Topliss Approach Research Articles

Insights into Molecular Basis of hERG Inhibition by Studying a Library of Dofetilide Derivatives

Understanding the molecular basis of hERG (Kv11.1) inhibition is essential for drug development. Here we systematically analyzed the mechanism and potency of hERG inhibition by a library of 13 dofetilide derivatives1. Currents through hERG channels stably expressed in HEK 293 cells were studied applying whole-cell configuration using planar patch clamp technique2.The estimated IC50s ranged between 4.3±0.7nM (LUF6200) and 297±77nM (LUF6139). An inverse relation was observed between potency (IC50) and rate of block development. Analysis of the kinetics of block development revealed that potency of dofetilide derivatives is predominantly determined by the drug dissociation rate constant. In general, higher molecular weight led to higher apparent drug affinity (r = 0.9).LUF6200, the most active compound, has 2 nitro groups in para position of the two aromatic rings and an ethyl moiety at the basic nitrogen atom. Pursuing a Topliss approach at the phenoxy group further supports the positive contribution of the nitro group1, showing that substituents with electron withdrawing groups in para position of the phenyl ring are beneficial for hERG blocking activity. This points towards a pi-pi interaction of at least one of the aromatic rings of dofetilide analogs with respective aromatic amino acids in the channel. Docking of the set of compounds into a homology model of the hERG channel supports this finding. A refined molecular model for dofetilide-hERG interaction based on the novel functional data and mutational studies is proposed.1. Shagufta et al. Exploring Chemical Substructures Essential for hERG K+ Channel Blockade by Synthesis and Biological Evaluation of Dofetilide Analogues. ChemMedChem 4, 1722-1732 (2009).2. Farre, C. & Fertig, N. HTS techniques for patch clamp-based ion channel screening - advances and economy. Expert Opin. Drug Discov. 7, 515-524 (2012).

Inhibition of IGF-1R and lipoxygenase by nordihydroguaiaretic acid (NDGA) analogs

Herein, we pursue the hypothesis that the structure of nordihydroguaiaretic acid (NDGA) can be refined for selective potency against the insulin-like growth factor 1 receptor (IGF-1R) as a potential therapeutic target for breast cancer while diminishing its action against other cellular targets. Thus, a set of NDGA analogs ( 7a– 7h) was prepared and examined for inhibitory potency against IGF-1R kinase and an alternative target, 15-lipoxygenase (15 LOX). The anti-cancer effects of these compounds were determined by their ability to inhibit IGF-1 mediated cell growth of MCF-7 breast cancer cells. The design of the analogs was based upon a cursory Topliss approach in which one of NDGA’s aromatic rings was modified with various substituents. Structural modification of one of the two catechol rings of NDGA was found to have little effect upon the inhibitory potency against both kinase activity of the IGF-1R and IGF-1 mediated cell growth of MCF-7 cells. 15-LOX was found to be most sensitive to structural modifications of NDGA. From the limited series of NDGA analogs examined, the compound that exhibited the greatest selectivity for IGF-1 mediated growth compared to 15-LOX inhibition was a cyclic analog 7h with a framework similar to a natural product isolated from Larrea divaricata. The results for 7h are significant because while NDGA displays biological promiscuity, 7h exhibits greater specificity toward the breast cancer target IGF-1R with that added benefit of possessing a 10-fold weaker potency against 15-LOX, an enzyme which has a purported tumor suppressing role in breast cancer. With increased specificity and potency, 7h may serve as a new lead in developing novel therapeutic agents for breast cancer.

Structure−Activity Relationships in 1,4-Benzodioxan-Related Compounds. 8. {2-[2-(4-Chlorobenzyloxy)phenoxy]ethyl}-[2-(2,6-dimethoxyphenoxy)ethyl]amine (Clopenphendioxan) as a Tool to Highlight the Involvement of α1D- and α1B-Adrenoreceptor Subtypes in the Regulation of Human PC-3 Prostate Cancer Cell Apoptosis and Proliferation

A series of new alpha1-adrenoreceptor antagonists (5-18) was prepared by introducing various substituents (Topliss approach) into the ortho, meta, and para positions of the benzyloxy function of the phendioxan open analogue 4 ("openphendioxan"). All the compounds synthesized were potent antagonists and generally displayed, similarly to 4, the highest affinity values at alpha1D- with respect to alpha1A- and alpha1B-AR subtypes and 5-HT1A subtype. By sulforhodamine B (SRB) assay on human PC-3 prostate cancer cells, the new compounds showed antitumor activity (estimated on the basis of three parameters GI50, TGI, LC50), at low micromolar concentration, with 7 ("clopenphendioxan") exhibiting the highest efficacy. Moreover, this study highlighted for the first time alpha1D- and alpha1B-AR expression in PC3 cells and also demonstrated the involvement of these subtypes in the modulation of apoptosis and cell proliferation. A significant reduction of alpha1D- and alpha1B-AR expression in PC3 cells was associated with the apoptosis induced by 7. This depletion was completely reversed by norepinephrine.

