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At least 55 records · Page 3Linked to original sources
PubMed2005

Organolanthanide-mediated intramolecular hydroamination/cyclization of conjugated aminodienes: a computational exploration of diverse mechanistic pathways for the regioselective generation of functionalized azacycles supported by a lanthanocene-based catalyst complex.

The complete catalytic reaction course for the organolanthanide-mediated intramolecular hydroamination/cyclization (IHC) of (4E,6)-heptadien-1-amine by a prototypical achiral Cp*(2)LaCH(TMS)(2) precatalyst is critically scrutinized by employing a gradient-corrected DFT method. The condensed free-energy profile for the overall reaction, comprised of thermodynamic and kinetic aspects of individual elementary steps, is presented. A computationally verified, revised mechanistic scenario has been proposed, which is consistent with the empirical rate law, accounts for crucial experimental observations, and provides a first understanding of the origin of the measured negative DeltaS(++). It involves rapid substrate association/dissociation equilibria and facile intramolecular diene insertion, linked to turnover-limiting protonolysis of the eta(3)-butenyl-Ln functionality, with the amine-amidodiene-Ln adduct complex representing the catalyst's resting state. The thermodynamic and kinetic factors that determine the high regio- and stereoselectivity of the mechanistically diverse IHC of aminodienes have been elucidated. These achievements allow a deeper understanding and a consistent rationalization of the experimental results for aminodiene IHC and furthermore enhance the insights into general mechanistic aspects of the organolanthanide-mediated cycloamination.

Journal Article↗
PubMed1989

Design of potential anticonvulsant agents: mechanistic classification of GABA aminotransferase inactivators.

Because of the importance of the inactivation of GABA aminotransferase to the design of anticonvulsant agents, a seemingly wide variety of inactivators has been investigated; all of the compounds, however, are analogues of GABA, beta-alanine, or delta-aminovaleric acid, which are substrates for the enzyme. Relatively minor modifications in the inactivator structures result in major differences in inactivation mechanisms and enzyme adduct structures. Compounds that inactivate GABA aminotransferase by a Michael addition mechanism, leading to modification of an active-site residue are Class I inactivators. Those that proceed by an enamine mechanism and give ternary adducts are Class II inactivators. Class III inactivators modify only the PLP cofactor; if the inactivation involves aromatization of the inactivator, it is a Class IIIA inactivation, and if no aromatization is involved, then it is a Class IIIB inactivation. The last class of inactivators (Class IV) are not classified on the basis of the mechanism, but, rather, that they require the enzyme to be in the PMP form. There appears to be no trend in partition ratio values when comparing Class I with Class II inactivators. Class III inactivations alter only the cofactor, so it may be possible for these adducts to diffuse slowly out of the active site; reactivation of the apoenzyme would require additional PLP. These inactivators also inactivate a variety of other PLP-dependent enzymes. At this point there does not seem to be a therapeutic advantage of one class of inactivators over another, although the only current example of these inactivators to be useful clinically is gamma-vinyl GABA (vigabatrin), a Class I inactivator recently approved for the drug market in France and the U.K. There is a mechanistic significance, however, for one class over another. If labeling of an active-site amino acid residue is desired, then Class I inactivators should be selected; desire for attachment of the inactivator to both the protein and the cofactor or just to the cofactor would determine whether Class II or Class III inactivators would be chosen. The classification presented here should allow us to think about inactivator structures in terms of their mechanistic potential and, as a result of this, should afford us the opportunity to be able to make predictions regarding inactivation mechanisms for hypothetical new structural classes of inactivators. Since the different mechanistic pathways lead to different types of enzyme adducts, inactivator design may be driven by the class of adduct that is desired.(ABSTRACT TRUNCATED AT 400 WORDS)

4-Aminobutyrate Transaminase↗
PubMed2005

Theoretical analysis of the high versatility in PtCl2-mediated cycloisomerization of enynes on a common mechanistic basis.

[Reaction: see text]. Transformations of enynes upon treatment with electrophilic transition-metal complexes, such as PtCl2, are strongly substrate-dependent processes and may yield a wide variety of cyclic compounds. Despite the high versatility, many of these processes could be closely related from a mechanistic point of view. Theoretical analyses of the plausible reaction mechanisms provide support for a unified mechanistic picture based on the electrophilic activation of the triple bond by the catalyst, which triggers the nucleophilic alkene attack through an endo- or exo-cyclization mode, to form the cyclopropylcarbene species. Then, these common key intermediates may evolve through alternative paths to afford a range of cyclic compounds. The preference for each path and the evolution of these intermediates are governed by the nature of the starting enyne. The effects induced by different structural motifs, such as the role played by a heteroatom directly attached to the triple bond, the tether length, the substitution on the acetylenic position, and the gem-dialkyl substitution on the tether, among others, are discussed. The proposed common mechanistic scheme can rationalize and account for the experimental observations accumulated.

