Correlation of antimutagenic activity and suppression of CYP1A with the lipophilicity of alkyl gallates and other phenolic compounds

Alkyl gallates are widely used as food antioxidants. Methyl, ethyl, propyl, lauryl, and cetyl gallates showed antimutagenicity to activated 2-aminoanthracene (2AA)-induced SOS responses in Salmonella typhimurium TA1535/pSK1002. They also exhibited a suppressive effect on 3-methylcholanthrene (3-MC)-induced cytochrome P450 1A (CYP1A) in human hepatoma HepG2 cells, as indexed by the 7-ethoxyresorufin-O-deethylase (EROD) activity, and on CYP1A protein level. Both antimutagenicity and suppression of CYP1A appeared to be dependent on alkyl chain lengths, which suggested lipophilicity dependence. Based on those results, we investigated 26 other phenolic compounds for their lipophilicity, antimutagenicity and inhibition of EROD activity. The lipophilicity correlated well with the inhibition of EROD activity (r=0.78), and the inhibition of EROD activity correlated with the antimutagenicity of those compounds (r=0.71). The results suggest that the lipophilicity of the phenolic compounds may be an important factor in their ability to inhibit EROD activity.     

On the topological evidences for modelling lipophilicity

Topological evidences for modelling lipophilicity of a large series of diversed compounds have been provided on the basis of distance-based topological indices. A pool of topological indices along with indicator parameters related to the type of the compounds present in the set of 140 compounds were used for this purpose. The results have shown that topology as well as the type of compounds are the responsible parameters for modelling lipophilicity.     

The role of lipophilicity in determining binding affinity and functional activity for 5-HT2A receptor ligands

The lipophilicity of a set of 5-HT(2A) ligands was determined using immobilized-artificial-membrane chromatography, a method that generates values well correlated with octanol-water partition coefficients. For agonists, a highly significant linear correlation was observed between binding affinity and lipophilicity. For ligands exhibiting partial agonist or antagonist properties, the lipophilicity was consistently higher than would be expected for an agonist of comparable affinity. The results suggest a possible method for distinguishing agonists from antagonists in high-throughput screening when a direct assay for functional activity is either unavailable or impractical.     

A quantitative assessment of hERG liability as a function of lipophilicity

The impact of lipophilicity as a factor contributing to hERG potency is assessed for a large dataset of compounds of differing ionisation type. This dataset is derived from compounds tested in the IonWorks-based in vitro electrophysiology hERG assay at AstraZeneca. Using logistic regression, a quantification of the risk associated with increasing lipophilicity is presented. The anticipated differences between acidic, basic and neutral compounds are apparent in the data but lipophilicity is shown to be a stronger driver for hERG potency than might have been expected. Simple rules defining target lipophilicity values for minimizing hERG liability are derived.     

Evaluation of lipophilicity and antitumour activity of parallel carboxamide libraries

Searching for molecules possessing antitumour activity, a parallel molecule library of aromatic carboxamides has been designed and synthesised. This work resulted in a "thiophene" sub-library containing a thiophene core and of a "furoyl" sub-library with a furoyl core, respectively. In both sub-libraries substitutions were carried out with six different groups resulting in six pairs of compounds differing in only the heteroatom of aromatic ring of the cores. To study the importance of the type of cores and the specific substitutions in relation to their lipophilicity and antitumour activity, lipophilicity of carboxamides was determined by chromatographical data (log k') and by software calculated parameters (CLOGP). Pairs of compounds were tested for their ability to inhibit the proliferation of the A431 cells by MTT assay. The isosteric molecule pairs were successfully separated. Our results showed that the experimentally determined (log k') and the calculated (CLOGP) lipophilicity parameters correlated well with each other. Furthermore, lipophilicity values of the thiophene sub-library were always higher than those in the furoyl sub-library. Moreover, compounds of the thiophene sub-library were more active than their respective furoyl pairs in our MTT antiproliferative assay. From these observations we can conclude that the higher the lipophilicity values the higher the antitumour activity of the carboxamides synthesised. Therefore, determination of lipophilicity by measuring the log k' or by calculating the CLOGP values of the carboxamide sub-libraries may help to predict their biological activities.     

A novel method of estimation of lipophilicity using distance-based topological indices: dominating role of equalized electronegativity

Attempt is made to propose yet another method of estimating lipophilicity of a heterogeneous set of 223 compounds. The method is based on the use of equalized electronegativity along with topological indices. It was observed that excellent results are obtained in multiparametric regression upon introduction of indicator parameters. The results are discussed critically on the basis various statistical parameters.     

Role of lipophilicity and hydrogen peroxide formation in the cytotoxicity of flavonols.

We compared the lipophilicity and toxicity of the four flavonols, galangin, kaempferol, quercetin and myricetin, which respectively have no, one, two and three hydroxyl groups on the B-ring. The lipophilicity was in the order of myricetin < quercetin < kaempferol < galangin. The cytotoxicity determined by a colony-formation assay with Chinese hamster lung fibroblast V79 cells was in the order of quercetin < kaempferol < galangin < myricetin. Apart from myricetin, the order of lipophilicity was the same as that of cytotoxicity, implying that the cytotoxicity was attributable to the lipophilicity. The cytotoxicity of myricetin was attributable to the hydrogen peroxide formed by autoxidation.     

