Conformationally-restricted Analogues Research Articles

Design, synthesis, biological evaluation, and modeling studies of novel conformationally-restricted analogues of sorafenib as selective kinase-inhibitory antiproliferative agents against hepatocellular carcinoma cells.

Sorafenib is one of the clinically used anticancer agents that inhibits several kinases. In this study, novel indole-based rigid analogues of sorafenib were designed and synthesized in order to enhance kinase selectivity and hence minimize the side effects associated with its use. The target compounds possess different linkers; urea, amide, sulfonamide, or thiourea, in addition to different terminal aryl moieties attached to the linker in order to investigate their impact on biological activity. They were tested against Hep3B, Huh7, and Hep-G2 hepatocellular carcinoma (HCC) cell lines to study their potency. Among all the tested target derivatives, compound 1h exerted superior antiproliferative potency against all the three tested HCC cell lines compared to sorafenib. Based on these preliminary results, compound 1h was selected for further biological and in silico investigations. Up to 30μM, compound 1h did not inhibit 50% of the proliferation of WI-38 normal cells, which indicated promising selectivity against HCC cells than normal cells. In addition, compound 1h exerted superior kinase selectivity than sorafenib. It is selective for VEGFR2 and VEGFR3 angiogenesis-related kinases, while sorafenib is a multikinase inhibitor. Superior kinase selectivity of compound 1h to sorafenib can be attributed to its conformationally-restricted indole nucleus and the bulky N-methylpiperazinyl moiety. Western blotting was carried out and confirmed the ability of compound 1h to inhibit VEGFR2 kinase inside Hep-G2 HCC cells in a dose-dependent pattern. Compound 1h induces apoptosis and necrosis in Hep-G2 cell line, as shown by caspase-3/7 and lactate dehydrogenase (LDH) release assays, respectively. Moreover, compound 1h is rather safe against hERG. Thus, we could achieve a more selective kinase inhibitor than sorafenib with retained or even better antiproliferative potency against HCC cell lines. Furthermore, molecular docking and dynamic simulation studies were carried out to investigate its binding mode with VEGFR2 kinase. The molecule has a unique orientation upon binding with the kinase.

Assessment of dopamine D1 receptor affinity and efficacy of three tetracyclic conformationally-restricted analogs of SKF38393

To assess the effect of conformational mobility on receptor activity, the β-phenyl substituent of dopamine D1 agonist ligands of the phenylbenzazepine class, (±)-6,6a,7,8,9,13b-hexahydro-5H-benzo[d]naphtho[2,1-b]azepine-11,12-diol (8), and its oxygen and sulfur bioisosteres 9 and 10, respectively, were synthesized as conformationally-restricted analogs of SKF38393, a dopamine D1-selective partial agonist. Compounds trans-8b, 9, and 10 showed binding affinity comparable to that of SKF38393, but functionally, they displayed only very weak agonist activity. These results suggest that the conformationally-restricted structure of the analogs cannot adopt a binding orientation that is necessary for agonist activity.

Rimonabant Redux and Strategies to Improve the Future Outlook of CB1 Receptor Neutral‐Antagonist/Inverse‐Agonist Therapies

Rimonabant Redux and Strategies to Improve the Future Outlook of CB1 Receptor Neutral‐Antagonist/Inverse‐Agonist Therapies

SYNTHESIS AND BIOLOGICAL EVALUATION OF CONFORMATIONALLY RESTRICTED AND NUCLEOBASE-MODIFIED ANALOGS OF THE ANTICANCER COMPOUND 3′-C-ETHYNYLCYTIDINE (ECYD)

A series of conformationally restricted and nucleobase-modified analogs of the anticancer compound 3′-C-ethynylcytidine (ECyd) and its uracil analog (EUrd) have been synthesized. While none of, the conformationally restricted analogs displayed anticancer activity, 5-iodo-EUrd and 5-bromo-EUrd displayed potent anticancer activity with IC50 values of 35 nM and 0.73 μM.

Conformationally-restricted analogues of efflux pump inhibitors that potentiate the activity of levofloxacin in Pseudomonas aeruginosa.

Conformational restriction of the ornithine residue of the efflux pump inhibitor D-ornithine-D-homophenylalanine-3-aminoquinoline (MC-02,595, 2) furnished bioisosteric proline derivatives that were less toxic in vivo and as active as the lead in potentiating the activity of the fluoroquinolone levofloxacin via the inhibition of efflux pumps in Pseudomonas aeruginosa.