Alkynes↗
PubMed2006

Chiral phosphoramide-catalyzed aldol additions of ketone trichlorosilyl enolates. Mechanistic aspects.

The mechanism of the catalytic, enantioselective addition of trichlorosilyl enolates to aldehydes has been investigated. Kinetic studies using ReactIR and rapid injection NMR (RINMR) spectroscopy have confirmed the simultaneous operation of dual mechanistic pathways involving either one or two phosphoramides bound to a siliconium ion organizational center. This mechanistic dichotomy was initially postulated on the basis of catalyst loading studies and nonlinear effects studies. This duality explains the difference in reactivity and stereoselectivity of various classes of phosphoramides. Determination of Arrhenius activation parameters revealed that aldol addition occurs through the reversible albeit unfavorable formation of an activated complex, and natural-abundance 13C NMR kinetic isotope effect (KIE) studies have determined that the turnover limiting step is the aldol addition. A thorough examination of a range of phosphoramides has established empirical structure-activity selectivity relationships. In addition, the effects of catalyst loading, rate of addition, solvents, and additives have been studied and together allow the formulation of a unified mechanistic picture for the aldol addition.

Journal Article↗
PubMed2007

Electrophilic chemistry related to skin sensitization. Reaction mechanistic applicability domain classification for a published data set of 106 chemicals tested in the mouse local lymph node assay.

This article presents an overview of electrophilic reaction mechanisms relevant to skin sensitization, with reference to a published skin sensitization test data set for 106 chemicals. Where appropriate to aid the interpretation, additional data on a small number of further compounds are also discussed. It is shown that there is a close correspondence in the way differences and similarities in skin sensitization potency of chemicals relate to differences and similarities in their physical organic chemistry and electrophilic reaction mechanistic chemistry. The 106 chemicals are classified into their reaction mechanistic applicability domains, and reactivity-sensitization trends are analyzed for each domain: the Michael acceptor and pro-Michael acceptor electrophile domain; the SNAr electrophile domain; the SN2 electrophile domain; the Schiff base electrophile domain; the acyl transfer electrophile domain; and the non-electrophilic non-pro-electrophilic domain. The last of these domains should be populated mainly by non-sensitizers. Classification of 87 of the 106 compounds, using these domains, was straightforward. In most of the domains and subdomains where there are sufficient compounds, clear trends can be seen, in conformity with the Relative Alkylation Index (RAI) model, between sensitization potential and reactivity/hydrophobicity. Of the remaining 19 compounds, 7 are alpha-X-methyl-gamma-lactones that on the basis of published organic chemistry studies and guinea pig sensitization data can be classed as pro-Michael acceptors by elimination of HX but that are mostly negative in the LLNA, indicating a difference in bioactivation capabilities between mice and guinea pigs. The other 12 compounds, whose chemistry was not immediately obvious, were found after further analysis and literature research to fit into appropriate mechanistic domains that rationalize their skin sensitizing properties.

Animals↗
PubMed2003

Mechanistic models for myelosuppression.

As myelosuppression is the dose-limiting toxicity for most chemotherapeutic drugs, modelers attempt to find relationships between drug and toxicity to optimize treatment. Mechanistic models, i.e. models based on physiology and pharmacology, are preferable over empirical models, as prior information can be utilized and as they generally are more reliable for extrapolations. To account for different dosing-regimens and possible schedule-dependent effects, the whole concentration-time profile should be used as input into the pharmacokinetic-pharmacodynamic model. It is also of importance to model the whole time course of myelosuppression to be able to predict both the degree and duration of toxicity as well as consecutive courses of therapy. A handful of (semi)-mechanistic pharmacokinetic-pharmacodynamic models with the above properties have been developed and are reviewed. Ideally, a model of myelosuppression should separate drug-specific parameters from system related parameters to be applicable across drugs and useful under different clinical settings. Introduction of mechanistic models of myelosuppression in the design and evaluation of clinical trials can guide in the decision of optimal sampling times, contribute to knowledge of optimal doses and treatment regimens at an earlier time point and identify sub-groups of patients at a high risk of myelosuppression.

