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Ribonucleotide reductase (RR) is an important therapeutic target for anticancer drugs. The structure of human RR features a 1:1 complex of two homodimeric subunits, hRRM1 and hRRM2. p53R2 is a newly identified homologue of hRRM2. We have devised a holoenzyme-based in vitro assay for the determination of the potency and subunit-selectivity of small-molecule inhibitors of RR. The assay was implemented using two forms of recombinant RR (hRRM2/hRRM1 and p53R2/hRRM1) and based on their [ 3 H]CDP reduction activity. Hydroxyurea was used to standardize the assay. We found that the activities of hRRM2/hRRM1 and p53R2/hRRM1 were decreased by hydroxyurea in a dose-dependent manner. The –NH–OH segment of hydroxyurea was shown to be essential for inhibition. In the presence of Fe(III) and reductants, less inhibition of enzymatic activity by hydroxyurea was observed, especially for p53R2/hRRM1. The potency of four hydroxyurea analogues (Schiff bases of hydroxysemicarbazide, SB-HSC) decreased in the order SB-HSC 21 > SB-HSC 24 > SB-HSC 2 > hydroxyurea (HU) > SB-HSC 29. SB-HSC 2 and SB-HSC 24 inhibited p53R2/hRRM1 significantly more than hRRM2/hRRM1, whereas SB-HSC 21 and SB-HSC 29 showed low subunit-selectivity. Electron paramagnetic resonance (EPR) measurements showed that inhibition of RR was accompanied by reduction of its tyrosyl radical. The method was validated by comparison with data obtained using cell-based assays. We suggest that this novel recombinant-holoenzyme-based in vitro assay is a useful tool for the discovery of more potent and subunit-selective inhibitors of RR.

Summary Background: From the deductive point of view, neurotransmitter receptors can be divided into categories such as cholinergic (muscarinic, nicotinic), adrenergic (α- and β-), dopaminergic, serotoninergic (5-HT1∼5-HT5), and histaminergic (H1 and H2). Selective agonists and antagonists of each receptor subtype can have specific useful therapeutic applications. For understanding the molecular mechanisms of action, an inductive method of analysis is useful. Objective: The aim of the present study is to examine the structure–activity relationships of agents acting on G-protein coupled receptors. Method: Representative sets of G-PCR agonists and antagonists were identified from the literature and Medline [P.M. Walsh (2003) Physicians’ desk reference; M.J. O'Neil (2001) The Merck index]. The molecular weight (MW), calculated logarithm of octanol/water partition coefficient (C log P) and molar refraction (CMR), dipole moment (DM), Elumo (the energy of the lowest unoccupied molecular orbital, a measure of the electron affinity of a molecule and its reactivity as an electrophile), Ehomo (the energy of the highest occupied molecular orbital, related to the ionization potential of a molecule, and its reactivity as a nucleophile), and the total number of hydrogen bonds (Hb) (donors and receptors), were chosen as molecular descriptors for SAR analyses. Results: The data suggest that not only do neurotransmitters share common structural features but their receptors belong to the same ensemble of G-protein coupled receptor with seven to eight transmembrane domains with their resultant dipoles in an antiparallel configuration. Moreover, the analysis indicates that the receptor exists in a dynamic equilibrium between the closed state and the open state. The energy needed to open the closed state is provided by the hydrolysis of GTP. A composite 3-D parameter frame setting of all the neurotransmitter agonists and antagonists are presented using MW, Hb and μ as independent variables. Conclusion: It appears that all neurotransmitters examined in this study operate by a similar mechanism with the G-protein coupled receptors.