Cycloisomerisation of modified terpenoid 1,6-enynes—synthesis of conformationally-restricted cyclic farnesyl analogues

The cycloisomerisation of various 1,6-enynes containing a modified terpenoid chain has been investigated to provide cyclopentanes with great potential as novel conformationally-restricted analogues of farnesyl diphosphate. The 4-diethylphosphono-ester substituent is shown to serve as a diastereocontrol element for the 1,6-enyne cycloisomerisation process.

Analogues of Human Parathyroid Hormone (1–31)NH 2: Further Evaluation of the Effect of Conformational Constraint on Biological Activity

A series of conformationally-restricted analogues of hPTH was prepared, based on the parent peptide agonist, cyclo(Lys 18-Asp 22)[Ala 1,Nle 8,Lys 18,Asp 22,Leu 27]hPTH(1–31)NH 2 ( 2, EC 50=0.29 nM). Truncation of 2 at either the N- or C-termini resulted in peptides with reduced agonist activity as measured by stimulation of adenylate cyclase activity in the rat osteosarcoma cell line (ROS 17/2.8). Alanine- and glycine-scanning at the N-terminus of 2 was consistent with data previously obtained on linear hPTH(1–34). Other locations within the primary sequence of hPTH(1–31)NH 2 were evaluated by the placement of the [ i, i+4] lactam constraining element. Ring size and lactam orientations at the 18–22 positions were also examined.

Effects of a 3-Alkyl-, 4-Hydroxy- and/or 8-Aromatic-substituent on the Phenylethanolamine N-Methyltransferase Inhibitor Potency and α 2-Adrenoceptor Affinity of 2,3,4,5-Tetrahydro-1 H-2-benzazepines

2,3,4,5-Tetrahydro-1 H-2-benzazepine (THBA; 1) is nearly 100-fold more selective an inhibitor of phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28) versus the α 2-adrenoceptor than is 1,2,3,4-tetrahydroisoquinoline (THIQ; 2) ( 1: PNMT K i=3.3 μM, α 2-adrenoceptor K i=11 μM, selectivity [α 2 K i/PNMT K i]=3.3; 2: PNMT K i=9.7 μM, α 2 K i=0.35 μM, selectivity=0.036;). Since the PNMT inhibitory activity and selectivity of THIQ were enhanced by the introduction of a hydrophilic electron-withdrawing 7-substituent and a 3-alkyl-substituent, a similar study was conducted on THBA. 8-Nitro-THBA ( 3) was found to be as potent an inhibitor of PNMT as its THIQ analogue ( 21) and to be more selective due to its reduced α 2-adrenoceptor affinity ( 3: PNMT K i=0.39 μM, α 2 K i=66 μM, selectivity=170; 21: PNMT K i=0.41 μM, α 2 K i=4.3 μM, selectivity=10). Introduction of a 3-alkyl substituent on the THBA nucleus decreased both the α 2-adrenoceptor affinity and the PNMT inhibitory activity, suggesting an area of steric bulk intolerance at both sites. 4-Hydroxy-THBA ( 15), which can be considered a conformationally-restricted analogue of 3-hydroxymethyl-THIQ ( 30), exhibited poorer PNMT inhibitory activity and less selectivity than 30 ( 15: PNMT K i=58 μM, α 2 K i=100 μM, selectivity=1.7; 30: PNMT K i=1.1 μM, α 2 K i=6.6 μM, selectivity=6.0). While the addition of an 8-nitro group to 15 increased the selectivity of 16 as compared to its THIQ analogue ( 31), it was not as potent at PNMT nor as selective as 8-nitro-THBA ( 3) ( 16, PNMT K i=5.3 μM, α 2 K i=680 μM, selectivity=130; 31: PNMT K i=0.29 μM, α 2 K i=19 μM, selectivity=66). Compound 3 is the most selective (PNMT/α 2) and one of the more potent at PNMT compounds yet reported in the benzazepine series, and should have sufficient lipophilicity to penetrate the blood–brain barrier (CLogP=1.8).

