SAR Information Research Articles

Systematic Extraction of Structure–Activity Relationship Information from Biological Screening Data

A data mining approach is introduced that automatically extracts SAR information from high-throughput screening data sets and that helps to select active compounds for chemical exploration and hit-to-lead projects. SAR pathways are systematically identified consisting of sequences of similar active compounds with gradual increases in potency. Fully enumerated SAR pathway sets are subjected to pathway scoring, filtering, and mining, and pathways with the most significant SAR information content are prioritized. High-scoring SAR pathways often reveal activity cliffs contained in screening data. Subsets of SAR pathways are analyzed in SAR trees that make it possible to identify microenvironments of significant SAR discontinuity from which hits are preferentially selected. SAR trees of alternative pathways leading to activity cliffs identify key compounds and help to develop chemically intuitive SAR hypotheses.

Synthesis and structure–activity relationship of 3β-(4-alkylthio, -methylsulfinyl, and -methylsulfonylphenyl)tropane and 3β-(4-alkylthiophenyl)nortropane derivatives for monoamine transporters

Early studies led to the identification of 3β-(4-methoxyphenyl)tropane-2β-carboxylic acid methyl ester ( 5) with high affinity at the DAT (IC 50 = 6.5 nM) and 5-HTT ( K i = 4.3 nM), while having much less affinity at the NET ( K i = 1110 nM). In the present study, we replaced the 4′-methoxy group of the 3β-phenyl ring with a bioisosteric 4′-methylthio group to give 7a. We also synthesized a number of 3β-(4-alkylthiophenyl)tropanes 7b– e, 3β-(4-methylsulfinylphenyl) and 3β-(4-methylsulfonylphenyl)tropane analogues 7f– h as well as the 3β-(4-alkylthiophenyl)nortropane derivatives 8– 11 to further characterize the structure–activity relationship of this type of compound for binding at monoamine transporters. With exception of the 4′-methylsulfonyl analogue 7h, all the tested compounds possessed high binding affinities at the 5-HTT. The K i values ranged from 0.19 nM to 49 nM. The 3β-(4-methylthiophenyl)tropane 7a and its N-(3-fluoropropyl) analogue 9a and N-allyl analogue 10a are the most selective compounds for the 5-HTT over the NET (NET/5-HTT = 314–364) in the series. However, none of the compounds showed selectivity similar to 5 for both the DAT and 5-HTT relative to the NET. This study provided useful SAR information for rational design of potent and selective monoamine transporter inhibitors.

Optimization of 2-piperidin-4-yl-acetamides as melanin-concentrating hormone receptor 1 (MCH-R1) antagonists: Designing out hERG inhibition

Herein, we disclose the discovery and optimization of 2-piperidin-4-yl-acetamide derivatives as MCH-R1 antagonists. Structural investigation of piperidin-4-yl-amide and piperidin-4-yl-ureas identified 2-piperidin-4-yl-acetamide-based MCH-R1 antagonists with outstanding in vivo efficacy but flawed with high affinity towards the hERG potassium channel. While existing hERG SAR information was employed to discover highly potent MCH-R1 antagonists with minimized hERG inhibition, additional hurdles prevented their subsequent clinical exploration.

Structure–activity relationships of lipopolysaccharide sequestration in N-alkylpolyamines

We have previously shown that simple N-acyl or N-alkyl polyamines bind to and sequester Gram-negative bacterial lipopolysaccharide, affording protection against lethality in animal models of endotoxicosis. Several iterative design-and-test cycles of SAR studies, including high-throughput screens, had converged on compounds with polyamine scaffolds which have been investigated extensively with reference to the number, position, and length of acyl or alkyl appendages. However, the polyamine backbone itself had not been explored sufficiently, and it was not known if incremental variations on the polymethylene spacing would affect LPS-binding and neutralization properties. We have now systematically explored the relationship between variously elongated spermidine [NH 2–(CH 2) 3–NH–(CH 2) 4–NH 2] and norspermidine [NH 2–(CH 2) 3–NH–(CH 2) 3–NH 2] backbones, with the N-alkyl group being held constant at C 16 in order to examine if changing the spacing between the inner secondary amines may yield additional SAR information. We find that the norspermine-type compounds consistently showed higher activity compared to corresponding spermine homologues.

Synthesis, antimicrobial and cytotoxic activities of some 5-arylidene-4-thioxo-thiazolidine-2-ones

Several 5-arylidene-4-thioxo-thiazolidine-2-ones ( 3a– n) were synthesized and evaluated as antimicrobial agents against representative strains, including multidrug-resistant strains of clinical isolates. Also, the antiproliferative activity was evaluated against two human carcinoma cell lines (NCI-H292 and HEp-2). The compounds containing the 5-arylidene subunit presented greater antimicrobial activities against Gram positive bacteria, including the multidrug-resistant clinical isolates, than the 4-thioxo-thiazolidine-2-one. Important SAR information was also gathered, such as the contribution of thiocarbonyl attached at 4-position on the thiazolidine heterocyclic for antimicrobial properties. None of the derivatives exhibited significant antiproliferative activity against the human carcinoma cell lines.