Summary Objective: A large number of structurally and functionally diverse compounds act as substrates or modulators of p-glycoprotein (p-gp). Some of them possess multiple drug resistance (MDR)-reversing activity, but only a small number of them have entered clinical study. In order to uncover the factors which exert a significant impact on the interaction between substrates/modulators and p-gp, we have performed structure–activity relationship (SAR) analyses, including molecular modelling, two-dimensional (2D) and three-dimensional (3D) parameter-frame-setting analysis, quantitative structure activity relationship (QSAR) analysis among substrates/modulators, as well as clinically promising MDR-reversing agents. Methods: The physicochemical parameters C log P, CMR and all regression equations were derived by using C log P version 4·0 and the latest CQSAR software, respectively. Molecular modelling and all other parameter calculations were performed by using HyperChem version 5·0 program, after geometry optimization and energy minimization using the AM1 semiempirical method. Results: SAR analyses indicate that MDR reversal activity is correlated with the lipophilicity (C log P), molecular weight (log Mw), longest chain (Nlc) of the molecule and the energy of the highest occupied orbital (Ehomo). In addition, the presence of a basic tertiary nitrogen atom in the structure is also an important contributor to p-gp inhibitory activity. Some separation in space is achieved for different subsets of p-gp substrates and inhibitors using Nlc, C log P and Ehomo as three independent parameters in the 3D-parameter-frame setting. Conclusion: A highly effective p-gp modulator candidate should possess a log P value of 2·92 or higher, 18-atom-long or longer molecular axis, and a high Ehomo value, as well as at least one tertiary basic nitrogen atom. The results obtained may be useful in explaining drug–p-gp interactions for different compounds, including drug interactions and the development of new MDR chemosensitizers.

Purpose. The main purpose of this study is to analyze the quantitative structure-activity relationship of two series of dihydroorotate dehydrogenase inhibitors (leflunomide and quinoline carboxylic acid analogues), and to determine the structural requirements for optimum activity of these analogues.

The theoretical basis of stereoselectivity in drug targeting in terms of eudismic ratio and quantitative structure-activity relationship has been presented. Specific examples of the advantages of using the correct stereoisomers (eutomers) rather than the distomers or racemic mixtures have been discussed. With the recent development of new methods of chiral synthesis and chiral analysis, it is not longer justifiable to continue to use racemic mixtures as therapeutic agents, unless it can be proven to be safe to do so. In the area of using peptides, proteins, glycoproteins and polysaccharides as therapeutic agents, mother nature has been very selective in choosing the optically active starting materials (Bradley, 1994), it is a necessity to design and test the proper optical isomer when a mimetic or antagonist compound is contemplated as a therapeutic agent.

The 2-hydroxy-1H-isoindole-1,3-dione (HISD) derivatives are inhibitors of ribonucleotide reductase (RR). Among the seven new compounds of the PL series, three were found to be active in cell lines sensitive (CEM/0) or resistant to ara-C (CEM/ara-C/7A; CEM/dCk[-]). The compounds PL4, PL7 and PL8 exhibited IC50 values in micromolar range against the three CEM cell lines. The 3 compounds showed 100- to 1000-fold higher cytotoxicity compared to HU against all three CEM cell lines. Combination of each of the three active PL compounds with ara-C showed high degree of synergism in comparison to the combinations of HU with ara-C against both CEM/0 and CEM/ara-C/7A cell lines. The DNA synthetic capacity of CEM/0 cells treated with 10 μM PL4 for 24 or 48 h was inhibited ≥ 99.8% simultaneously the cellular NTP pools were severely depleted. Treatment of CEM/0 cells with 10 μM PL4 showed steady depletion in all the dNTP pools at 1 or 2 h and complete depletion by 4 h. The enzyme activity did not recover up to 48 h in ...

The hydrophobicity of any peptide is a physicochemical property not only of the amino acid sequence, but also of the secondary and tertiary structure. It is also an essential factor to consider in peptide drug delivery, which has become increasingly important in recent years with the discovery of many peptides with potential pharmaceutical uses. The hydrophobicities (log P) of dito pentapeptides reported by Akamatsu and Fujita have been correlated with 12 parameters including 7 indicator variables. We have tried to simply this equation by using more common and simple parameters. Good correlations have been obtained for log P with a five-parameter equation using the sum of the hydrophobicity of component amino acids (log Paa), molecular weight (log MW), the frequency of beta-turn formation (F beta) of peptides, which is an important tertiary structural parameter, the dipole moment (mu) calculated with a computer-assisted program, and the number of amino acids in a peptide (N). This equation should be useful in drug delivery in predicting the relative hydrophobicity of new peptides with no ionizable side chains.

