The action modes of Lippia sidoides (Cham) essential oil as penetration enhancers on snake skin

The aim of this work was to study the effect of Lippia sidoides essential oil (LSEO) on stratum corneum lipids and the permeation of salicylic acid. DSC and FTIR spectroscopy were applied. LSEO 1% (v/v) significantly enhanced salicylic acid flux through snake skin. According to the DSC curves changes in the transition temperature of the lipids were observed indicating that LSEO can interact with stratum corneum. The IR spectrum of skin treated with LSEO showed a decrease in the peak intensity for CH₂ stretchings (2920–2850 cm^–1) however the peak positions did not alter suggesting the extraction of the lipids.     

Synthesis of novel ceramide-like penetration enhancers

Ceramide-like penetration enhancers have been synthesized by isosteric replacements of the 1-hydroxymethyl and amide moieties of natural ceramides. Metabolically more stable oxime and five-membered heterocyclic (1,2,4-oxadiazole, 1,2,4-triazole, tetrazole) analogues are more polar and possess H-bond acceptor properties, which make them potentially useful in optimizing key intermolecular features in interactions between the modified ceramide structures and the lipid layers of stratum corneum.     

Destabilization of whole skin lipid bio-liposomes induced by skin penetration enhancers and FT-IR/ATR (Fourier transform infrared/attenuated total reflection) analysis of stratum corneum lipids.

Whole skin lipid bio-liposomes (skin bio-liposomes), in size ranging from 2 to 8 microns, were prepared by a reverse phase evaporation technique using rat full thickness skin. Leakage of an encapsulated fluorescence probe, ANTS (delta-amino-1,3,6-naphthalene-trisulfonate), was measured by adding transdermal penetration enhancers (penetrants) into the medium where the skin bio-liposomes were present. Oleylamine induced a fast release of ANTS from the liposomes compared to lauryl-amine which showed a weak action. With these penetrants, the degree of ANTS release from the prepared bio-liposomes was found to correlate well with the results of frequency changes in the CH-asymmetric stretching band near 2920 cm-1 in the rat stratum corneum. The penetrant which caused relatively strong leakage of ANTS induced the significantly large shift of the peak toward the higher wave-numbers due to the perturbation in the structure of lipids of the stratum corneum. The skin bio-liposomes prepared from the rat full thickness skin could be useful in evaluating the penetrants.     

Analysis of the internal representations developed by neural networks for structures applied to quantitative structure--activity relationship studies of benzodiazepines

An application of recursive cascade correlation (CC) neural networks to quantitative structure-activity relationship (QSAR) studies is presented, with emphasis on the study of the internal representations developed by the neural networks. Recursive CC is a neural network model recently proposed for the processing of structured data. It allows the direct handling of chemical compounds as labeled ordered directed graphs, and constitutes a novel approach to QSAR. The adopted representation of molecular structure captures, in a quite general and flexible way, significant topological aspects and chemical functionalities for each specific class of molecules showing a particular chemical reactivity or biological activity. A class of 1,4-benzodiazepin-2-ones is analyzed by the proposed approach. It compares favorably versus the traditional QSAR treatment based on equations. To show the ability of the model in capturing most of the structural features that account for the biological activity, the internal representations developed by the networks are analyzed by principal component analysis. This analysis shows that the networks are able to discover relevant structural features just on the basis of the association between the molecular morphology and the target property (affinity).     

Synthesis of caprazamycin analogues and their structure--activity relationship for antibacterial activity

Synthesis of palmitoyl caprazol 7, which possesses a simple fatty acyl side chain at the 3' '-position of the diazepanone moiety, was carried out and their antibacterial activity was evaluated. The key elements of our approach include the improved synthesis of the key 5'-beta-O-aminoribosyl-glycyluridine derivative, installation of the palmitoyl side chain to the cyclization precursor, and the construction of the diazepanone by an intramolecular reductive amination. The second generation synthesis of (+)-caprazol was also established. Palmitoyl caprazol 7 exhibited antibacterial activity against Mycobacterium smegmatis ATCC607 (MIC = 6.25 microg/mL) with potency similar to that of the caprazamycins (CPZs). Palmitoyl caprazol 7 and N6'-desmethyl palmitoyl caprazol 28 also exhibited antibacterial activity against drug-resistant bacteria including methyciline-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) strains (MIC = 3.13-12.5 microg/mL).     

