Investigating the activity of 2-substituted alkyl-6-(2,5-dioxopyrrolidin-1-yl)hexanoates as skin penetration enhancers

Skin penetration enhancers are used in the formulation of transdermal delivery systems for drugs that are otherwise not sufficiently skin-permeable. We generated two series of esters by multi-step synthesis with substituted 6-aminohexanoic acid as potential transdermal penetration enhancers by multi-step synthesis. The synthesis of all newly prepared compounds is presented here. Structure confirmation of all generated compounds was accomplished by (1)H NMR, (13)C NMR, IR and MS spectroscopy. All the prepared compounds were analyzed using RP-HPLC and their lipophilicity (logk) was determined. The hydrophobicity (logP/ClogP) of the studied compounds was also calculated using two commercially available programs and 3D structures of the selected compounds were investigated by means of ab initio calculations of geometry and molecular dynamic simulations. All the synthesized esters were tested for their in vitro transdermal penetration-enhancing activity and showed higher enhancement ratios than oleic acid. The highest enhancement ratios were exhibited by compound 5f (C((2)) substituted with piperidine-2-one, C(11) ester chain) and 5a (C((2)) substituted with piperidine-2-one, C(6) ester chain). The series with a ω-lactam ring (piperidin-2-one; 5a-g), showed slightly higher activities than those with morpholine (6a-6g). All of the agents showed minimal anti-proliferative activity (IC(50) >6.25μM), indicating they would have low cytotoxicity when administered as chemical penetration enhancers. The relationships between the lipophilicity and the chemical structure of the studied compounds, as well as the correlation between their chemical structure and transdermal penetration-enhancing activity, are discussed.     

Structure-activity study of phosphoramido acid esters as acetylcholinesterase inhibitors

Phosphoramido acid esters (CH(3))(2)NP(O)X(p-OC(6)H(4)-CH(3)) (containing P-Cl (1), P-O (2), P-F (3), P-CN (5), and P-N (4,6) bonds, X for 2, 4 and 6 is OCH(3), (C(2)H(5))(2)N and morpholin) have been synthesized to investigate the structure-activity study of AChE enzyme inhibition, through the parameters logP, delta(31)P and IC(50). After their characterization by (31)P, (31)P{(1)H}, (13)C, (1)H NMR, IR and mass spectroscopy, the parameters logP and delta(31)P ((31)P chemical shift in NMR) were used to evaluated the lipophilicity and electronical properties. The ability of compounds to inhibit human AChE was predicted by PASS software (version 1.193), and experimentally evaluated by a modified Ellman's assay.     

Investigation of substituted 6-aminohexanoates as skin penetration enhancers

Skin penetration enhancers are compounds used to facilitate the transdermal delivery of drugs that are otherwise not sufficiently permeable. Through a synthetic route implementing two series of esters, we generated transdermal penetration enhancers by a multi-step reaction with substituted 6-aminohexanoic acid. We present the synthesis of all newly prepared compounds here with structural confirmation accomplished by (1)H NMR, (13)C NMR, IR and mass spectroscopy (MS). The lipophilicity (logk) of all compounds was determined via RP-HPLC and their hydrophobicity (logP/ClogP) was also calculated using two commercially available programs. Ab initio calculations of geometry and molecular dynamic simulations were employed to investigate the 3-dimensional structures of selected compounds. The transdermal penetration-enhancing activity of all the synthesized esters were examined in vitro and demonstrated higher enhancement ratios than oleic acid. Compounds 2e (C(10) ester chain) and 2f (C(11) ester chain) exhibited the highest enhancement ratios. It can be concluded that the series non-substituted at the C((2)) position by a ω-lactam ring showed significantly higher activity than those with azepan-2-one. None of the prepared compounds penetrated through the skin. All of the investigated agents demonstrated minimal anti-proliferative activity using the SK-N-MC neuroepithelioma cell line (IC(50)>6.25μM), suggesting these analogs would have a low cytotoxic profile when administered in vivo as chemical penetration enhancers. The correlation between the chemical structure of the studied compounds and their lipophilicity is discussed in regards to transdermal penetration-enhancing activity.     