The parameters sometimes used to describe relative polarity of the solvents are dielectric constant (e) and partition coefficient (log P). Both of them have their limitations in terms of assessing relative solubilities of various organic/inorganic compounds in solvents commonly used. In an attempt to rectify this problem, we propose to use a new term “relative dipolarity (Dr)” which is defined as Dr = μ · M/L, and a two-dimensional Log P-Dr plot to classify all solvents from nonpolar to polar. We have found that among the single parameters examined Dr is the best single parameter to assess the relative polarity of the commonly used solvents. Dr also correlates better (than μ or e) with Log P. We have analyzed the relationship between Log P values of 25 solvents and their physicochemical parameters including molecular weight (MW), maximum hydrogen-bond ability (HBm), and either Dr, μ or e. The Log Poct/w values of 110 disubstituted benzenes are also very well correlated with parameters including MW, μ (or μ1 and μ2 of the substituent group dipole moments), HBm (or HBa as hydrogen-bond acceptor and HBd as hydrogen-bond donor).

Acquired immunodeficiency syndrome (AIDS) is an immunosuppressive disease characterized by an immune impairment and a high susceptibility to unusual forms of certain neoplasms. Since the brain is an important site of the infection, it is necessary to explore new classes of drugs that have the ability to penetrate across the blood–brain barrier, and the potency to suppress viral replication within the central nervous system (CNS). Therefore, the ability to predicate the lipophilicity of the potent anti-AIDS drugs may provide useful information about the potential of the drugs to enter CNS. In this paper, the correlations of log P (octanol-buffer partition coefficient) and log f R (retention time in HPLC; R , was used by Balzarini et al.) with some physical constants like log MW (molecular weight), hydrogen bond forming ability (HB) of the substitu- ents, and the substituent group dipole moments (s) are analyzed. Good correlations of log P and log f R with log MW, HB, and s have been obtained.

The tumor cell growth inhibitory activities (log 1/GI 50 ) of 166 anticancer agents studied at the National Cancer Institute (NCI) in vitro anticancer screening program have allowed us to analyze the relative importance of physicochemical parameters in influencing the inhibitory activities. Increased molecular weight, as measured by the logarithm of molecular weight (log MW), is found to be an important contributor to the tumor cell growth inhibitory activities. The tumor cell growth inhibitory activities in different subpanels of the tumor cells are highly inter-correlated with each other. A simple binary quantitative structure-activity relationship (QSAR) model was derived from the 166 anticancer drugs, based on the tumor cell growth inhibitory activities transformed into a binary (active or inactive) data format. The model obtained can be tested with additional new data, and may be useful to identify active compounds from a large compound library to be included in high throughput screening.

A general mathematical model involving partition coefficient, molecular weight and hydrogen bonding is used to correlate the structures and permeability of various organic compounds through the toad urinary bladder and human red blood cell (RBC) membranes. Log Per (permeability) is correlated with log Po/w (partition coefficient in olive oil/water, or ether/water), log MW (molecular weight) and Hb (hydrogen bonds). Log Po/w is the most important factor among three parameters examined. While increased MW always has a negative effect on the permeability, increased Hb can have either a slightly positive or a slightly negative effect depending on the solvent and membrane systems used. Systematic comparison of the QSAR's (quantitative structure activity relationship) of different biological membranes may serve as a useful guide in drug targeting to different tissues and cell types.

The relationships between 210 aliphatic group dipole moments (mu) and Taft polar constants (sigma *) are explored, and they are shown to be correlated by a general equation: mu = -a X sigma * -b X n' -c, where a, b, and c are constants. The value n' is a parameter reflecting the attenuating factor due to the number and electronic nature of the interval atoms between the most electronegative atom and the first atom connected to the acetate in the measurement of sigma *. The mu and sigma * values of over 214 aliphatic substituents are compiled for future correlation studies. Comparative examples using sigma * and mu in quantitative structure-activity relationships are presented.