Synthesis of chemically stabilized phosmidosine analogues and the structure--activity relationship of phosmidosine

Phosmidosine is known to have potent antitumor activity and the unique property of stopping cell growth at the G(1) phase in the cell cycle. However, this natural product having N-prolylphosphoramidate and O-methyl ester linkages on the 5'-phosphoryl residue is unstable under basic conditions and even during the chemical synthesis due to its inherent methyl transfer activity. To find stable derivatives of phosmidosine, a variety of phosmidosine analogues 1a-d replaced by longer alkyl groups in place of the methyl group on the phosphoramidate linkage were synthesized by reaction of alkyl N-(N-tritylprolyl)phosphorodiamidite derivatives 7a-d with an 8-oxoadenosine derivative 4 protected with acid-labile protecting groups. Consequently, the O-ethyl ester derivative 1b was found to be sufficiently stable in aqueous solution. When the prolyl group was replaced by other aminoacyl moieties, the reaction of N-tritylaminoacylamide derivatives 25a-d with an appropriately protected 8-oxoadenosine 5'-(ethyl phosphoramidite) derivative 9 gave better results than the above coupling reaction. A phosphoramidothioate derivative 17 and several simple compounds such as 11, 13, and 15 lacking partial structures of phosmidosine were also synthesized. The antitumor activities of these modified analogues were extensively studied to clarify the structure-activity relationship of phosmidosine. As a result, the two diastereoisomers of longer alkyl-containing phosmidosine analogues both proved to have similar antitumor activities. Replacement of l-proline with other l-amino acids or d-proline resulted in considerable decrease of the antitumor activity. The non-nucleotidic materials 13 did not show any antitumor activity, but a simple core compound of 11 exhibited weak cytotoxicity. The phosphoramidothioate derivative 17 maintained essentially a similar antitumor activity, but the efficiency decreased slightly.     

Fragment-based quantitative structure-activity relationship (FB-QSAR) for fragment-based drug design

In cooperation with the fragment-based design a new drug design method, the so-called "fragment-based quantitative structure-activity relationship" (FB-QSAR) is proposed. The essence of the new method is that the molecular framework in a family of drug candidates are divided into several fragments according to their substitutes being investigated. The bioactivities of molecules are correlated with the physicochemical properties of the molecular fragments through two sets of coefficients in the linear free energy equations. One coefficient set is for the physicochemical properties and the other for the weight factors of the molecular fragments. Meanwhile, an iterative double least square (IDLS) technique is developed to solve the two sets of coefficients in a training data set alternately and iteratively. The IDLS technique is a feedback procedure with machine learning ability. The standard Two-dimensional quantitative structure-activity relationship (2D-QSAR) is a special case, in the FB-QSAR, when the whole molecule is treated as one entity. The FB-QSAR approach can remarkably enhance the predictive power and provide more structural insights into rational drug design. As an example, the FB-QSAR is applied to build a predictive model of neuraminidase inhibitors for drug development against H5N1 influenza virus.     

Binary quantitative structure-activity relationship (QSAR) analysis of estrogen receptor ligands

The use of high throughput screening (HTS) to identify lead compounds has greatly challenged conventional quantitative structure-activity relationship (QSAR) techniques that typically correlate structural variations in similar compounds with continuous changes in biological activity. A new QSAR-like methodology that can correlate less quantitative assay data (i.e., "active" versus "inactive"), as initially generated by HTS, has been introduced. In the present study, we have, for the first time, applied this approach to a drug discovery problem; that is, the study of the estrogen receptor ligands. The binding affinities of 463 estrogen analogues were transformed into a binary data format, and a predictive binary QSAR model was derived using 410 estrogen analogues as a training set. The model was applied to predict the activity of 53 estrogen analogues not included in the training set. An overall accuracy of 94% was obtained.     

Molecular modeling of polymers, 14 quantitative structure-property relationship analyses of multicomponent systems containing polymers

One general class of polymer modeling applications involves materials which are large, in terms of molecular degrees of freedom, and poorly defined in terms of composition and morphology. Such materials are often multicomponent with respect to number of distinct polymers, fillers, additives, etc. Two obstacles limit the modeling of these materials. First, one normally does not have any idea about the key physicochemical molecular properties governing the system. Second, the functional dependence of the target properties of the material upon the key physicochemical molecular properties is usually totally unknown. Torsion angle unit (TAU) theory, a molecular decomposition technique, permits an arbitrarily large number of physicochemical properties to be computed in an open-ended fashion, and thus addresses the first problem. Genetic function approximation (GFA) analysis tackles the second problem by efficiently exploring any desired number of functional relationships between target properties and physicochemical molecular properties. Case studies of (TAU theory)-(GFA analysis) applications to estimate glass, Tg, and crystal-melt, Tm, transition temperatures will be described.     