Animals↗
PubMed2003

A rational approach to personalized anticancer therapy: chemoinformatic analysis reveals mechanistic gene-drug associations.

PURPOSE: To predict the response of cells to chemotherapeutic agents based on gene expression profiles, we performed a chemoinformatic study of a set of standard anticancer agents assayed for activity against a panel of 60 human tumor-derived cell lines from the Developmental Therapeutics Program (DTP) at the National Cancer Institute (NCI). METHODS: Mechanistically-relevant gene:drug activity associations were identified in the scientific literature. The correlations between expression levels of drug target genes and the activity of the drugs against the NCI's 60 cell line panel were calculated across and within each tumor tissue type, using published drug activity and gene expression data. RESULTS: Compared to other mechanistically-relevant gene-drug associations, that of triciribine phosphate (TCN-P) and adenosine kinase (ADK) was exceptionally strong--overall and within tumor tissue types-across the 60 cell lines profiled for chemosensitivity (1) and gene expression (2). CONCLUSION: The results suggest ADK expression may be useful for stratifying TCN-P-responsive vs. non-responsive tumors. Based on TCN-P's mechanism of action and the observed TCN-P:ADK association, we contend that catalytic drug activation provides a rational, mechanistic basis for personalizing cancer treatment based on tumor-specific differences in the expression of drug-activating enzymes.

Acenaphthenes↗
PubMed2003

Mechanistic fracture criteria for the failure of human cortical bone.

A mechanistic understanding of fracture in human bone is critical to predicting fracture risk associated with age and disease. Despite extensive work, a mechanistic framework for describing how the microstructure affects the failure of bone is lacking. Although micromechanical models incorporating local failure criteria have been developed for metallic and ceramic materials, few such models exist for biological materials. In fact, there is no proof to support the widely held belief that fracture in bone is locally strain-controlled, as for example has been shown for ductile fracture in metallic materials. In the present study, we provide such evidence through a novel series of experiments involving a double-notch-bend geometry, designed to shed light on the nature of the critical failure events in bone. We examine how the propagating crack interacts with the bone microstructure to provide some mechanistic understanding of fracture and to define how properties vary with orientation. It was found that fracture in human cortical bone is consistent with strain-controlled failure, and the influence of microstructure can be described in terms of several toughening mechanisms. We provide estimates of the relative importance of these mechanisms, such as uncracked-ligament bridging.

Bone and Bones↗
PubMed1997

Oxidation process of bovine heart ubiquinol-cytochrome c reductase as studied by stopped-flow rapid-scan spectrophotometry and simulations based on the mechanistic Q cycle model.

Stopped-flow rapid-scan spectrophotometry was employed to study complicated oxidation processes of ubiquinol-cytochrome c reductase (QCR) that was purified from bovine heart mitochondria and maximally contained 0.36 mol of ubiquinone-10/mol of heme c1. When fully reduced QCR was allowed to react with dioxygen in the presence of cytochrome c plus cytochrome c oxidase, the oxidation of b-type hemes accompanied an initial lag, apparently low potential heme bL was oxidized first, followed by high potential heme bH. Antimycin A inhibited the oxidation of both b-type hemes. The oxidation of heme c1 was triphasic and became biphasic in the presence of antimycin A. On the other hand, starting from partially reduced QCR that was poised at a higher redox potential with succinate and succinate-cytochrome c reductase, the b-type hemes were oxidized immediately without a lag. When the ubiquinone content in QCR was as low as 0.1 mol/mol heme c1 the oxidation of the b-type hemes was almost suppressed. As the Q-deficient QCR was supplemented with ubiquinol-2, the rapid oxidation of b-type hemes was restored to some extent. These results indicate that a limited amount of ubiquinone-10 found in purified preparations of QCR is obligatory for electron transfer from the b-type hemes to iron-sulfur protein (ISP) and heme c1. The characteristic oxidation profiles of heme bL, heme bH, and heme c1 were simulated successfully based on a mechanistic Q cycle model. According to the simulations the two-electron oxidation of ubiquinol-10 via the ISP and heme c1 pathway, which is more favorable thermodynamically than the bifurcation of electron flow into both ISP and heme bL, does really occur as long as heme bL is in the reduced state and provides ubiquinone-10 at center i. Mechanistically this process takes time, thus explaining the initial lag in the oxidation of the b-type hemes. With the partially reduced QCR, inherent ubisemiquinone at center i immediately oxidizes reduced heme bH thus eliminating the lag. The mechanistic Q cycle model consists of 56 reaction species, which are interconnected by the reaction paths specified with microscopic rate constants. The simulations further indicate that the rate constants for electron transfer between the redox centers can be from 10(5) to 10(3) s-1 and are rarely rate-limiting. On the other hand, a shuttle of ubiquinone or ubiquinol between center o and center i and the oxidation of heme c1 can be rate-limiting. The interplay of the microscopic rate constants determines the actual reaction pathway that is shown schematically by the "reaction map." Most significantly, the simulations support the consecutive oxidation of ubiquinol in center o as long as both heme bL and heme bH are in the reduced state. Only when heme bL is oxidized and ISP is reduced can SQo donate an electron to heme bL. Thus, we propose that a kinetic control mechanism, or "a kinetic switch," is significant for the bifurcation of electron flow.