Structure−Activity Landscape Index: Identifying and Quantifying Activity Cliffs

A new method for analyzing a structure-activity relationship is proposed. By use of a simple quantitative index, one can readily identify "structure-activity cliffs": pairs of molecules which are most similar but have the largest change in activity. We show how this provides a graphical representation of the entire SAR, in a way that allows the salient features of the SAR to be quickly grasped. In addition, the approach allows us view the SARs in a data set at different levels of detail. The method is tested on two data sets that highlight its ability to easily extract SAR information. Finally, we demonstrate that this method is robust using a variety of computational control experiments and discuss possible applications of this technique to QSAR model evaluation.

Design, Synthesis, and Biological Evaluation of Caprolactam‐Modified Bengamide Analogues

A series of potent, water-soluble N-substituted bengamide analogues were discovered through diverse derivatives of the caprolactam unit of bengamide. Important SAR information was also gathered, and is different from previously reported SARs of this compound class. We therefore present a new view of bengamide natural products.

Synthesis and biological evaluation of novel analogues of dictyostatin

Novel analogues of the microtubule-stabilising agent dictyostatin were designed using existing SAR information from the structurally related discodermolide, synthesised by a late-stage diversification strategy and evaluated in vitro for growth inhibition against a range of human cancer cell lines, including those known to exhibit Taxol-resistance (AsPC-1, DLD-1, PANC-1, NCI/ADR).

Pushing the boundaries of 3D-QSAR

Based primarily on further studies of a collection of eleven publications reporting fifteen successful 3D-QSAR relations, several phenomena are preliminarily described. The RMS error of 133 ligand binding energy predictions based on these successful 3D-QSARs is 0.75 kcal/mole, which compares favorably to the prediction accuracies of approaches that include the receptor. A similar result is obtained when topomer alignments are substituted for those published, with seemingly profound implications for the future of 3D-QSAR. The "alignment-averaged" molecular properties, log P and molar refractivity, have very little correlative power for these data sets, either alone or in combination with the 3D-QSAR field descriptors. The q (2 )metric for the number of PLS components necessarily tends to discard any unique or unconfirmed SAR information. Large drops in q (2) are thus to be expected whenever such unique information is first encountered. Predictive r (2) values from an exploratory new "series trajectory" analysis of these 3D-QSAR though highly variable do not differ much from their q (2) values, a phenomenon that seems to encourage prediction even when there are so few structures underlying a 3D-QSAR so that almost all information is unique.

Synthesis and Structure−Activity Relationships of Carbazole Sulfonamides as a Novel Class of Antimitotic Agents Against Solid Tumors

Two series of carbazole sulfonamides related to Combretastatin A4 (1) were synthesized and evaluated for antiproliferative activity. Thirteen of the 26 new sulfonamides exhibited IC(50) values of <1 muM against CEM leukemia cells. Five compounds were evaluated against a panel of eight human tumor cell lines. 9-Ethyl-N-(3,4,5-trimethoxyphenyl)-carbazole-3-sulfonamide (11a) showed significant antitumor activity in two human xenograft models (MCF-7 and Bel-7402). Preliminary studies with 11a showed that the mode of action involves arrest of M-phase cell cycle and induction of apoptosis by increasing expression of p53 and promoting bcl-2 phosphorylation. Unexpectedly, 11a only weakly inhibits tubulin polymerization, which suggests that the mode of action of 11a differs from 1 and involves an unidentified target(s). Also, the SAR information gleaned from ring A-substituted analogues varies significantly from that of 1. Carbazole sulfonamides are a novel promising class of antimitotic agents with clinical development potential.

Using a priori information to improve soil moisture retrieval from ENVISAT ASAR AP data in semiarid regions

This paper presents a retrieval algorithm that estimates spatial and temporal distribution of volumetric soil moisture content, at an approximate depth of 5 cm, using multitemporal ENVISAT Advanced Synthetic Aperture Radar (ASAR) alternating polarization images, acquired at low incidence angles (i.e., from 15/spl deg/ to 31/spl deg/). The algorithm appropriately assimilates a priori information on soil moisture content and surface roughness in order to constrain the inversion of theoretical direct models, such as the integral equation method model and the geometric optics model. The a priori information on soil moisture content is obtained through simple lumped water balance models, whereas that on soil roughness is derived by means of an empirical approach. To update prior estimates of surface parameters, when no reliable a priori information is available, a technique based solely on the use of multitemporal SAR information is proposed. The developed retrieval algorithm is assessed on the Matera site (Italy) where multitemporal ground and ASAR data were simultaneously acquired in 2003. Simulated and experimental results indicate the possibility of attaining an accuracy of approximately 5% in the retrieved volumetric soil moisture content, provided that sufficiently accurate a priori information on surface parameters (i.e., within 20% of their whole variability range) is available. As an example, multitemporal soil moisture maps at watershed scale, characterized by a spatial resolution of approximately 150 m, are derived and illustrated in the paper.