Synthesis of [formula omitted] acid and two of its conformationally-restricted analogs

Synthesis of the titled tetrahydropyrimidoazepine-based folate ( 6a) is described using a regiospecific γ-alkylation reaction between the dienolate generated from 3-carboethoxy- N-2,4-dimethoxybenzyl-1,5,6,7-tetrahydro-(1 H)-azepin-2-one ( 33) and methyl 4-formylbenzoate, as the key step. The isoxazolinopyrimidoazepine and isoxazolopyrimidoazepine-based folates ( 7a and 8a respectively) were also prepared (via intramolecular 1,3-dipolar cycloaddition chemistry) as conformationally-restricted analogs of 6a. All three compounds were prepared as potential antitumor agents based on the known, structurally related, antitumor agent 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF). Both 7a and 8a were inactive in the human colon carcinoma (GC3c1) cell culture assay. Compound 6a, however, was weakly active (IC 50 = 2.0 μM) in the above assay.

Nonsteroidal progesterone receptor antagonists based on a conformationally-restricted subseries of 6-aryl-1,2-dihydro-2,2,4-trimethylquinolines

A series of nonsteroidal human progesterone receptor (hPR) antagonists based on conformationally-restricted analogues of a 6-aryl-1,2-dihydro-2,2,4-trimethylquinoline pharmacophore were synthesized and evaluated for their ability to bind to the human progesterone receptor and inhibit progesterone-stimulated reporter gene expression in mammalian cells.

Design, synthesis and properties of conformationally-restricted lipid mimetics.

Polyunsaturated fatty acids (PUFAs) and arachidonic acid in particular, play an important role in membrane biogenesis, metabolic processes and signalling pathways [ 1,2]. At the molecular level, little is known concerning the mechanism by which fatty acids exert their effects despite the fact that specific conformations usually correspond to specific biological activities. It should be possible therefore to select a particular activity by structural modifications of the PUFAs, leading to restricted conformational mobility. Computer simulation studies of arachidonic acid [3,4] enabled the design of conformationally-restricted PUFAs analogues. In particular, peptido-PUFAs where the C=C bonds were replaced by peptide isosters have proved to be successfully constrained analogues, when molecular dynamics simulations have been applied to them [4]. Here we report, for the fmt time, the structural properties, studied by high field NMR, of a series of lipid mimetics detailed in Figure I . Peptido and retro ieptido-arachidonate analogues (M, = 372g/mol), peptido and retro peptido:icosapentaenoate analogues (M, = 387g/mol), peptido and retro peptidodocosahexenoate analogue (M, = 430 g/mol), based on a glycine backbone will be referred respectively thereafter as the Gly3, RetroGly3, Gly4, RetroGly4, Gly5, RetroGlyS analogues. The equivalent analogues with a methyl group at each C, positions will be named after the alanine motif they contain ie : Ala3, RetroAla3 (M, = 414g/mol), Ala4, RetroAld (M, = 443g/mol), Alas, RetroAla5 (M, = 500g/mol). The entire series of analogues except Ala3, Ala4, Alas was synthesized by solid phase synthesis, purified by HPLC and the molecular weight confirmed by electrospray mass spectrometry. ID and 2D high field NMR experiments were performed on a Bruker AM 600 spectrometer. All the analogues were studied in TFE-d2, but RetroAla3, RetroAla4 and RetroAla5 were also studied in D,O plus TSP. Chemical shifts were then referenced to the residual signals for TFE-d2 at 3.9 ppm or TSP at 0 ppm. 2D

Design, synthesis, and pharmacological evaluation of potent xanthone dicarboxylic acid leukotriene B4 receptor antagonists.

In an effort to develop increasingly potent and specific leukotriene B4 (LTB4) receptor antagonists, several xanthone dicarboxylic acids were synthesized and evaluated. Two separate synthetic routes were used to construct a xanthone nucleus containing a regiospecific orientation of each carboxylic acid pharmacophore. These compounds represent the major conformationally-restricted analogues of benzophenone dicarboxylic acids previously shown to antagonize the activation of human neutrophils by LTB4. The most potent agent was compound 32, which inhibited the specific binding of [3H]LTB4 to receptors on intact human neutrophils (IC50, 6.2 +/- 0.1 nM), LTB4-induced luminol-dependent chemiluminescence (IC50, 55 +/- 11 nM), aggregation (IC50, 133 +/- 42 nM), and chemotaxis (IC50, 899 +/- 176 nM). The compound was a poor antagonist of N-formyl-L-methionyl-L-leucyl-L-phenylalanine-induced chemiluminescence (IC50, 1599 +/- 317 nM) and aggregation (IC50, 2166 +/- 432 nM), indicating specificity in the inhibition of LTB4-stimulated events. Compound 32 (LY210073), which was completely devoid of agonist activity, appears to be one of the strongest inhibitors of LTB4 receptor binding reported so far.