Multiple field three dimensional quantitative structure-activity relationship (MF-3D-QSAR)

A new drug design method, the multiple field three-dimensional quantitative structure-activity relationship (MF-3D-QSAR), is proposed. It is a combination and development of classical 2D-QSAR and traditional 3D-QSAR. In addition to the electrostatic and van der Waals potentials, more potential fields (such as lipophilic potential, hydrogen bonding potential, and nonthermodynamic factors) are integrated in the MF-3D-QSAR. Meanwhile, a principal component analysis (PCA) and iterative double least square (IDLS) technique is developed for predicting the bioactivity of query drug candidates. As an example, the MF-3D-QSAR is applied to the design of neuraminidase inhibitor and to prove its predictive power, and some useful findings are obtained for developing drugs against influenza virus.     

Preparations of cyclic sulfoxide derivatives and their evaluation as transdermal penetration enhancers.

Novel cyclic sulfoxides, such as 2-octyl, 2-dodecyl and 2-hexadecyltetrahydrothiophene-1-oxide were prepared by the alkylation of tetrahydrothiophene-1-oxide. Additionally, 2-methyl, 2-ethyl and 2-propyl-5-dodecyltetrahydro-thiophene-1-oxide were conducted by further alkylation. Their enhancing activity on the penetration of indomethacin through rabbit skin was evaluated in in vitro experiments, and the effect of the alkyl length on the enhancing activity was discussed. Among the 2-alkyl-tetrahydrothiophene-1-oxides, the compounds containing dodecyl and hexadecyl groups promoted a much greater penetration of the drug through the skin than the compound containing an octyl group. A stronger effect was observed in the experiment using 2-dodecyl-5-alkyltetrahydrothiophene-1-oxide, as compared with the that of 2-dodecyl-tetrahydrothiophene-1-oxide. The substitution of the alkyl groups to the next position of the sulfoxide group seemed to make the enhancing activities large.     

基于吲哚类的ROCK激酶抑制剂定量构效关系的研究

基于计算生物学方法对61个ROCK激酶靶标分子建立三维定量构效关系(3DQSAR)模型.在基于配体叠合的基础上,发现CoMSIA中2个场组合(位阻场和疏水场)为最好的模型(Q2=0.509,R2ncv=0.987,SEE=0.131,F=287.999和R2pre=0.837).基于此模型基础上的三维等势线图形象地说明了在各个位置增加疏水性的大取代基或者亲水性基团有利于提高分子的生物活性.此外,分子对接模拟结果显示了氨基酸Glu170,Met172和Asp232在受体调节剂中发挥着重要作用.这些结果能够帮助深入了解ROCK激酶的作用机理,并且能够为今后的药物设计提供新的方向.     

An efficient quantitative technique for the simultaneous analyses of radon daughters (210)Pb, (210)Bi and (210)Po

An improved and time efficient technique has been developed for quantitative determination of the long-lived (222)Rn daughters ((210)Pb, (210)Po and (210)Bi) in atmospheric and oceanic samples. The sample is first spiked with yield tracers for polonium (208 or 209), bismuth (207), and lead (stable lead carrier). These nuclides may then be scavenged through iron hydroxide precipitation and redissolved in a dilute (pH approximately 2) nitric acid plating medium with citrate and hydroxylamine hydrochloride at 90 degrees centrigrade with constant stirring. First a silver planchet is suspended in the solution which plates polonium to high efficiency. Second, a nickel planchet is suspended in the same solution which is maintained hermetic (e.g. bubbling with helium) and bismuth is plated next with high efficiency. Third, lead is purified from the same solution using anion exchange techniques and isolated for beta counting as the sulfate. Polonium is analyzed by isotope dilution alpha spectrometry. Bismuth and lead are analyzed by anti-coincident beta counting in a low level shield. In the case of bismuth, the 207 tracer is added in quantities at least comparable to the background of the beta system such that counting before and after the decay of (210)Bi gives the bismuth yield. The unique characteristics of this technique are its speed and efficiency; all three radon daughters can be isolated for counting within 4 hr of pre-treating the sample. The remaining solution can be treated subsequently for other analyses as appropriate.