Animals↗
PubMed2003

Mechanistic characterization of a bacterial malonate semialdehyde decarboxylase: identification of a new activity on the tautomerase superfamily.

Malonate semialdehyde decarboxylase (MSAD) has been identified as the protein encoded by the orf130 gene from Pseudomonas pavonaceae 170 on the basis of the genomic context of the gene as well as its ability to catalyze the decarboxylation of malonate semialdehyde to generate acetaldehyde. The enzyme is found in a degradative pathway for the xenobiotic nematocide trans-1,3-dichloropropene. MSAD has no sequence homology to previously characterized decarboxylases, but the presence of a conserved motif (Pro1-(X)8 -Gly-Arg11-X-Asp-X-Gln) in its N-terminal region suggested a relationship to the tautomerase superfamily. Sequence analysis identified Pro1 and Arg75 as potential active site residues that might be involved in the MSAD activity. The results of site-directed mutagenesis experiments confirmed the importance of these residues to activity and provided further evidence to implicate MSAD as a new member of the tautomerase superfamily. MSAD is the first identified decarboxylase in the superfamily and is possibly the first characterized member of a new and distinct family within this superfamily. Malonate semialdehyde is analogous to a beta-keto acid, and enzymes that catalyze the decarboxylation of these acids generally utilize metal ion catalysis, a Schiff base intermediate, or polarization of the carbonyl group by hydrogen bonding and/or electrostatic interactions. A mechanistic analysis shows that the rate of the reaction is not affected by the presence of a metal ion or EDTA while the incubation of MSAD with the substrate in the presence of sodium cyanoborohydride results in the irreversible inactivation of the enzyme. The site of modification is Pro1. These observations are consistent with the latter two mechanisms, but do not exclude the first mechanism. Based on the sequence analysis, the outcome of the mutagenesis and mechanistic experiments, and the roles determined for Pro1 and the conserved arginine in all tautomerase superfamily members characterized thus far, two mechanistic scenarios are proposed for the MSAD-catalyzed reaction in which Pro1 and Arg75 play prominent roles.

Aldehyde Oxidoreductases↗
PubMed2007

The application of a Bayesian approach to the analysis of a complex, mechanistically based model.

The Bayesian approach has been suggested as a suitable method in the context of mechanistic pharmacokinetic-pharmacodynamic (PK-PD) modeling, as it allows for efficient use of both data and prior knowledge regarding the drug or disease state. However, to this day, published examples of its application to real PK-PD problems have been scarce. We present an example of a fully Bayesian re-analysis of a previously published mechanistic model describing the time course of circulating neutrophils in stroke patients and healthy individuals. While priors could be established for all population parameters in the model, not all variability terms were known with any degree of precision. A sensitivity analysis around the assigned priors used was performed by testing three different sets of prior values for the population variance terms for which no data were available in the literature: "informative", "semi-informative", and "noninformative", respectively. For all variability terms, inverse gamma distributions were used. It was possible to fit the model to the data using the "informative" priors. However, when the "semi-informative" and "noninformative" priors were used, it was impossible to accomplish convergence due to severe correlations between parameters. In addition, due to the complexity of the model, the process of defining priors and running the Markov chains was very time-consuming. We conclude that the present analysis represents a first example of the fully transparent application of Bayesian methods to a complex, mechanistic PK-PD problem with real data. The approach is time-consuming, but enables us to make use of all available information from data and scientific evidence. Thereby, it shows potential both for detection of data gaps and for more reliable predictions of various outcomes and "what if" scenarios.

Algorithms↗
PubMed1999

Chemical diversity approach for evaluating mechanistic relatedness among toxicological phenomena.