Relationship between cucurbitacins reversed-phase high-performance liquid chromatography hydrophobicity index and basal cytotoxicity on HepG2 cells

Drug development of cucurbitacins requires derivatives that have lower cytotoxicity. Therefore, the effect of structural modification on in vitro cytotoxicity has been investigated. Lipophilicity or chromatographic hydrophobicity index (CHI) was chosen as molecular property. CHI was determined by RP-HPLC in both aqueous acetonitrile and aqueous methanol. Compounds CHI range was wide and better defined in acetonitrile (CHI(ACN)=46-88 and 38-102) than in methanol (CHI(MeOH)=56-78). Higher resolution was achieved in acetonitrile, and higher precision on the shorter C18 column. Cucurbitacins cytotoxicity (IC(50)) was measured on the hepatocyte-derived HepG2 cells. Strong relationship between CHI and logarithmic IC(50) was found. As a result, cytotoxicity increased linearly with increasing hydrophobicity (r>/=0.90). Other lipophilicity parameters, such as logP and ClogP were also estimated. Cytotoxicity correlated well with logP (r=0.95) and slightly with ClogP (r=0.74). The logP and ClogP data showed good correlation with CHI (r>0.92). Overall, alkylation of C1 hydroxyl, unsaturation of C1C2 bond, and acetylation of C25 hydroxyl increased both lipophilicity and cytotoxicity. This assay should prove useful for monitoring cucurbitacin homologues or other drug candidates for their cytotoxicity.     

Investigation of new acyloxy derivatives of cholic acid and their esters as drug absorption modifiers

Skin penetration enhancers are used in the formulation of transdermal delivery systems for drugs that are otherwise not sufficiently skin-permeable. Intestinal absorption promoters/enhancers are used as excipients in oral formulations of poorly oral-bioavailable drugs. Series of fourteen acyloxy derivatives of 5β-cholic acid as potential drug absorption modifiers was generated by multistep synthesis. The synthesis of all newly prepared compounds is presented here. Structure confirmation of all generated compounds was accomplished by (1)H NMR, (13)C NMR, IR and MS spectroscopy methods. All the prepared compounds were analyzed using RP-TLC, and their lipophilicity (R(M)) was determined. The hydrophobicity (logP) and solubility (logS) of the studied compounds were also calculated using two commercially available programs. All the target compounds were tested for their in vitro transdermal penetration activity and as potential intestinal absorption enhancers. The anti-proliferative activity of all the final compounds was also assessed against the human cancer cell lines: T-lymphoblastic leukemia cell line and the breast adenocarcinoma cell line. Their cytotoxicity was also evaluated against the normal human skin fibroblast cells. Two compounds showed anti-proliferative effect on cancer cells without affecting the growth of normal cells, which should be promising in potential development of new drugs. Most of the target compounds showed minimal anti-proliferative activity (IC(50)>37 μM), indicating they would have low cytotoxicity when administered as chemical absorption modifiers. The relationships between the lipophilicity and the chemical structure of the studied compounds as well as the relationships between their chemical structure and enhancement effects are discussed in this article.     

QSAR study on bioconcentration factor (BCF) of polyhalogented biphenyls using the PI index

Attempt has been made to estimate the accuracy, predictive power, and domain of application of the PI (Padmakar-Ivan) index for modeling bioconcentration factor (BCF) of polyhalogenated biphenyls. Relative potential of PI index is investigated by comparing the results obtained using this index with those obtained from Wiener (W) and Szeged (Sz) indices. In addition, attempt has also been made to model hydrophobicity/lipophilicity (logP) of the polyhalogenated biphenyls using these indices. It was observed that these distance-based topological indices gave better results for modeling log BCF than logP.     

Investigating biological activity spectrum for novel quinoline analogues

The lack of the wide spectrum of biological data is an important obstacle preventing the efficient molecular design. Quinoline derivatives are known to exhibit a variety of biological effects. In the current publication, we tested a series of novel quinoline analogues for their photosynthesis-inhibiting activity (the inhibition of photosynthetic electron transport in spinach chloroplasts (Spinacia oleracea L.) and the reduction of chlorophyll content in Chlorella vulgaris Beij.). Moreover, antiproliferative activity was measured using SK-N-MC neuroepithelioma cell line. We described the structure-activity relationships (SAR) between the chemical structure and biological effects of the synthesized compounds. We also measured the lipophilicity of the novel compounds by means of the RP-HPLC and illustrate the relationships between the RP-HPLC retention parameter logK (the logarithm of capacity factor K) and logP data calculated by available programs.     

