N-Alkyl barbiturates. A series of compounds for the study of metabolic structure-activity relationships

Many therapeutic agents are metabolised along multiple pathways, but up to now there have been few investigations addressing the question of which chemical features of drugs govern the participation in, and quantitative significance of, different biotransformation pathways. To assess the influence of variations of the chemical structure upon metabolism, a series of novel barbiturate analogues has been synthesized. The N1-monoalkylated and N1,N2-dialkylated phenobarbitones and 2-desoxyphenobarbitones have been synthesized via condensation of ethylphenylmalonic acid derivatives with different N-alkylated ureas or thioureas, and/or by base-catalyzed N-alkylation of different barbituric acids.     

Quantitative structure-activity relationships for gammadelta T cell activation by bisphosphonates

gammadelta T cells are the first line of defense against many infectious organisms and are also involved in tumor cell surveillance and killing. They are stimulated by a broad range of small, phosphorus-containing antigens (phosphoantigens) as well as by the bisphosphonates commonly used in bone resorption therapy, such as pamidronate and risedronate. Here, we report the activation of gammadelta T cells by a broad range of bisphosphonates and develop a pharmacophore model for gammadelta T cell activation, in addition to using a comparative molecular similarity index analysis (CoMSIA) approach to make quantitative relationships between gammadelta T cell activation by bisphosphonates and their three-dimensional structures. The CoMSIA analyses yielded R(2) values of approximately 0.8-0.9 and q(2) values of approximately 0.5-0.6 for a training set of 45 compounds. Using an external test set, the activities (IC(50) values) of 16 compounds were predicted within a factor of 4.5, on average. The CoMSIA fields consisted of approximately 40% hydrophobic, approximately 40% electrostatic, and approximately 20% steric interactions. Since bisphosphonates are known to be potent, nanomolar inhibitors of the mevalonate/isoprene pathway enzyme farnesyl pyrophosphate synthase (FPPS), we also compared the pharmacophores for gammadelta T cell activation with those for FPPS inhibition, using the Catalyst program. The pharmacophores for gammadelta T cell activation and FPPS inhibition both consisted of two negative ionizable groups, a positive charge feature and an endocyclic carbon feature, all having very similar spatial dispositions. In addition, the CoMSIA fields were quite similar to those found for FPPS inhibition by bisphosphonates. The activities of the bisphosphonates in gammadelta T cell activation were highly correlated with their activities in FPPS inhibition: R = 0.88, p = 0.002, versus a human recombinant FPPS (N = 9 compounds); R = 0.82, p < 0.0001, for an expressed Leishmania major FPPS (N = 45 compounds). The bisphosphonate gammadelta T cell activation pharmacophore differs considerably, however, from that reported previously for gammadelta T cell activation by phosphoantigens (Gossman, W.; Oldfield, E. J. Med. Chem. 2002, 45, 4868-4874), suggesting different primary targets for the two classes of compounds. The ability to quite accurately predict the activity of bisphosphonates as gammadelta T cell activators by using 3D QSAR techniques can be expected to help facilitate the design of additional bisphosphonates for potential use in immunotherapy.     

Cytotoxicity of furoxans: quantitative structure-activity relationships study

Furoxans are interesting biological active compounds. Recent studies demonstrate that they are cytotoxic under aerobic conditions. This paper shows that this cytotoxicity could be related with E(LUMO), calculated LogP and Mulliken charge on heterocycle nitrogen 2 calculated at ab initio level (3-21G* basis). It was possible to propose a tentative mechanism of cytotoxicity and structural modifications to modulate the cytotoxic potency of furoxan derivatives.     

Aziridinyldinitrobenzamides: synthesis and structure-activity relationships for activation by E. coli nitroreductase