The CASE/MULTICASE structure-activity relationship (SAR) system was used to assess a new procedure to investigate the mechanistic relatedness of various toxicological endpoints. The method consisted of predicting the activity of 10,000 randomly selected chemicals using validated and characterized SAR models from a variety of biological and toxicological endpoints. The prevalence of chemicals predicted to possess the ability to induce two or more toxicological effects simultaneously should provide a measure of the mechanistic relatedness of these phenomena. Eight toxicological endpoints were predicted and the results were compared to predictions based on an eye irritation SAR model. Allergic contact dermatitis demonstrated a 29.6% greater than expected overlap between expected and observed results (p < 0.001). Similar results were seen for respiratory hypersensitivity (33.1%), sensory irritation (28.9%), cell toxicity (25.9%), and Ah receptor binding (19.8%). A lesser degree of overlap was seen between eye irritation and Salmonella mutagenicity (11.5%) and the inhibition of gap junction intercellular communication (6.7%). Moreover, a negative overlap, suggesting possibly an antagonistic phenomena, was observed between eye irritation and alpha 2 mu-induced nephropathy. These results indicate that this method can provide a useful tool to investigate mechanistic relatedness between diverse toxicological endpoints.

Animals↗
PubMed2005

Mechanistic analytical models for long-distance seed dispersal by wind.

We introduce an analytical model, the Wald analytical long-distance dispersal (WALD) model, for estimating dispersal kernels of wind-dispersed seeds and their escape probability from the canopy. The model is based on simplifications to well-established three-dimensional Lagrangian stochastic approaches for turbulent scalar transport resulting in a two-parameter Wald (or inverse Gaussian) distribution. Unlike commonly used phenomenological models, WALD's parameters can be estimated from the key factors affecting wind dispersal--wind statistics, seed release height, and seed terminal velocity--determined independently of dispersal data. WALD's asymptotic power-law tail has an exponent of -3/2, a limiting value verified by a meta-analysis for a wide variety of measured dispersal kernels and larger than the exponent of the bivariate Student t-test (2Dt). We tested WALD using three dispersal data sets on forest trees, heathland shrubs, and grassland forbs and compared WALD's performance with that of other analytical mechanistic models (revised versions of the tilted Gaussian Plume model and the advection-diffusion equation), revealing fairest agreement between WALD predictions and measurements. Analytical mechanistic models, such as WALD, combine the advantages of simplicity and mechanistic understanding and are valuable tools for modeling large-scale, long-term plant population dynamics.

Models, Theoretical↗
PubMed2001

Mechanistic considerations in small fish carcinogenicity testing.

Historically, small fish species have proven useful both as environmental sentinels and as versatile test animals in toxicity and carcinogenicity bioassays. They can be bred in large numbers, have low maintenance and bioassay costs, and have a low background incidence of tumors. However, more mechanistic information is needed to help validate the information garnered from these models and to keep pace with other more fully developed animal models. This paper focuses on mechanistic considerations when using small fish models for carcinogenicity testing. Several small aquarium fish species have proven useful. The Japanese medaka is perhaps the best characterized small fish model for carcinogenicity testing; however, the zebrafish is emerging as an important model because it is well characterized genetically. Both route and methodology of exposure may affect the outcome of the study. Most studies have been conducted by introducing the test compound into the ambient water, but dietary exposures and embryo microinjection have also been used. Other considerations in study design include use of an initiating carcinogen, such as diethlynitrosamine, and differences in xenobiotic metabolism, such as the fact that fish CYP2B is refractory to phenobarbital induction. The small size of these models has perhaps limited some types of mechanistic studies, such as formation and repair of DNA adducts in response to carcinogen exposure. However, improved analytical methods are allowing greater resolution and should be applied to small fish species. Slide-based methods such as immunohistochemistry are an important adjunct to routine histopathology and should be included in study design. However, there is a need for development of more species-specific antibodies for fish research. There is also a need for more fish-specific data on cytokines, serum biochemistry, and oncogenes to strengthen the use of these important test models.

Animals↗
PubMed2001

Applications of mechanistic data in risk assessment: the past, present, and future.