Comparative structural connectivity spectra analysis (CoSCoSA) models of steroids binding to the aromatase enzyme

A method that combines NMR spectral and structural information into a constructed three-dimensional (3D)-connectivity matrix is developed for modeling biological binding activity of small molecules. The 3D-connectivity matrix for a molecule is defined by associating the distances between all possible carbon-to-carbon connections with their assigned carbon NMR chemical shifts. In this project we selected from the total 3D-connectivity matrix a subset, the two-dimensional (2D) (13)C-(13)C COSY and a theoretical long range 2D (13)C-(13)C distance connectivity spectral plane. Patterns of (13)C chemical shifts observed at these two relative distances for 50 steroids were used to produce a mathematical relationship for the steroids' relative binding affinity (pK(i)) to the aromatase enzyme. We call this technique comparative structural connectivity spectra analysis (CoSCoSA) modeling. Using combinations of the 2D COSY and 2D long-range distance spectra as modeling parameters, we built four CoSCoSA models. One model was made from the 2D COSY spectra alone and another was developed using only the 2D long-range distance spectra. Then the COSY and long-distance spectra were combined in two different ways: starting with the combined principal components (PCs) from the separately calculated COSY and distance spectra or using the combined raw spectra (3D). The best CoSCoSA model was based on the combined PCs from COSY and distance spectra. This model had an r(2) of 0.96 and a leave-one-out cross-validation (q(2)) of 0.92. In general CoSCoSA modeling combines the quantum mechanical information inherent in NMR chemical shifts with internal molecular atom-to-atom distances to give a reliable and straightforward basis for predictive modeling. The technique has the flexibility and accuracy to outperform not only the cross-validated variance q(2) of previously published quantitative structure-activity relationships (QSAR) but also those obtained by related quantitative spectral data-activity relationships (QSDARs) lacking connectivity dimensions.     

QSAR studies on 1,2-dithiole-3-thiones: modeling of lipophilicity, quinone reductase specific activity, and production of growth hormone

Studies on modeling of lipophilicity (logP) quinone reductase specific activity (logCDQR) and production of growth hormone (logCDGH) of 1,2-dithiole-3-thiones have been carried out using distance-based topological indices. The regression analysis of the data has shown that the set of compounds exhibit 'familial' relationships in that excellent results are obtained by dividing the data set into two or more classes (families).     

Biotransformation in double-phase systems: physiological responses of Pseudomonas putida DOT-T1E to a double phase made of aliphatic alcohols and biosynthesis of substituted catechols

Pseudomonas putida strain DOT-T1E is highly tolerant to organic solvents, with a logP(ow) (the logarithm of the partition coefficient of a solvent in a two-phase water-octanol system of > or =2.5. Solvent tolerant microorganisms can be exploited to develop double-phase (organic solvent and water) biotransformation systems in which toxic substrates or products are kept in the organic phase. We tested P. putida DOT-T1E tolerance to different aliphatic alcohols with a logP(ow) value between 2 and 4, such as decanol, nonanol, and octanol, which are potentially useful in biotransformations in double-phase systems in which compounds with a logP(ow) around 1.5 are produced. P. putida DOT-T1E responds to aliphatic alcohols as the second phase through cis-to-trans isomerization of unsaturated cis fatty acids and through efflux of these aliphatic alcohols via a series of pumps that also extrude aromatic hydrocarbons. These defense mechanisms allow P. putida DOT-T1E to survive well in the presence of high concentrations of the aliphatic alcohols, and growth with nonanol or decanol occurred at a high rate, whereas in the presence of an octanol double-phase growth was compromised. Our results support that the logP(ow) of aliphatic alcohols correlates with their toxic effects, as octanol (logP(ow) = 2.9) has more negative effects in P. putida cells than 1-nonanol (logP(ow) = 3.4) or 1-decanol (logP(ow) = 4). A P. putida DOT-T1E derivative bearing plasmid pWW0-xylE::Km transforms m-xylene (logP(ow) = 3.2) into 3-methylcatechol (logP(ow) = 1.8). The amount of 3-methylcatechol produced in an aliphatic alcohol/water bioreactor was 10- to 20-fold higher than in an aqueous medium, demonstrating the usefulness of double-phase systems for this particular biotransformation.     