Optimizing phenylethylphosphonamidates for the inhibition of prostate-specific membrane antigen

A series of eight N-2-phenylethylphosphonyl derivatives of glutamic acid was prepared to determine if the inhibitory potency of a phenylethylphosphonyl derivative of glutamic acid against prostate-specific membrane antigen (PSMA) could be improved through rational substitutions on the phenyl ring. The design of these eight analogs was based upon the Topliss batchwise approach. Of the inhibitors from the first generation, the 3,4-dichlorophenyl analog exhibited the greatest improvement over the lead compound which was an unsubstituted phenyl derivative, while the 4-methoxyphenyl analog was essentially void of inhibitory potency against PSMA in single-dose studies. From the potency ranking order of the first generation, the parameter most important to the pharmacophore was determined to be π+σ. Attempts to optimize further the potency of inhibitors by preparing a second generation of compounds did not result in structures with greater potency than that of the 3,4-dichlorophenyl analog from the first generation. Based upon Ki values, the 3,4-dichlorophenyl analog represented a potency improvement of nearly one order of magnitude. These results confirm further the usefulness of the Topliss approach to analog development when large library synthesis cannot be achieved readily.

Design, synthesis, and development of novel caprolactam anticonvulsants

Epilepsy afflicts 1–2% of the world's population and often goes untreated; nearly 70% of those with a form of epilepsy fail to receive proper treatment. Therefore, there is great demand for the design of novel, effective anticonvulsants to combat epilepsy in its numerous forms. Previously, α-hydroxy-α-phenylcaprolactam was found to have rather potent antiepileptic activity [anti-maximal electroshock (MES) ED 50=63 mg/kg and anti-subcutaneous Metrazol (scMet) ED 50=74 mg/kg] when administered intraperitoneally in mice. We focused our attention on the development of this compound through traditional medicinal chemistry techniques—including the Topliss approach, isosteric replacement, methylene insertion, and rigid analogue approach—in the hopes of determining the effect of caprolactam α-substitution and other structural modifications on anticonvulsant activity. A number of the desired targets were successfully synthesized and submitted to the Anticonvulsant Screening Program of the National Institute of Neurological Disorders and Stroke (NINDS). Phase I results were quite promising for at least three of the compounds: α-ethynyl-α-hydroxycaprolactam ( 10), α-benzyl-α-hydroxycaprolactam ( 11), and α-hydroxy-α-(phenylethynyl)caprolactam ( 13). Phase II results for 11 strongly suggested it as a new structural class for further development, as it exhibited an anti-MES T.I. in excess of 4.0. Further, the potent activity of 13 in all models also pointed to the substituted alkynylcaprolactams as a new anticonvulsant structural class.

Design, synthesis and biological evaluation of pyridine-phenylpiperazines: A novel series of potent and selective α 1a-adrenergic receptor antagonist

Beginning from the screening hit and literature α 1-adrenergic compounds, a hybridized basic skeleton A was proposed as the pharmacophore for potent and selective α 1a-AR antagonists. Introduction of a hydroxy group to increase the flexibility afforded B which served as the screening model and resulted in the identification of the second-generation lead 1. Using the Topliss approach, a number of potent and selective α 1a-AR antagonists were discovered. In all cases, binding affinity and selectivity at the α 1a-AR of S-hydroxy enantiomers were higher than the R-hydroxy enantiomers. As compared to the des-hydroxy analogues, the S -hydroxy enantiomers displayed comparable potency and better selectivity at α 1a-AR. The S-hydroxy enantiomer 17 ( K i=0.79 nM; α 1b α 1a =800 ; α 1d α 1a =104 ) was slightly less potent but much more selective at α 1a-AR than tamsulosin ( K i=0.13 nM, α 1b α 1a =15 , α 1d α 1a =1.4 ). Compound 17 displayed higher selectivity in inhibiting rat prostate contraction over rat aorta contraction and also exhibited a higher degree of uroselectivity than tamsulosin in the anesthetized dog model.