Mechanistic data, when available, have long been considered in risk assessment, such as in the development of the nitrate RfD based on effects in a sensitive group (infants). Recent advances in biology and risk assessment methods have led to a tremendous increase in the use of mechanistic data in risk assessment. Toxicokinetic data can improve extrapolation from animals to humans and characterization of human variability. This is done by the development of improved tissue dosimetry, by the use of uncertainty factors based on chemical-specific data, and in the development of physiologically based pharmacokinetic (PBPK) models. The development of the boron RfD illustrates the use of chemical-specific data in the improved choice of uncertainty factors. The draft cancer guidelines of the U.S. Environmental Protection Agency emphasize the use of mode of action data. The first choice under the guidelines is to use a chemical-specific, biologically based dose-response (BBDR) model. In the absence of a BBDR model, mode of action data are used to determine whether low-dose extrapolation is done using a linear or nonlinear (margin of exposure) approach. Considerations involved in evaluating a hypothesized mode of action are illustrated using 1,3-dichloropropene, and use of a BBDR model is illustrated using formaldehyde. Recent developments in molecular biology, including transgenic animals, microarrays, and the characterization of genetic polymorphisms, have significant potential for improving risk assessments, although further methods development is needed. Overall, use of mechanistic data has significant potential for reducing the uncertainty in assessments, while at the same time highlighting the areas of uncertainty.

Allyl Compounds↗
PubMedDate not supplied

The Newtonian mechanistic paradigm, special education, and contours of alternatives: an overview.

The concept of paradigm as a set of ontological and epistemological benchmarks is the basis for a discussion of the influence the Newtonian mechanistic paradigm has exerted over special education theory, research, and practice. Discussions of "malcontents" with the mechanistic paradigm across the social sciences and within special education are noted. Recent literature in the field of special education is critiqued for renaming theories as paradigms, thereby leaving mechanistic assumptions in place. The contours are then drawn of theoretical reorientations and of the emerging alternative holistic paradigm and its importance for special education. It is concluded that we do not have paradigms or paradigm shifts within the field, but that the field is part of a paradigm that is undergoing change across the sciences and social sciences.

Child↗
PubMed1999

Comparative analyses of mechanistic differences among antiestrogens.

Antiestrogens such as tamoxifen are one of the most effective methods of treating estrogen receptor (ERalpha) positive breast cancers; however, the effectiveness of this therapy is limited by the almost universal development of resistance to the drug. If antiestrogens are recognized differently by the cell as it has been suggested, then in disease conditions where tamoxifen fails to function effectively, a mechanistically different antiestrogen might yield successful results. Although many antiestrogens have been developed, a direct comparison of their mechanisms of action is lacking, thus limiting their utility. Therefore, to determine if there are mechanistic differences among available antiestrogens, we have carried out a comprehensive analysis of the molecular mechanisms of action of 4-hydroxy-tamoxifen (40HT), idoxifene, raloxifene, GW7604, and ICI 182,780. Using a novel set of peptides that recognize different surfaces on ERalpha, we have found that following binding to ERalpha, each ligand induces a distinct ERalpha-ligand conformation. Furthermore, transcriptional assays indicate that each ERalpha-ligand complex is recognized distinctly by the transcription machinery, and consequently, antiestrogens vary in their ability to inhibit estradiol- and 40HT-mediated activities. Relative binding assays have shown that the affinity of these ligands for ERalpha is not always representative of their inhibitory activity. Using this assay, we have also shown that the pharmacology of each antiestrogen is influenced differently by hormone binding proteins. Furthermore, GW7604, like ICI 182,780, but unlike the other antiestrogens evaluated, decreases the stability of the receptor. Overall, our results indicate that there are clear mechanistic distinctions among each of the antiestrogens studied. However, GW7604 and ICI 182,780 differ more significantly from tamoxifen than idoxifene and raloxifene. These data, which reveal differences among antiestrogens, should assist in the selection of compounds for the clinical regulation of ERalpha function.

Blood Proteins↗
PubMed1985

Computer-assisted mechanistic structure-activity studies: application to diverse classes of chemical carcinogens.

In the first part of this paper we have indicated how the techniques and capabilities of theoretical chemistry, together with experimental results, can be used in a mechanistic approach to structure-activity studies of toxicity. In the second part, we have illustrated how this computer-assisted approach has been used to identify and calculate causally related molecular indicators of relative carcinogenic activity in five classes of chemical carcinogens: polycyclic aromatic hydrocarbons and their methyl derivatives, aromatic amines, chloroethanes, chloroalkenes and dialkyl nitrosamines. In each class of chemicals studied, candidate molecular indicators have been identified that could be useful in predictive screening of unknown compounds. In addition, further insights into some mechanistic aspects of chemical carcinogenesis have been obtained. Finally, experiments have been suggested to both verify the usefulness of the indicators and test their mechanistic implications.

Amines↗