Summary In this review a summary of the literature on the excretion of drugs in milk is reported. Because of the current trend of a return to breast-feeding and the ever-increasing number of drugs available, a thorough understanding of the potential hazard of medication to a nursing mother becomes very important for clinical pharmacists and other health professionals in advising their patients. This review focuses on the physiological and physicochemical factors affecting secretion of different types of drugs into milk. A brief discussion of the mechanisms of drug excretion is also given. Both plasma (or serum) and milk levels of various drugs reported in humans are compiled. Because of the variations in dose regimens, experimental conditions, analytical methods, and subject to subject variations, wide ranges of both plasma and milk levels have been observed for many drugs. More uniform data will be needed to allow meaningful analysis of various physicochemical models proposed to account for the milk/plasma ratio of various drugs in human subjects. Potentially adverse effects of various drugs present in human milk are presented.

The theoretical basis for using dipole moment as a free-energy related parameter in studying drug-receptor interaction and quantitative structure-activity relationship (QSAR) is presented. Over 300 group dipole moments for aromatic substituents were compiled using the dipole moments of monosubstituted benzene derivatives. Examples in the literature of using dipole moment in QSAR studies are also presented.

SUMMARY From a literature survey, over 130 (about 7·8%) drugs and chemicals have been associated with ototoxicities. The major classes are basic aminoglycoside and other antibiotics, anti-inflammatory drugs, antimalarials, β-blockers, anti-neoplastic agents, heavy metals, diuretics, some topical agents and various miscellaneous drugs. Possible mechanisms of action are presented and discussed. These include inhibition of protein synthesis, the glycolytic cycle, the TCA cycle, energy utilization, energy generation and the respiratory system within the mitochondria membrane of the hair cell, and also alteration of the permeability of the endolymphatic membrane or alteration of the excretion system for the basic aminoglycosides in the lateral wall of the membranous cochlea. The relative rank order of ototoxicity and reactivity toward mucopolysaccharides of five aminoglycosides is found to be related to the number of basic groups in each molecule.

The hydrophobicity constants (μ) of different aromatic substituents have been factored into three major components, a volume factor (MW, or Vw), an electronic factor as represented by dipole moment (μ), and H-bonding factor. The following general equation has been shown to be applicable to a wide range of nonpolar to polar substituents, with only a few notable outliers: π = a · MW (or Vw) - b · HB - c · μ + d. The usefulness and the limitations of such a general correlation are discussed.

Although relatively few systematic studies have been reported on the disposition of various toxicants or pollutants, considerable effort has been devoted to disposition studies on various drugs and simple organic molecules. Our group and others have in the last few years reported the quantitative structure-activity relationships (QSAR) on the absorption, distribution and metabolism of several series of organic compounds. The mathematical model embodies the concept of the pH partition hypothesis and the Sutherland-Einstein diffusion equation, as well as Hansch's parabolic model. For most exogenous molecules of intermediate mol wt (102 to 104), passive diffusion through the lipoprotein barrier appears to be the most important route among the known mechanisms of absorption, with an ideal lipophilic character (log P0) around 0.5 to 3. For polar and/or high mol wt compounds (>104) passage through interstitial space becomes mainly a negative function of log mol wt. High mol wt compounds and strong acids and bases (highly ionized) should not be absorbed readily based on the generalizations obtained. However, this does not eliminate the adsorption or binding of these compounds onto the membrane, or direct tissue damage caused by the strong acidity or basicity. Other mechanisms of absorption such as pinocytosis of liquid droplets and phagocytosis of solids are possible, but no quantitative data are available for analysis. Evidence is also presented to show that strong acids or bases can be absorbed as ion pairs with appropriate counter ions. Specific examples of QSAR using the following general equation and its simplified forms are presented log A = -a · (log P)2 + b · log P + c · log (U/D) + d · log mol wt + e · χ + f. The types of compounds discussed include nonelectrolytes, weak acids and bases, cationic molecules, strong acids, surfactants and some high mol wt substances. Relationships of the absorption via different routes (e.g., gastric, intestinal, percutaneous and corneal) are compared.

This report presents statistically significant empirical correlations between the potency (as expressed by log 1/C) and the molecular weight (log M.W.) of water soluble vitamins, various centrally acting drugs and anticancer agents. The implications of these correlations are discussed in terms of protein binding, renal elimination and drug-receptor binding. The limitations of this type of correlation are also presented.