Lipophilicity and antiproliferative activity profiling of 2-benzylidencycloalkanones

High performance liquid chromatographic (HPLC) method has been developed to separate the members of a library including 24 benzylidenecycloalkanone-type structures and to characterize their lipophilicity. The experimental lipophilicity data (k) of the compounds have been compared with their calculated lipophilicity parameters (CLOGP). In general, good correlations between the measured and calculated lipophilicities have been found and these results were in good accordance with our previously data obtained in case of structurally related molecular libraries. In addition, cytotoxicity screening has been performed to determine the antiproliferative activity of these compounds. Some of the investigated compounds possessed noticeable inhibitory potential. Based on the correlation between the antiproliferative activity and experimentally determined lipophilicity of the molecules investigated, limited structural demands to obtain more potent compounds can be exhibited to support the synthetic design.     

Relationship between lipophilicity and antitumor activity of molecule library of Mannich ketones determined by high-performance liquid chromatography, clogP calculation and cytotoxicity test

A series of Mannich ketones were synthesized in order to study the relative importance of structure and specific substitutions in relation to their lipophilicity and antitumor activity. Substitutions were carried out with morpholinyl, pirrolidinyl, piperidyl and tetrahydro-isoquinolyl groups in various positions on three different skeletons. Lipophilicity of Mannich ketones was characterised by chromatography data (log k') and by software calculated parameters (clogP). Compounds were tested on their ability to inhibit the proliferation of the A431 human adenocarcinoma cell line evaluated by MTT and apoptosis assays. The results suggest that the higher the lipophilicity values (log k' and clogP), the higher the antitumor and apoptotic activity of Mannich ketones. Determination of lipophilicity by measuring the log k' or by calculating the clogP values of the compounds may help to predict their biological activities.     

Topological modeling of lipophilicity, diuretic activity, and carbonic inhibition activity of benzene sulfonamides: a molecular connectivity approach

A large series of distance-based topological indices has been used for modeling lipophilicity, diuretic activity, and carbonic anhydrase inhibition activity of a library of simple substituted benzene sulfonamides. The results have shown that the topological approach used is quite useful for modeling carbonic anhydrase inhibition and the use of molecular connectivity is the best for this purpose. Excellent results are obtained in multiparametric regressions. The results are critically discussed on the basis of statistical parameters.     

Lipophilicity of amino acids

Summary The lipophilicity (or hydrophobicity) of amino acids is an important property relevant for protein folding and therefore of great interest in protein engineering. For peptides or peptidomimetics of potential therapeutic interest, lipophilicity is related to absorption and distribution, and thus indirectly relates to their bioactivity. A rationalization of peptide lipophilicity requires basic knowledge of the lipophilicity of the constituting amino acids. In the present contribution we will review methods to measure or calculate the lipophilicities of amino acids, including unusual amino acids, and we will make a comparison between various lipophilicity scales.     

Pyridyl-phenyl ether monoamine reuptake inhibitors: Impact of lipophilicity on dual SNRI pharmacology and off-target promiscuity

A novel series of pyridyl-phenyl ethers are disclosed, which possess dual 5-HT and NA reuptake pharmacology with good selectivity over dopamine reuptake inhibition. An analysis of the relationship between lipophilicity and pharmacology highlighted that potent dual SNRI activity was only achievable at c log P > 3.5. The series was found to possess significant polypharmacology issues, and we concluded that this off-target promiscuity was related to lipophilicity.     

Lipophilicity and the perception of bitterness

Evidence suggesting that lipophilicity is an important parameterin inducing a bitter taste is collated. The implications ofthis association are discussed and lipophilic effects used toexplain some phenomena connected with the bitterness response.Consideration of lipophilicity offers a rationale for the observedbitterness of many sweeteners at high concentration and forthe influence of hydrogen-bonding on bitterness. ^*Present address: 1 Ham Barn Cottages, Farnham Road, Liss, Hants,England.     

A method for measuring the lipophilicity of compounds in mixtures of 10

Lipophilicity is an important parameter for any potential drug candidate. Accurate and efficient lipophilicity measurements facilitate the development of high-quality predictive in silico models that support the design of future drugs. Lipophilicity estimates derived from the traditional 1-octanol/water shake flask techniques have been the most widely employed and are therefore the best understood. This technique can be considered to give a good measure of a compound's lipophilicity, albeit slower and more labor intensive to run compared with some other methodologies. Herein is described and validated an efficient 1-octanol/water shake flask technique that has sufficient capacity to be run as a primary screen within the drug discovery process. This is achieved by the simultaneous measurement of the distribution coefficients of mixtures of up to 10 compounds using high-performance liquid chromatography and tandem mass spectrometry. Concerns regarding ion pair partitioning that could result in erroneous results due to interactions between compounds within a mixture are discussed.     

Quantitative structure-activity relationships (QSARs) for inhibitors and substrates of CYP2B enzymes: importance of compound lipophilicity in explanation of potency differences

The results of quantitative structure-activity relationship (QSAR) studies on inhibitors and substrates of cytochrome P450 2B (CYP2B) subfamily enzymes are reported. It was found that lipophilicity (in the form of log P) is the most important property for explaining the variations in inhibitory activity, and there are similarities between QSARs for both substrates and inhibitors for CYP2B6 (human), and also between those of other CYP2B enzymes, such as CYP2B1 (rat) and CYP2B4 (rabbit). Both linear and quadratic lipophilicity relationships are evidenced in human and other mammalian species, and the particular type of expression found is probably due to the nature of the compounds under investigation, as it is usually the homologous series which tend to show quadratic relationships in log P. The findings from QSAR studies can be rationalized by molecular modelling of the active site interactions with both P450 crystal structures and homology models of CYP2B subfamily enzymes.     

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).