A cyclic peptide T analogue with high chemotactic activity

Peptide T is an octapeptide (H-Ala-Ser-Thr-Thr-Thr-Asn-Tyr-Thr-OH) based on a consensus sequence that has been identified in HIV proteins. Two conformationally-restricted analogues of peptide T fragment (H-Thr-Thr-Asn-Tyr-Thr-OH) were synthesized by cyclisation of the N-terminal amino group of Thr to the α- or β-carboxyl moiety of Asp introduced at the C-terminus of the peptide. The cyclo Thr-Thr-Asn-Tyr-Thr-Asp(OH) (Cα) showed high in vitro chemotactic activity, whereas the conformational restriction introduced into Thr-Thr-Asn-Tyr-Thr-A sp-OH was incompatible with the CD 4 receptor. The cyclic analogue Cα was more active than its ester and the open-chain reference compound H-Thr-Thr-Asn-Tyr-Thr-Asp-OH. It also proved to be highly resistant to degradation by plasma or brain enzymes.

GABAA agonists as targets for drug development.

1. Agents with selective actions on bicuculline-sensitive GABAA receptors have been developed by systematically restricting the conformational mobility of the GABA molecule. 2. THIP, a bicyclic isoxazole that represents GABA held in a relatively rigid and partially extended conformation, is an analgesic of potency comparable to that of morphine. THIP represents a lead compound for a novel series of analgesics acting independently of Naloxone-sensitive opiate systems. 3. ZAPA, a conformationally-restricted analogue of GABA containing an isothiouronium moiety, is a selective agonist for low affinity GABAA receptors and is a lead compound for the development of a novel series of anthelmintics. 4. (+)-TACP, a cyclopentane analogue of GABA, may activate a different subclass of GABAA receptors from THIP. 5. Pharmacological, molecular modelling and molecular biological studies provide evidence for a heterogeneity of GABAA receptors which might be exploited for drug development.

Molecular features necessary for the uptake of diamines and related compounds by the polyamine receptor of rat lung slices

The influence of 17 putrescine analogues on the uptake of putrescine and/or paraquat by rat lung slices has been determined. Most of these compounds are competitive inhibitors of putrescine and/ or paraquat uptake, but three show no inhibiting activity. Apparent K i values of the putrescine derivatives increase, and thus the inhibitory effects decrease, with increasing N-methylation. Comparison of N-methyl-1,4-diaminobutane ( K i , = 8 μM) with N, N′-bis-methyl-1,4-diaminobutane ( K i = 25.5 μM) shows that a single primary amino group is desirable for high inhibiting activity. Dimethylation at one amino function does not greatly decrease inhibitory potential (thus N, N′-dimethyl-1,4-diaminobutane has K i = 11.5 μM). Increasing the size of N-alkyl substituents in putrescine derivatives, decreased their inhibitory action on the uptake of putrescine. Investigation of the effect of conformationally-restricted analogues of putrescine shows that both ( E) and ( Z) isomers of 1,4-diaminobut-2-ene are poor inhibitors of putrescine uptake. Analogues of putrescine with bulky substituents on the butyl chain, i.e. the meso-and rac-isomers of l,1-dichloro-2,3-diaminomethylcyclopropane, do not inhibit putrescine uptake. Inhibiting putrescine derivatives which contain aziridine groups are competitive inhibitors of putrescine and paraquat uptake. Surprisingly, N-(4-aminobutyl)aziridine is the most effective inhibitor of putrescine uptake studied, and is a better inhibitor of paraquat uptake than the endogenous polyamine, putrescine. N-(4-Aminobutyl)aziridine binds reversibly to the polyamine transporter and its inhibitory effects do not appear to be due to any cytotoxic activity of the aziridine. The parameter A (mM) −1 defined as 1000 K i (where K i units are μM) was taken as a measure of the affinity of a compound for the polyamine receptor in this paper.

