing reversion phase high-performance liquid chromatography (RP-HPLC). The results showed that the derivatives had improved lipophilicity compared with alendronate. The in vivo bioactivities of the derivatives were investigated using the hindlimb unloading growing rats’ model. The results showed that the derivatives had in vivo bioactivity against hindlimb unloading growing rats’ bone loss, which indicated that the lipophilic derivative would be a promising new potent bisphosphates for treatment of the osteoporosis.     

Nickel‐Catalyzed Synthesis of Phosphonium Salts from Aryl Halides and Triphenylphosphine

An efficient method to synthesize functionalized tetraarylphosphonium salts is described. The nickel‐catalyzed coupling reaction between aryl iodides, bromides, chlorides, or triflates and triphenylphosphine generates tetraarylphosphonium salts in high yields. The coupling is wide in scope and tolerates a variety of functional groups such as alcohols, amides, ketones, aldehydes, phenols, phosphines and amines.     

Physicochemical Properties of Zwitterionic Drugs in Therapy

In solution, amphoteric compounds exist in anionic, uncharged, zwitterionic and cationic forms. The importance of zwitterionic drugs is currently under-represented in the literature. Herein, the acid-base parameters, lipophilicity and solubility of such compounds are discussed to deepen the molecular-level understanding of their pharmacokinetic and pharmacodynamic behaviour. Our recent studies show there are many drug molecules, including thyroid hormones and 5-hydroxytryptophan, the precursor of the neurotransmitter serotonin, for which the contribution of the zwitterionic microspecies to the overall lipophilicity exceeds that of the uncharged one, which is of higher individual lipophilicity, but occurs in much lower concentration. The second part of the minireview highlights the most important zwitterionic compounds in therapy, grouped into therapeutic classes. The importance of the charge of the molecules is emphasized in their binding to the target molecules.     

Effect of Oil Phase Lipophilicity on In Vitro Drug Release from O/W Microemulsions with Low Surfactant Content

ABSTRACT

In this work we investigated the effects of oil phase lipophilicity on in vitro drug release from topical o/w microemulsions (MEs) containing low percentages of emulsifiers. Three different lipids, isopropyl myristate (IPM), isopropyl palmitate (IPP), and isopropyl stearate (IPS), whose lipophilicity increased in the order IPM < IPP <IPS, were used as oil phase to prepare o/w MEs containing low amounts (7.7% w/w) of two surfactant/cosurfactant mixtures, isoceteth-20/glyceryl oleate (5:2) (MEs 1–3) and oleth-20/glyceryl oleate (5:2) (MEs 4–6). All the MEs were prepared using the phase inversion temperature (PIT) method.

Three active compounds (0.5% w/w), Naproxen (NAP), Idebenone (IDE), and Butylmethoxydibenzoylmethane (BMBM), were selected as model drugs and their release rates from PIT MEs were evaluated using Franz-type diffusion cells. All the MEs gave a mean droplet diameter ranging from 28 to 44 nm and showed a single peak in size distribution. The addition of IDE to MEs 1–6 did not significantly change ME droplet size. On the contrary, an increase of the droplet size beyond the ME limit (150 nm) was observed when isoceteth-20 was used as surfactant to prepare MEs containing NAP or MEs containing BMBM and IPS as oil phase. Pseudo-first order release rates were observed only for NAP from MEs 1–3, while MEs containing IDE showed an initial slow release followed by an increased release of the test compound. The release rate constants were found to be dependent on the ME composition and on the active compound incorporated. The highest release rate was observed from ME 1 containing IPM as oil phase and NAP as drug. As regards BMBM, its release rate was not calculated since no release was observed until 6 h from the beginning of the experiment. The cumulative amount of active compound released after 22 h was inversely related to drug lipophilicity (NAP Log P = 2,9; IDE Log P 3,5; BMBM Log P 4,8). These findings could be attributable to a reduced thermodynamic activity of the drugs in the vehicles containing the most lipophilic oil phase due to an increase of drug solubility which could lead to an unfavorable drug partition from the oil phase. The results of this study suggest that the choice of proper combinations of oil phase lipids and emulsifiers may allow achieving drug controlled delivery from topical o/w MEs with low emulsifier content.     

Lipophilicity of Flavonoids Estimated by Reversed-Phase High Performance Thin-Layer Chromatography: Chemically Bonded Plates vs. Impregnated Plates with Oils,Animal, and Human Fats

Silica gel plates impregnated with a variety of oils (olive oil, sunflower oil, corn oil, trioctylamine, and paraffin oil) and fats (margarine, butter, cod liver fat, pig fat, sheep fat, pullet fat, and human fat) were evaluated and compared with the commercially available reversed-phases TLC plates (RP-18, RP-18 W, and CN). A representative series of flavonoids is employed to evaluate the suitability of oils and fats as reversed-phases for TLC and to provide different lipophilicity indices: R_M0, scores corresponding to first principal component of R_F and/or R_M, arithmetic mean of R_F and R_M values obtained with solvent mixture containing various concentrations of methanol in water. The retention results were excellent (r > 0.96) and allowed for accurate estimation of lipophilicity of selected flavonoids and to ranking the lipophilicity of oils and fats when comparing with chemically bonded phases. The human fat-impregnated plates provided lipophilicity values closely associated with those obtained for margarine and butter. Moreover, the human fat lipophilic character seems to be placed between pullet and cod fats. Concerning the lipophilicity scale of vegetable oils, it is worth noting that the corn oil presents the highest lipophilicity, closely followed by the sunflower and olive oils.