Antitumor agents 247. New 4-ethoxycarbonylethyl curcumin analogs as potential antiandrogenic agents

4-Ethoxycarbonylethyl curcumin (ECECur) ( 3) is a current drug candidate for the treatment of prostate cancer. Due to problems inherent in the tautomerism of ECECur, 4-fluoro-4-ethoxycarbonylethyl curcumin ( 4) and 4-ethoxycarbonylethylenyl curcumin ( 5) were designed and synthesized. These two target compounds and their synthetic intermediates ( 4– 9) were evaluated for their inhibitory activity against androgen receptor transcription in LNCaP and PC-3 prostate cancer cell lines. While the enol–keto analogs showed varying anti-androgen potencies, the di-keto analogs showed no activity. Tetrahydropyranylation of the phenoxy groups had a positive impact on the anti-AR activity of 4-ethoxycarbonylethylenyl curcumin, but a negative impact on the activity of ECECur. With potent anti-AR activity, di-tetrapyranylated 4-ethoxycarbonylethylenyl curcumin ( 9), which exists in only one form, is a good drug lead for further structural modification. Based on the SAR information obtained from the above study, five new compounds were designed and subsequently synthesized. Among them, compound 10 was found to be the most potent anti-AR agent and is considered to be a promising drug candidate for the treatment of prostate cancer.

Synthesis of N-benzylated-2-aminoquinolines as ligands for the Tec SH3 domain

In recent work, we have been developing 2-aminoquinolines as ligands for Src Homology 3 (SH3) domains, so far the only reported examples of small-molecule ligands for these domains. In this paper, we report the synthesis of a series of N-benzylated-2-aminoquinolines by reductive amination of aryl aldehydes with 2-aminoquinoline. These ligands bound the SH3 domain with ca. one and a half to twofold reduced affinity relative to 2-aminoquinoline; however, some evidence was found to suggest that the benzylic substituents made new contacts with the SH3 domain surface. These results provide useful SAR information that may assist in future ligand design.

Synthesis and Structure−Activity Relationship of Novel 6-Aryl-1,4- dihydrobenzo[d][1,3]oxazine-2-thiones as Progesterone Receptor Modulators Leading to the Potent and Selective Nonsteroidal Progesterone Receptor Agonist Tanaproget

Tanaproget represents a potential first-in-class nonsteroidal PR agonist for contraception with improved safety and side effect profiles versus currently available steroidal oral contraceptives. Additional SAR, biological activity, and structural information from a tanaproget/hPR-LBD (hPR-LBD = human progesterone receptor ligand binding domain) cocrystal structure will also be presented.

Allosterism at Muscarinic Receptors: Ligands and Mechanisms

The evaluation of allosteric ligands at muscarinic receptors is discussed in terms of the ability of the experimental data to be interpreted by the allosteric ternary complex model. The compilation of useful SAR information of allosteric ligands is not simple, especially for muscarinic receptors, where there are multiple allosteric sites and complex interactions.

Recent Developments in the Chemical Biology of Epothilones

Epothilones A and B are naturally occurring microtubule-stabilizers, which inhibit the growth of human cancer cells in vitro at nM or even sub-nM concentrations. In contrast to paclitaxel (Taxol) epothilones are also active against different types of multidrug-resistant cancer cell lines in vitro and against multidrug-resistant tumors in vivo (epothilone B). Their attractive preclinical profile has made epothilones important lead structures in the search for improved cytotoxic anticancer drugs and epothilone B is currently undergoing phase II clinical trials. Numerous synthetic and semi-synthetic analogs have been prepared since the absolute stereochemistry of epothilone B was first disclosed in mid-1996 and their in vitro biological activity has been determined. Apart from generating a wealth of SAR information, these efforts have led to the identification of at least four compounds (in addition to epothilone B), which are currently at various stages of clinical evaluation in humans. This review is first intended to provide a summary of the basic features of the in vitro biological profile of epothilone B, with particular emphasis on recent developments in this area. A second part will outline the most relevant aspects of the epothilone SAR with regard to effects on tubulin polymerization, in vitro antiproliferative activity, and in vivo antitumor activity. This will include a brief discussion of research directed at the determination of the bioactive conformation of epothilones. In a final section, the preclinical profile of those epothilone analogs currently in clinical development will be discussed in greater detail.