Conformationally-restricted analogs of TXA 2 antagonist SQ 33,961: Receptor binding conformation of the carboxyl sidechain

Two distinct conformational families, exemplified by 1 and 2, of thromboxane A 2 (TxA 2 receptor antagonist SQ 33,961 have been determined by molecular modeling. Synthesis and biological evaluation of confromationally-restricted mimic 3Z suggested that the hairpin conformer, 1, is the bioactive conformation.

1,4-thiazanes as conformationally-restricted analogs of the peptido-leukotrienes

A new class of leukotriene antagonists is proposed which represent rigidified approximations of the solution conformation of the peptido-leukotrienes. A representative member of this class has been synthesized and shown to elicit response in the guinea pig ileum assay.

Structure-activity studies on amphetamine analogs using drug discrimination methodology

Animals (rats) trained to discriminate 1.0 mg/kg of S(+)-amphetamine sulfate from saline, using a standard operant training procedure, were administered doses of various amphetamine analogs in tests of stimulus generalization in order to study structure-activity relationships (SAR). The types of structural variation of the amphetamine molecule that were investigated included (a) benz-fusion of the aromatic nucleus, (b) alpha-demethylation of the alkyl side chain, (c) conversion of the benzylic methylene to a carbonyl group, and (d) conformational restriction of the side chain. Benz-fusion and alpha-demethylation appear to have a detrimental effect on activity in that none of these analogs produced amphetamine-appropriate responding. However, the carbonylated analog, i.e., cathinone, was found to be equipotent with amphetamine. Furthermore, as with amphetamine, the S-isomer of cathinone was found to be more active than its enantiomer. With respect to the conformationally-restricted analogs, the most potent compound was 2-aminotetralin which was about half as active as racemic amphetamine.

ChemInform Abstract: STEREOCHEMISTRY OF CONFORMATIONALLY RESTRICTED ANALOGS OF THE ANTITUMOR AGENT ICRF‐159: CRYSTAL AND MOLECULAR STRUCTURES OF CIS‐ AND TRANS‐CYCLOPROPYLBIS(DIOXOPIPERAZINE)

Chemischer InformationsdienstVolume 13, Issue 39 Physical Organic Chemistry ChemInform Abstract: STEREOCHEMISTRY OF CONFORMATIONALLY RESTRICTED ANALOGS OF THE ANTITUMOR AGENT ICRF-159: CRYSTAL AND MOLECULAR STRUCTURES OF CIS- AND TRANS-CYCLOPROPYLBIS(DIOXOPIPERAZINE) A. HEMPEL, A. HEMPELSearch for more papers by this authorN. CAMERMAN, N. CAMERMANSearch for more papers by this authorA. CAMERMAN, A. CAMERMANSearch for more papers by this author A. HEMPEL, A. HEMPELSearch for more papers by this authorN. CAMERMAN, N. CAMERMANSearch for more papers by this authorA. CAMERMAN, A. CAMERMANSearch for more papers by this author First published: September 28, 1982 https://doi.org/10.1002/chin.198239083AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume13, Issue39September 28, 1982 RelatedInformation

Excitatory and inhibitory actions of ibotenic acid on frog spinal motoneurones in vitro

Ibotenic acid (IBO), a conformationally-restricted analogue of the putative excitatory transmitter glutamate, produced biphasic effects on frog spinal motoneurones recorded with DC-coupled Ag/AgCl electrodes placed on the central end of ventral roots. The initial effect consisted of a motoneuronal depolarization with an increase in excitability tested with low-intensity dorsal root stimulation (the depolarizing activity of IBO was about 6 times greater than that of glutamate). On washout, the depolarizing effect of IBO subsided and complete motoneuronal repolarization occured; however, motoneuronal responses to glutamate and to trans-synaptic stimulation remained depressed for prolonged periods. This depressant effect was not reproduced following prolonged administration of depolarizing doses of glutamate but it was similar to that produced by muscimol, an agonist on inhibitory GABA receptors. Unlike the muscimol-evoked depression, the IBO-induced depression was insensitive to bicuculline and was antagonized by local anaesthetics or high Mg 2+ solutions. It is suggested that a substantial part of the IBO depressant action is likely due to release of long-acting inhibitory transmitters onto motoneurones.