Design, synthesis, and structure-activity relationships of phthalimide-phenylpiperazines: a novel series of potent and selective alpha(1)(a)-adrenergic receptor antagonists.

Beginning from the screening hit and literature alpha(1)-adrenergic compounds, a hybridized basic skeleton A was proposed as the pharmacophore for potent and selective alpha(1a)-AR antagonists. Introduction of a hydroxy group to increase the flexibility afforded B which served as the screening model and resulted in the identification of the second-generation lead 1. Using the Topliss approach, a number of potent and selective alpha(1a)-AR antagonists were discovered. In all cases, binding affinity and selectivity at the alpha(1a)-AR of S-hydroxy enantiomers were higher than those of the R-hydroxy enantiomers. As compared to the des-hydroxy analogues, the S-hydroxy enantiomers had slightly lower binding affinity at alpha(1a)-AR but gained more than 2-fold selectivity for alpha(1a)-AR over alpha(1b)-AR, and 2- to 6-fold selectivity for alpha(1a)-AR over alpha(1d)-AR. They also had less cross activities against a panel of 25-35 peripheral and CNS receptors. The S-hydroxy enantiomers 23 and 24 (K(i) = 0.29 nM, 0.33 nM; alpha(1b)/alpha(1a) >5690, >6060; alpha(1d)/alpha(1a) = 186, 158, respectively) were slightly less potent but much more selective at alpha(1a)-AR than tamsulosin (K(i) = 0.13 nM, alpha(1b)/alpha(1a) = 14.8, alpha(1d)/alpha(1a) = 1.4). In the functional assay, the S-hydroxy enantiomers 20, 23, and 24 were less potent than tamsulosin in inhibiting contractions of rat prostate tissue but more selective in the inhibition of tissue contractions of rat prostate versus rat aorta. Compound 24 was selected as the development candidate for the treatment of BPH.

ChemInform Abstract: Relationships Between the Chemical Structure of Substances and Their Antimycobacterial Activity to Atypical Strains. Part 12. Combination of the Topliss Approach with the Free—Wilson Analysis in the Study of Antimycobacterial Activity of 4‐Alkylthiobenzanilides.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Combination of the Topliss Approach with the Free-Wilson Analysis in the Study of Antimycobacterial Activityof 4-Alkylthiobenzanilides

On the basis of a preliminary study of the antimycobacterial activity of thiobenzanilides, a group of 4'-isopropyl- and 4'-butylthiobenzanilides have been synthesized and tested against Mycobacterium tuberculosis, Mycobacterium kansasii, Mycobacterium avium and Mycobacterium fortuitum. The effect of the substituents on minimum inhibitory concentrations was calculated by the Free-Wilson method. The separated values were analyzed by the Topliss approach. The substitution of the thiobenzanilide in position 4' by the isopropyl group or butyl group increased the antimycobacterial activity less than the cyclohexyl group. The substitution in position 4 decreased the activity by the steric effect.

ChemInform Abstract: Topliss Approach to the Synthesis of Biologically Active Substituted N‐ Benzoyl Taxol Analogues.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Topliss approach to the synthesis of biologically active substituted N-benzoyl taxol analogues

A series of compounds, directed by the Topliss Operational Scheme, were synthesized and evaluated to investigate structure activity relationships of the N-benzoyl moiety of taxol. Evaluation of the newly prepared derivatives in the microtubule assembly assay and for cytotoxicity revealed that they possessed biological properties similar to taxol. Nine novel substituted N-benzoyl analogues of taxol were prepared, using the Topliss approach to drug design. The taxanes were prepared from N-acyl-3-hydroxy-4-phenyl-2-azetidinones and baccatin III or by acylation of N-debenzoyltaxol. In vitro biological evaluation revealed that these analogues had activity similar to taxol.

Antibacterial Organophosphorus Compounds: Phosphoranilidohydrazones of 5-Nitro-2-furaldehyde

A series of phosphoranilidohydrazones of 5-nltro-2-furaldehyde was synthesized and evaluated for antibacterial activity. The series was prepared to examine the applicability of phosphoramidic hydrazones as carriers for the antibacterial nitrofuran moiety. Designed as analogues of nitrofurantoin, members of the series were chosen according to the Topliss approach to analogue design. The title compounds were devoid of gram-negative activity but possessed moderate antistaphylococcal activity. The most potent members of the series were equipotent with nitrofurantoin against Staphylococcus aureus. The relationship between structure and antistaphylococcal activity is discussed.