Structural Requirements for Factor Xa Inhibition by 3-Oxybenzamides with Neutral P1 Substituents: Combining X-ray Crystallography, 3D-QSAR, and Tailored Scoring Functions

The design, synthesis, and structure-activity relationship of 3-oxybenzamides as potent inhibitors of the coagulation protease factor Xa are described on the basis of X-ray structures, privileged structure motifs, and SAR information. A total of six X-ray structures of fXa/inhibitor complexes led us to identify the major protein-ligand interactions. The binding mode is characterized by a lipophilic dichlorophenyl substituent interacting with Tyr228 in the protease S1 pocket, while polar parts are accommodated in S4. This alignment in combination with docking allowed derivation of 3D-QSAR models and tailored scoring functions to rationalize biological affinity and provide guidelines for optimization. The resulting models showed good correlation coefficients and predictions of external test sets. Furthermore, they correspond to binding site topologies in terms of steric, electrostatic, and hydrophobic complementarity. Two approaches to derive tailored scoring functions combining binding site and ligand information led to predictive models with acceptable predictions of the external set. Good correlations to experimental affinities were obtained for both AFMoC (adaptation of fields for molecular comparison) and the novel TScore function. The SAR information from 3D-QSAR and tailored scoring functions agrees with all experimental data and provides guidelines and reasonable activity estimations for novel fXa inhibitors.

Pattern Recognition on the Structure−Activity Relationship of Nano Pt−Ru Catalysts: Methodology and Preliminary Demonstration

The activity of nano Pt-Ru catalysts is a multivariate function of particle size, alloyed degree, oxide composition, and so forth. The monodependencies of catalytic activity on individual structure parameters (structure-activity relationship, SAR) are of great importance but, unfortunately, unobtainable in practical measurements. A pattern-recognition methodology is proposed for the first time to extract SAR information from all of the relative experimental data, which we hope will cast new light on the in-depth understanding of this important catalyst. As a preliminary demonstration, a multivariate linear regression and a generalized regression neural network were applied to analyze a small data set for methanol oxidation. It was found that both increasing the content of hydrous ruthenium oxides and decreasing the particle size would benefit the catalytic activity, whereas the effect of the Pt-Ru alloy degree turned out to be unremarkable.

Synthesis of 5-, 6- and 7-substituted-2-aminoquinolines as SH3 domain ligands

The Src homology 3 (SH3) domains are small protein-protein interaction domains that mediate a range of important biological processes and are considered valuable targets for the development of therapeutic agents. We have been developing 2-aminoquinolines as ligands for SH3 domains--so far the only reported examples of entirely small-molecule ligands for the SH3 domains. The highest affinity 2-aminoquinolines so far identified are 6-substituted compounds. In this article, the synthesis of several new 2-aminoquinolines, including 5-, 6- and 7-substituted compounds, for Tec SH3 domain ligand binding studies is presented. As a part of the synthetic investigation, the utility of different methods for the synthesis of 2-aminoquinolines was explored and potentially powerful methods were identified for the synthesis of 2-aminoquinolines with diverse functionality. Of the compounds prepared, the 5-substituted-2-aminoquinolines generally bound with similar affinities to unsubstituted 2-aminoquinoline, whilst the 7-substituted compounds generally bound with similar or lower affinity than unsubstituted 2-aminoquinoline. However, the 6-substituted-2-aminoquinolines generally bound with significantly higher affinity than unsubstituted 2-aminoquinoline. In addition, one 6-substituted-N-benzylated-2-aminoquinoline was also tested for SH3 binding and some evidence for the formation of additional contacts at other regions of the SH3 domain was found. These results provide new and useful SAR information that should greatly assist with the challenge of developing high affinity small-molecule ligands for the SH3 domains.

Synthesis and structure-activity relationships of 3-aminobenzophenones as antimitotic agents.

A new series of 3-aminobenzophenone compounds as potent inhibitors of tubulin polymerization was discovered based on the mimic of the aminocombretastatin molecular skeleton. Lead compounds 5 and 11, with alkoxy groups at the C-4 position of B-ring, were potent cytotoxic agents and inhibitors of tubulin polymerization through the binding to the colchicine-binding site of tubulin. The corresponding antitubulin activities of 5 and 11 were similar to or greater than combretastatin A-4 and AVE-8063. Replacement of the methoxy group with a chloro group in the B ring of aminobenzopheneones (3, 8, and 9) caused drastic decrease in cytotoxic and antitubulin activity except in compounds 4 and 10, which could result from a unique alignment between chloro and amino groups located at the para position to each other. SAR information revealed that introduction of an amino group at the C-3 position in B ring of benzophenones, in addition to a methoxy group at the C-4 position, plays an important role for maximal cytotoxicity.