The 5-aziridinyl-2,4-dinitrobenzamide CB 1954 is a substrate for the oxygen-insensitive nitroreductase (NTR) from E. coli and is in clinical trial in combination with NTR-armed adenoviral vectors in a GDEPT protocol; CB 1954 is also of interest for selective deletion of NTR-marked cells in normal tissues. Since little further drug development has been carried out around this lead, we report here the synthesis of more soluble variants and regioisomers and structure-activity relationship (SAR) studies. The compounds were primarily prepared from the corresponding chloro(di)nitroacids through amide side chain elaboration and subsequent aziridine formation. One-electron reduction potentials [E(1)], determined by pulse radiolysis, were around -400 mV, varying little for aziridinyldinitrobenzamide regioisomers. Cytotoxicity in a panel of NTR-transfected cell lines showed that in the CB 1954 series there was considerable tolerance of substituted CONHR side chains. The isomeric 2-aziridinyl-3,5-dinitrobenzamide was also selective toward NTR+ve lines but was approximately 10-fold less potent than CB 1954. Other regioisomers were too insoluble to evaluate. While CB 1954 gave both 2- and 4-hydroxylamine metabolites in NTR+ve cells, related analogues with substituted carboxamides gave only a single hydroxylamine metabolite possibly because the steric bulk in the side chain constrains binding within the active site. CB 1954 is also a substrate for the two-electron reductase DT-diaphorase, but all of the other aziridines (regioisomers and close analogues) were poorer substrates with resulting improved specificity for NTR. Bystander effects were determined in multicellular layer cocultures and showed that the more hydrophilic side chains resulted in a modest reduction in bystander killing efficiency. A limited number of analogues were tested for in vivo activity, using a single ip dose to CD-1 nude mice bearing WiDr-NTR(neo) tumors. The most active of the CB 1954 analogues was a diol derivative, which showed a substantial median tumor growth delay (59 days compared with >85 days for CB 1954) in WiDr xenografts comprising 50% NTR+ve cells. The diol is much more soluble and can be formulated in saline for administration. The results suggest there may be advantages with carefully selected analogues of CB 1954; the weaker bystander effect of its diol derivative may be an advantage in the selective cell ablation of NTR-tagged cells in normal tissues.     

Bioreductive activation of a series of indolequinones by human DT-diaphorase: structure-activity relationships.

A series of indolequinones including derivatives of EO9 bearing various functional groups and related indole-2-carboxamides have been studied with a view to identifying molecular features which confer substrate specificity for purified human NAD(P)H:quinone oxidoreductase (DT-diaphorase), bioreductive activation to DNA-damaging species, and selectivity for DT-diaphorase-rich cells in vitro. A broad spectrum of substrate specificity exists, but minor changes to the indolequinone nucleus have a significant effect upon substrate specificity. Modifications at the 2-position are favorable in terms of substrate specificity as these positions are located at the binding site entrance as determined by molecular modeling studies. In contrast, substitutions at the (indol-3-yl)methyl position with bulky leaving groups or a group containing a chlorine atom result in compounds which are poor substrates, some of which inactivate DT-diaphorase. Modeling studies demonstrate that these groups sit close to the mechanistically important amino acids Tyr 156 and His 162 possibly resulting in either alkylation within the active site or disruption of charge-relay mechanisms. An aziridinyl group at the 5-position is essential for potency and selectivity to DT-diaphorase-rich cells under aerobic conditions. The most efficient substrates induced qualitatively greater single-strand DNA breaks in cell-free assays via a redox mechanism involving the production of hydrogen peroxide (catalase inhibitable). This damage is unlikely to form a major part of their mechanism of action in cells since potency does not correlate with extent of DNA damage. In terms of hypoxia selectivity, modifications at the 3-position generate compounds which are poor substrates for DT-diaphorase but have high hypoxic cytotoxicity ratios.     

Oximes: metabolic activation and structure-allergenic activity relationships

Metabolic activation of chemicals (prohaptens) in the skin can cause allergic contact dermatitis. We have explored structure-allergenic activity relationships for seven potential oxime prohaptens using the local lymph node assay and a GSH trapping screen with liver microsomes. The general structure-allergenic activity relationships found were that an alpha,beta-unsaturation is necessary for an oxime to be a prohapten and that increased steric hindrance around this double bond leads to reduction in sensitizing capacity. We also found that sensitizing oximes can be distinguished in vitro from nonsensitizers by monitoring of mono-oxidized (+16 Da) GSH conjugates in the GSH trapping screen. However, care should be taken when interpreting data from GSH trapping screens, as nonsensitizers may also form GSH conjugates via alternative mechanisms. This investigation emphasizes the importance of considering cutaneous bioactivation in toxicity assessment of chemicals used in contact with the skin.     

Electronic-topological study of the structure-activity relationships in a series of piperidine morphinomimetics

Structure-activity relationships (SAR) are studied in the series of 4,4-disubstituted piperidine morphinomimetics (42 compounds) by means of the Electronic-Topological Method (ETM). In the frameworks of this approach, its input data were taken as the results of conformational and quantum-mechanical calculations. These calculations had been carried out for all compounds from the series under study, taking into account their neutral and protonated by the nitrogen of piperidine cycle forms. The ETM application resulted in a set of pharmacophores and anti-pharmacophores, which formed a basis of a system used to predict analgesic activity. First of all, the system was tested on known analgesics. Testing has shown a good agreement with the experimental data. Then, the system was applied to a few compounds with similar structures but unknown activity. The results of the study could be used for computer screening and design of novel compounds with analgesics properties as new potential drugs.     