A list of 37 anticancer drugs with reported carcinogenicity or co-carcinogenicity has been compiled. These drugs include 16 alkylating agents, eight antimetabolites, four antibiotics, four hormones, one alkaloid, and four miscellaneous drugs. The reported carcinogenicity of these drugs in model systems and their possible mechanisms of action are reviewed together with structure-carcinogenicity relationships. These drugs have been reported to cause cancers in different sites in various test animals. Most of these drugs react with DNA, and the ultimate reactive forms of the drugs are electrophiles.

The IR and NMR spectra of the tosylate salts of 12 new N-hydroxyguanidine derivatives are compiled. The various IR absorption peaks in KBr pellets and the chemical shifts of the aldehyde moiety of the Schiff bases of N-hydroxy-N'-aminoguanidine and the N-hydroxy-N'-aminoguanidine group of these compounds in dimethyl sulfoxide are reported.

There have been many drugs reported to cause oculotoxic responses after their systemic administration. The severity of these toxicities range from minor ocular inconvenience to permanent loss of vision. This paper reviews the current literature and attempts to suggest some probable factors involved in the development of oculotoxicities by systemic drugs. Various drug entry and exit pathways in the eye are presented and the role of some intraocular structures in the toxicity development is examined. The issues of melanin binding, genetic heterogeneity, photosensitivity and environmental pollution are discussed.

SUMMARY It is shown by means of regression analysis that the lipophilic character of the molecule as expressed by log P in octanol/water is very important in determining the relative activities of these compounds in all of the three systems examined. In addition, molecular weight is also important in some of the systems. In general, activity increases with increasing lipophilicity and molecular weight for the limited number of compounds studied. The role of degree of ionization of these acidic drugs may affect both penetration and intrinsic activity in different ways. The finding by Sheu et al., (1) that long-chain fatty acids inhibit gram-positive bacteria (Bacillus subtilis) but not gram-negative bacteria such as E. coli, due to the protective layer of lipopolysaccharide, is in agreement with the correlations obtained for many different series of antibacterial agents by Lien, Hansch & Anderson (2).

A study was conducted in which the same organic solvent, 1-octanol, and different buffer systems were used to obtain intercorrelations among log Pcorr values given by log P (octanol-water) = a log P (octanol-buffer) + b, where a and b are different constants for the different systems used. The range of a was 0.418-1.156 and that of b was -1.962-1.176 for the four buffer systems examined. Only with neutral drugs was the slope (a) close to 1.0 and the intercept (b) close to 0.0 for the three buffer systems studied. For acidic drugs, only 1-octanol-phosphate buffer gave a 1:1 correlation with 1-octanol-water partition coefficients. Acetate and bicarbonate buffer systems gave different correlations. For basic drugs, none of the three systems examined gave a 1:1 correlation with 1-octanol-water partition coefficients.

Apparent correlations are found between the N-H chemical shifts of congeneric series of compounds and the dipole moments of the molecules, such as lactams and thiolactams, cyclic ureas and thioureas. When there is a high degree of correlation, either the N-H chemical shift or the dipole moment of the molecule can be used as an electronic parameter in correlating the biological activity with the chemical structure. In a series of substituted salicylaldehydes the Hammett σ constant gives better correlation with the biological activity than the O-H chemical shift. This is probably due to the anisotropic effect of the substituent besides the electronic effect. Other factors affecting the N-H chemical shift, e.g. intramolecular hydrogen-bonding of nitrosoureas and the deshielding effect of a benzene ring, in o-phenyleneureas are also presented. In spite of the limitations, the chemical shifts of many compounds can be obtained very easily, therefore, their uses in structure-activity correlations deserv...

The apparent partition coefficients (log Kapp chloroform-water) of 48 alkylsulfates of substituted quinolinium compounds and 19 alkylsulfates of substituted pyridinium derivatives were correlated with Bondi's group contribution to the surface area (Aw × 109), Hansch's π constant, and Hammett's σ constant. The surface area of the ring substituent and the alkyl group appears to be the most important factor in governing the apparent partition coefficient. The kinetic study of the dialysis of nicotinic acid N-methyl iodide through Visking cellulose membrane showed an effective rate constant of 1.6 × 10−2 min.−1 in the first hour and a rate constant of 0.3 × 10−2 min.−1 after the first hour. The in vitro intestinal absorption of four quaternary ammonium iodides was studied. It was found that the presence of equimolar concentration of sodium decylsulfate inhibited the transfer of the quaternary ammonium compounds.