Synthesis, lipophilicity study and in vitro evaluation of some rodenticides as acetylcholinesterase reversible inhibitors

The anti-AChE activity of phosphoramidates has been noticed for many years. Because of the wide application of phosphoramidates in recent years, there has been a continuing research for synthesis, purification and identification of effective and safe derivatives. In this study some rodenticides with the general formula Me(2)NP(O)(p-OC(6)H(4)-X)(2), where X = H, CH(3), Cl, have been synthesized in water (without organic solvent) and characterized by (31)P, (31)P {(1)H}, (13)C and (1)H NMR spectroscopy. Since lipophilicity has been recognized for its importance in QSAR studies, efforts have been made to determine the logP values. The ability of these rodenticides to inhibit human acetylcholinesterase (hAChE) has been predicted with PASS (Prediction of Activity Spectra for Substances) software (version 1.917) and then has been evaluated by a modified Ellman's assay and spectrophotometric measurements.     

Determination of the three-dimensional structure of oligosaccharides in the solid state from experimental 13C NMR data and ab initio chemical shift surfaces

A novel method for the determination of the three-dimensional (3D) structure of oligosaccharides in the solid state using experimental 13C NMR data is presented. The approach employs this information, combined with 13C chemical shift surfaces (CSSs) for the glycosidic bond carbons in the generation of NMR pseudopotential energy functions suitable for use as constraints in molecular modeling simulations. Application of the method to trehalose, cellobiose, and cellotetraose produces 3D models that agree remarkably well with the reported X-ray structures, with phi and psi dihedral angles that are within 10 degrees from the ones observed in the crystals. The usefulness of the approach is further demonstrated in the determination of the 3D structure of the cellohexaose, an hexasaccharide for which no X-ray data has been reported, as well as in the generation of accurate structural models for cellulose II and amylose V6.     

Synthesis,physico-chemical properties and penetration activity of alkyl-6-(2,5-dioxopyrrolidin-1-yl)-2-(2-oxopyrrolidin-1-yl)hexanoates as potential transdermal penetration enhancers

Skin penetration enhancers are used to allow formulation of transdermal delivery systems for drugs that are otherwise insufficiently skin-permeable. The series of seven esters of substituted 6-aminohexanoic acid as potential transdermal penetration enhancers was formed by multistep synthesis. The synthesis of all newly prepared compounds is presented here. Structure confirmation of all generated compounds was accomplished by ¹H NMR, ¹³C NMR, IR and MS spectroscopy. All the prepared compounds were analyzed using RP-HPLC method for the lipophilicity measurement and their lipophilicity (log k) was determined. Hydrophobicities (log P/C log P) of the studied compounds were also calculated using two commercially available programs and 3D structures of the selected compounds were investigated by means of ab initio/DFT calculations of geometry. All the synthesized esters were tested for their in vitro transdermal penetration enhancer activity. The relationships between the lipophilicity and the chemical structure (SLR) of the studied compounds as well as the relationships between their chemical structure and transdermal penetration activity are mentioned.     

QSAR studies on benzene sulfonamide carbonic anhydrase inhibitors: need of hydrophobic parameter for topological modeling of binding constants of sulfonamides to human CA-II

The binding constants (logK) of benzene sulfonamides to human CA-II have been modeled using a large series of distance-based topological indices. The need or otherwise of the hydrophobic parameter (logP) for such topological modeling of logK has been examined critically. In both the cases excellent results have been obtained. In multiparametric models involving indicator parameters we observed that introduction of hydrophobic parameter (logP) yields much improved statistics. The results are discussed on the basis of statistical parameters and also by using cross-validation method.