Prostacyclin-dependent activation of adenylate cyclase in a neuronal somatic cell hybrid: prostanoid structure-activity relationships.

1 Prostacyclin activates adenylate cyclase of the NCB-20 neuronal hybrid cell line. 2 There is a guanosine 5'-triphosphate requirement for the activation of adenylate cyclase by 5,6 beta-dihydroprostacyclin (a stable analogue of prostacyclin). 3 Steady-state kinetic analysis of the activation of adenylate cyclase by 5,6 beta-dihydroprostacyclin suggests a simple non-cooperative bimolecular interaction between the ligand and single receptor population. 4 Structure-activity relationships of selected prostanoids elucidated certain functional requirements for activation of adenylate cyclase.     

Progress with peptide scanning to study structure-activity relationships: the implications for drug discovery

ABSTRACT

Introduction: Peptides have gained renewed interest as candidate therapeutics. However, to bring them to a broader clinical use, challenges such as the rational optimization of their pharmacological properties remain. Peptide scanning techniques offer a systematic framework to gain information on the functional role of individual amino acids of a peptide. Due to progress in mastering new chemical synthesis routes targeting amino acid backbone, they are currently diversified. Structure-activity relationship (SAR) analyses such as alanine- or enantioneric- scanning can now be supplemented by N-substitution, lactam cyclisation- or aza-amino scanning procedures addressing not only SAR considerations but also the peptide pharmacological properties.

Areas covered: This review highlights the different scanning techniques currently available and illustrates how they can impact drug discovery.

Expert opinion: Progress in peptide scanning techniques opens new perspectives for peptide drug development. It comes with the promise of a paradigm change in peptide drug design in which peptide drugs will be closer to the parent peptides. However, scanning still remains assimilable to a trial and error strategy that could benefit from being combined with specific in silico approaches that start reaching maturity.     

他汀类化合物构效关系研究进展

他汀类化合物是羟甲戊二酰辅酶A还原酶(HMGR)抑制剂,能够调节血浆中低密度脂蛋白胆固醇(LDL-C)水平。由于他汀类化合物安全有效,不良反应少,已成为目前临床上治疗高血脂症的首选药物。开发结构简单且安全有效的他汀类化合物一直是降血脂药物研究的热点。本文对近年他汀类化合物的母环和侧链两方面的构效关系进行综述。     

Chemical potentials of solutes and quantitative structure-activity relationships: study in a series of barbiturates

The part, displayed by the solvatation of the solute in 2 solvents with witch log P is determined, is studied by 2 indirect process. They consist to test some QSAR where the corresponding chemical potentials are effective but with different weighs than in log P. The results obtained with barbiturics confirm the importance of the couple water/n-octanol and show that taking account of two partitionning process can improve the significativity of the QSAR.     

Carcinogenicity of general-purpose phthalates: structure-activity relationships

There does not appear to be any evidence that other GP phthalates pose higher-level risk than DEHP. There is evidence that a very significant fraction of GP phthalate production capacity is devoted to turning out products which may have about the same carcinogenic potency as DEHP, and that another significant fraction of that capacity is devoted to turning out products with less potency. Public and private risk control choice takers considering this family of products need to be aware of this evidence, its limitations, and the means for upgrading certainty.     

Conjugated dienes as prohaptens in contact allergy: in vivo and in vitro studies of structure-activity relationships, sensitizing capacity, and metabolic activation