A computerized sorting program was used to sort out 120 drugs that have been reported to cause skin sensitization from a data bank of 540 clinically useful drugs. Based on an analysis of functional groups, a number of unique common denominators were found for skin sensitization due to covalent bond formation with body proteins. These include potential epoxide-forming groups such as an electron-deficient benzene ring, a vinyl group, hydroxylamine and N-oxide precursors, drugs capable of forming a benzylic radical, β-lactam derivatives, and α,β-unsaturated ketones. By using multiple-regression analysis, the quantitative structure–activity relationship for skin-sensitizing properties of 3-alkyl catechols and 2,4-dinitrobenzene derivatives are also reported.

The role of hydrophobic interactions in inhibiting the relatively specific enzymatic reactions of five enzyme systems by series of congeneric drugs has been illustrated by the use of substituent constants and regression analysis. The inhibition of lipoxygenase by alcohols, the inhibition of D-amino acid oxidase by maleimides, and the inhibition of hydroxyindole-o-methyltransferase by N-acyltryptamines are found to be linearly dependent on the lipohydrophilic character of the inhibitors (log P or π). The inhibition of carbonic anhydrase by sulfonamides is found to be linearly dependent on the log P and Hammett's σconstant. For monoamine oxidase inhibition by substituted β-carbolines, a parabolic equation of log P gives the most significant correlation. The ideal lipohydrophilic character (log Po) for maximum inhibition is found to be 2.74.

The anticonvulsant and CNS-depressant activities of 16 commercially available antiepileptics were subjected to regression analysis. For the maximal electroshock seizure test and pentylenetetrazol seizure threshold test, good correlations were obtained only after diazepam, clonazepam, and carbamazepam were deleted; for the median toxic dose (rotorod ataxia), all 16 compounds can be included in one single equation using log MW, log P, and dipole moment ( μ ) terras. For the anticonvulsant activities of 7-substituted 1,4-benzodiazepinones, a parabolic equation of π combined with the Hammett σ constant gave fair correlations for most derivatives examined in three different tests. Based upon the correlations obtained, further molecular modifications are suggested. The dipole moments of seven clinically used antiepileptic drugs were measured in 1,4-dioxane for the first time.

Data presented show that lactams, which have the resonating structure commonly associated with CNS depressants and CNS stimulants, have significant CNS activities. Results of preliminary testing show that lactams of medium ring size and lacking N-substitution are fairly potent CNS stimulants. The acute lethal toxicity (log 1/C) of four CNS stimulants of the lactam type is found to be highly correlated with log P, where P is the 1-octanol-water partition coefficient for the compound. The rate of respiration in mice depressed with sodium pentobarbital is stimulated by 2-azacyclononanone, and the rate and depth of respiration were increased by 2-azacyclooctanone in dogs anesthetized with sodium pentothal. Both 2-azacyclooctanone and 2-azacyclononanone are capable of reducing considerably the sodium pentobarbital sleeping time in mice. At higher doses, the CNS stimulant effects of these drugs are manifested by convulsions. For 2-azacyclooctanone, the convulsant ED50 is about 37 mg./kg. and the LD50 is about 300 mg./kg. Direct evidence for CNS stimulation by 2-azacyclooctanone was obtained by recording changes in EEG patterns in artificially ventilated dogs paralyzed with d-tubocurarine. Diphenylhydantoin is much less effective as an antagonist to the convulsant actions of 2-azacyclooctanone than sodium pentobarbital. This finding, taken together with the tonic-clonic convulsions produced by this drug, strongly suggests that, like nikethamide and pentylenetetrazole, the site of action for its CNS effects is subcortical and supraspinal. The conclusion is drawn that the resonating moiety shown here confers upon many compounds CNS-stimulant activities.

A strong correlation between ratios of drug metabolism by microsomal subfractions with 1-octanol/water partition coefficient was found. Explanation for the spread of ratios is presented.