Antituberculotic 4'-Cyclohexylthiobenzanilides: Combination of Free-Wilson Method in QSAR with Topliss Approach

On the basis of a preliminary study of antimycobacterial activity of thiobenzanilides against Mycobacterium kansasii, a group of 4'-cyclohexylthiobenzanilids have been prepared which exhibit a significant activity against the microorganism mentioned. The whole set of 35 thiobenzanilides was tested with Mycobacterium tuberculosis, and on the basis of QSAR analysis conclusions have been made with regard to prognostics of structures suitable for further studies. The problem was solved by the method by Free and Wilson combined with the Topliss approach and by a Hansch type analysis.

ChemInform Abstract: SPIROSUCCINIMIDES AS POTENTIAL ANTICONVULSANTS

AbstractDie Spiroverbindungen (I) werden auf dem beschriebenen Weg erhalten.

Spirosuccinimides as Potential Anticonvulsants

A series of spirosuccinimides was synthesized and evaluated for anticonvulsant activity. The study was designed to apply the Topliss approach to structure–activity correlations in this novel series of 2-substituted-2-azaspiro[4.4]nonane-1,3-diones and 2,4-disubstituted-2-azaspiro[4.4]nonane-1,3-diones. While no correlation was noted with the 2-substituted derivatives, a good correlation was obtained in the 2,4-disubstituted series, indicating that anticonvulsant activity was related to increasing π values. The results of these anticonvulsant tests are presented and a rational approach to the structure–activity relationships of spirosuccinimides is provided.

ChemInform Abstract: INHIBITORS OF PHENYLETHANOLAMINE N‐METHYLTRANSFERASE AND EPINEPHRINE BIOSYNTHESIS. 2. 1,2,3,4‐TETRAHYDROISOQUINOLINE‐7‐SULFONANILIDES

AbstractDas Sulfonylchlorid (I) ergibt die Sulfonamide (II), die zu den Verbindungen (III) desacetyliert werden.

Inhibitors of phenylethanolamine N-methyltransferase and epinephrine biosynthesis. 2. 1,2,3,4-Tetrahydroisoquinoline-7-sulfonanilides.

1,2,3,4-Tetrahydroisoquinoline-7-sulfonanilides (1-14) related to 1,2,3,4-tetrahydroisoquinoline-7-sulfonamide (21,SK&F 29661) were prepared and studied for their ability to inhibit phenylethanolamine N-methyltransferase (PNMT) in vitro. The choice of substituents on the 7-phenyl group of the sulfonanilides was based on the Topliss approach to structure-activity relationship studies. Information about the importance of an acidic hydrogen atom on the sulfonamide nitrogen atom was obtained from the preparation and testing of a tertiary N-methylsulfonanilide (15). Other THIQ's (1,2,3,4-tetrahydroisoquinolines) containing sulfur substituents in the 7 position were prepared and tested and consisted of 7-N-benzyl and 7-N-phenethyl derivatives of SK&F 29661 (16-18) and 7-(phenacylthio)-and 7-(phenacylsulfonyl)-THIQ (19 and 20). The two most potent inhibitors were the 7-p-bromo- and -chlorosulfonanilides, 2 and 6. However, neither was an effective inhibitor of norepinephrine to epinephrine conversion when tested in an in vivo mouse assay at unit doses of 25 or 100 mg/kg.

Application of quantitative structure-activity relationships in the development of the antiallergic pyranenamines

QSAR techniques played a major role in development of the antiallergic pyranenamines (I). Graphical analysis of data resulting from an unsuccessful Topliss approach suggested that increased substituent hydrophilicity might enhance potency. The 3-NHAc-4-OH derivative which first resulted was an order of magnitude more potent than any preceding series member, and its deacylated congenar is clinical candidate SK&F 78729 (R1 = -NH2, R2 - OH, R3 = H). Further pursuit of hydrophilicity and other strategies suggested by multiple regression yielded 98 pyranenamines, the most active [R1 = R3 = NHCO(CHOH)2H, R2 = H] being 1000 times more potent than any original series member.