There is a great interest in developing in vitro/in silico methods for the prediction of contact allergenic activity. However, many proposed methods do not take the activation of prohaptens to sensitizers by skin metabolism into account. As a consequence, consumer products containing potent sensitizers could be marketed. To identify prohaptens, studies regarding their structure-activity relationships and the mechanisms of their activation must be conducted. In the present investigation, we have studied the structure-activity relationships for alkene prohaptens. A series of seven alkenes (1-7), all of the same basic structure but with variation in the number and position(s) of the double bond(s), were designed and screened for sensitizing capacity using the murine local lymph node assay. Compounds 1-7 were also incubated with liver microsomes in the presence of glutathione to trap and identify reactive metabolites. The metabolic conversion of three alkenes (9-11) to epoxides (12-15) was also studied along with comparison of their sensitizing capacity. Our results show that conjugated dienes in or in conjunction with a six-membered ring are prohaptens that can be metabolically activated to epoxides and conjugated with GSH. Related alkenes containing isolated double bonds and an acyclic conjugated diene were shown to be weak or nonsensitizers. For the first time, the naturally occurring monoterpenes alpha-phellandrene, beta-phellandrene, and alpha-terpinene were demonstrated to be prohaptens able to induce contact allergy. The difference in sensitizing capacity of conjugated dienes as compared to alkenes with isolated double bonds was found to be due to the high reactivity and sensitizing capacity of the allylic epoxides metabolically formed from conjugated dienes. We recommend that these structure-activity relationship rules are incorporated into in silico predictive databases and propose that the prediction of contact allergenic activity of suspected prohaptens is based on assessment of susceptibility to metabolic activation and chemical reactivity of potential metabolites.     

SAR index: quantifying the nature of structure-activity relationships

Structure-activity relationships (SARs) can display very different features. Small chemical modifications of active molecules often dramatically alter biological responses. By contrast, structurally diverse molecules can have similar activity. SARs can also be heterogeneous in nature. For example, for structurally diverse molecules with similar activity, closely related analogs might have significant differences in potency. Given the inherent complexity of SARs, it has been very difficult to estimate SAR characteristics from molecular structure. On the basis of systematic correlation of 2D structural similarity and compound potency, we have developed a function termed "SAR Index" that quantitatively describes the nature of SARs and establishes different SAR categories: continuous, discontinuous, heterogeneous-relaxed, and heterogeneous-constrained. These heterogeneous SAR categories are described for the first time. Given a set of active compounds and their potency values, SAR Index calculations can estimate how likely it is to identify structurally distinct molecules having similar activity.     

Cardiac glycosides with non-rotating steroid to sugar linkages: tools for the study of digitalis structure-activity relationships

Summary The 5H-cardenolide, gomphoside, is one of a small group of naturally occurring cardiac glycosides in which the sugar residue is bilinked to the steroid ring system. This arrangement prevents the sugar moiety from rotating and this makes gomphoside and related compounds potentially useful for structure-activity relationship (SAR) studies. When gomphoside was tested for inotropic activity using guinea pig left atria, the compound was found to have very high potency comparable to the most active 5H-cardenolides. Removal of the sugar moiety reduced inotropic activity almost 500-fold indicating that it was the presence of the sugar moiety that was mainly responsible for the drug's high potency. Modification of the steroid or sugar residue of gomphoside reduced activity in all cases. It would thus appear that gomphoside with its high potency and non-rotatable glycosidic linkage is an excellent tool for SAR studies.     

Electronic-topological study of the structure-activity relationships in a series of steroids with mineralocorticoid binding affinity

Conformational analysis and quantum chemical calculations were carried out using molecular mechanics (MMP2) and semi-empirical quantum chemistry (CNDO/2) methods for 51 steroid homologues belonging to a series of 17-spirolactones. Matrices called Electronic-Topological Matrices of Conjunction (ETMCs) were formed using data obtained from quantum chemical calculations. A structural fragment of activity was identified in the series of steroids. As seen from the fragment's properties, active compounds are characterized by the presence of two atoms of oxygen, O1 and O3, which are situated at a distance of 13.5 A and possess high negative charges (-0.29 to -0.31 e).     

Azaindenoisoquinolines as topoisomerase I inhibitors and potential anticancer agents: a systematic study of structure-activity relationships

A comprehensive study of a series of azaindenoisoquinoline topoisomerase I (Top1) inhibitors is reported. The synthetic pathways have been developed to prepare 7-, 8-, 9-, and 10-azaindenoisoquinolines. The present study shows that 7-azaindenoisoquinolines possess the greatest Top1 inhibitory activity and cytotoxicity. Additionally, the introduction of a methoxy group into the D-ring of 7-azaindenoisoquinolines improved their biological activities, leading to new lead molecules for further development. A series of QM calculations were performed on the model "sandwich" complexes of azaindenoisoquinolines with flanking DNA base pairs from the Drug-Top1-DNA ternary complex. The results of these calculations demonstrate how changes in two forces contributing to the π-π stacking (dispersion and charge-transfer interactions) affect the binding of the drug to the Top1-DNA cleavage complex and thus modulate the drug's Top1 inhibitory activity.