Biological activity partition coefficients

Wells, M.J.M., Clark, C.R., Patterson, R.M. (1981) Correlation of reversed-phase capacity factors for barbiturates with biological activities, partition coefficients and molecular connectivity indices. J. Chromatogr. Sci. 19, 573-582. 

M. J. M. Wells, R. C. Clark, and R. M. Patterson,/. Chromatogr. Sci., 19, 573 (1981). Correlation of Reserved-Phase Capacity Factors for Barbiturates with Biological Activities, Partition Coefficients, and Molecular Connectivity Indexes. 

The HYBOT descriptors were successfully applied to the prediction of the partition coefficient log P (>i--octanol/water) for small organic componnds with one acceptor group from their calculated polarizabilities and the free energy acceptor factor C, as well as properties like solubility log S, the permeability of drugs (Caco-2, human skin), and for the modeling of biological activities. 

The derivation of a QSAR equation involves a number of distinct stages. First, it is obviousl necessary to synthesise the compormds and determine their biological activities. Whe planning which compormds to synthesise, it is important to cover the range of propertie that may affect the activity. This means applying the data-checking and -manipulation prc cedures discussed earlier. For example, it would be unwise to make a series of coinpound with almost identical partition coefficients if this is believed to be an important property. 

Efforts have been made to correlate electronic stmcture and biological activity in the tetracycline series (60,61). In both cases, the predicted activities are of the same order as observed in vitro with some exceptions. The most serious drawback to these calculations is the lack of carryover to in vivo antibacterial activity. Attempts have also been made (62) to correlate partition coefficients and antibacterial activity. The stereochemical requirements are somewhat better defined. Thus 4-epitetracycline and 5a-epitetracycline [65517-29-5] C22H24N20g, are inactive (63). The 6-epi compound [19369-52-9] is about one-half as active as the 6a (or natural) configuration. 

C Hansch, RM Muir, T Fujita, PP Maloney, E Geiger, M Streich. The correlation of biological activity of plant growth regulators and chloromycetm derivatives with Hammett constants and partition coefficients. J Am Chem Soc 85 2817-2824, 1963. 

The toxicological or cumulative effect of illicit drugs on the ecosystems has not been studied yet. Moreover, their fate and transport in the environment is to a big extent still unknown. Due to their physical-chemical properties (octanol-water partition coefficient, solubility, etc.) some of them, such as cannabinoids, are likely to bioaccumulate in organisms or concentrate in sediments whereas the rest, much more polar compounds, will tend to stay in aqueous environmental matrices. However, continuous exposure of aquatic organisms to low aquatic concentrations of these substances, some of them still biologically active (e.g., cocaine (CO), morphine (MOR) and MDMA) may cause undesirable effects on the biota. 

In 1868 two Scottish scientists, Crum Brown and Fraser [4] recognized that a relation exists between the physiological action of a substance and its chemical composition and constitution. That recognition was in effect the birth of the science that has come to be known as quantitative structure-activity relationship (QSAR) studies a QSAR is a mathematical equation that relates a biological or other property to structural and/or physicochemical properties of a series of (usually) related compounds. Shortly afterwards, Richardson [5] showed that the narcotic effect of primary aliphatic alcohols varied with their molecular weight, and in 1893 Richet [6] observed that the toxicities of a variety of simple polar chemicals such as alcohols, ethers, and ketones were inversely correlated with their aqueous solubilities. Probably the best known of the very early work in the field was that of Overton [7] and Meyer [8], who found that the narcotic effect of simple chemicals increased with their oil-water partition coefficient and postulated that this reflected the partitioning of a chemical between the aqueous exobiophase and a lipophilic receptor. This, as it turned out, was most prescient, for about 70% of published QSARs contain a term relating to partition coefficient [9]. 

Despite the work of Overton and Meyer, it was to be many years before structure-activity relationships were explored further. In 1939 Ferguson [10] postulated that the toxic dose of a chemical is a constant fraction of its aqueous solubility hence toxicity should increase as aqueous solubility decreases. Because aqueous solubility and oil-water partition coefficient are inversely related, it follows that toxicity should increase with partition coefficient. Although this has been found to be true up to a point, it does not continue ad infinitum. Toxicity (and indeed, any biological response) generally increases initially with partition coefficient, but then tends to fall again. This can be explained simply as a reluctance of very hydrophobic chemicals to leave a lipid phase and enter the next aqueous biophase [11]. An example of this is shown by a QSAR that models toxicity of barbiturates to the mouse [12] ... 

Hansch C, Maloney PP, Fujita T. Correlation of biological activity of phenoxy-acetic acids with Hammett subsistent constants and partition coefficients. Nature 1962 194 178-80. 

Kier and coworkers found that the molecular connectivity-index and such molecular properties as polarizability, molecular volume," and partition coefficients between water and octanol"" show very good correlation. Because all of these properties could be correlated with biological activity. 

Soils and vadose zone information, including soil characteristics (type, holding capacity, temperature, biological activity, and engineering properties), soil chemical characteristics (solubility, ion specification, adsorption, leachability, cation exchange capacity, mineral partition coefficient, and chemical and sorptive properties), and vadose zone characteristics (permeability, variability, porosity, moisture content, chemical characteristics, and extent of contamination)... 

The octanol-water partition coefficient, Kow, is the most widely used descriptor of hydrophobicity in quantitative structure activity relationships (QSAR), which are used to describe sorption to organic matter, soil, and sediments [15], bioaccumulation [104], and toxicity [105 107J. Octanol is an amphiphilic bulk solvent with a molar volume of 0.12 dm3 mol when saturated with water. In the octanol-water system, octanol contains 2.3 mol dm 3 of water (one molecule of water per four molecules of octanol) and water is saturated with 4.5 x 10-3 mol dm 3 octanol. Octanol is more suitable than any other solvent system (for) mimicking biological membranes and organic matter properties, because it contains an aliphatic alkyl chain for pure van der Waals interactions plus the alcohol group, which can act as a hydrogen donor and acceptor. 

The octanol-water partition coefficient appears to correlate better with biological activity than partition coefficients in other solvent-water mixtures as, for example, hexane water, because the amphiphilic nature of octanol can accommodate a greater variety of more or less hydrophobic molecules. 

Recently, extensive research on partition coefficients has been developed in the field of medicinal chemistry because it has been observed that the action of drugs may be correlated with their partition coefficients. This parameter is an important component of structure-activity relationships (Sect. 2.2) for different series of biologically active compounds as well as for predicting environmental behavior and chemodynamics of complex mixtures [21, 62, 80-85, 88 - 90]. The octanol/water (K0Vf) system is used almost exclusively in such comparisons. 

Yonezawa, Y. and Umshigawa, Y. Chemical-biological interactions in biological pnrification systems. V. Relation between biodegradation rate constants of aliphatic alcohols by activated slndge and their partition coefficients in a 1 -octanol-water system, Chemosphere, 8(3) 139-142, 1979. 

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