PPARγ agonist DIM‐Ph‐4‐CF 3 , a template for RXRα agonist (E)‐3‐[5‐di(1‐methyl‐1H‐indol‐3‐yl)methyl‐2‐thienyl] acrylic acid: DIM‐Ph‐CF3 is reported to inhibit cancer growth independent of PPARγ and to interact with NR4A1. As both receptors dimerize with RXR, and natural PPARγ ligands activate RXR, DIM‐Ph‐4‐CF3 was investigated as an RXR ligand. It displaces 9‐cis‐retinoic acid from RXRα but does not activate RXRα. Structure‐based direct design led to an RXRα agonist.
Twofold sila‐substitution (C/Si exchange) of the clinically used RXR‐selective retinoid agonist bexarotene leads to disila‐bexarotene, which displays pharmacological potency similar to that of the parent carbon compound, as shown in a HeLa‐cell‐based RXR assay. Formal exchange of the SiCH2CH2Si group in disila‐bexarotene with a SiCH2Si or SiOSi moiety leads to the disila‐bexarotene analogues 8 and 9 . The silicon compounds 8 and 9 were synthesized in multistep syntheses, starting from HC?C(CH3)2SiCH2Si(CH3)2C?CH and HC?C(CH3)2SiOSi(CH3)2C?CH, respectively. The key step in the syntheses of 8 and 9 is a cobalt‐catalyzed [2+2+2] cycloaddition reaction that affords the 1,3‐disilaindane and 2‐oxa‐1,3‐disilaindane skeletons. Disila‐bexarotene and its analogues 8 and 9 were studied for their biological effects relative to all‐trans retinoic acid in cultured human pluripotent stem cells. The parent carbon compound bexarotene was included in some of these biological studies. Although the silicon‐containing bexarotene analogues disila‐bexarotene, 8 , and 9 appear not to regulate the differentiation of TERA2.cl.SP12 stem cells, preliminary evidence indicates that these compounds may possess enhanced functions over the parent compound bexarotene, such as induction and regulation of cell death and cell numbers. The biological data obtained indicate that bexarotene, contrary to the silicon‐containing analogues disila‐bexarotene, 8 , and 9 , may partially act to induce cell differentiation. 相似文献
The ρ‐containing γ‐aminobutyric acid type A receptors (GABAARs) play an important role in controlling visual signaling. Therefore, ligands that selectively target these GABAARs are of interest. In this study, we demonstrate that the partial GABAAR agonist imidazole‐4‐acetic acid (IAA) is able to penetrate the blood–brain barrier in vivo; we prepared a series of α‐ and N‐alkylated, as well as bicyclic analogues of IAA to explore the structure–activity relationship of this scaffold focusing on the acetic acid side chain of IAA. The compounds were prepared via IAA from l ‐histidine by an efficient minimal‐step synthesis, and their pharmacological properties were characterized at native rat GABAARs in a [3H]muscimol binding assay and at recombinant human α1β2γ2S and ρ1 GABAARs using the FLIPR? membrane potential assay. The (+)‐α‐methyl‐ and α‐cyclopropyl‐substituted IAA analogues ((+)‐ 6 a and 6 c , respectively) were identified as fairly potent antagonists of the ρ1 GABAAR that also displayed significant selectivity for this receptor over the α1β2γ2S GABAAR. Both 6 a and 6 c were shown to inhibit GABA‐induced relaxation of retinal arterioles from porcine eyes. 相似文献
Cellular DNA continuously suffers various types of damage, and unrepaired damage increases disease progression risk. 8‐Oxo‐2′‐deoxyguanine (8‐oxo‐dG) is excised by repair enzymes, and their analogues are of interest as inhibitors and as bioprobes for study of these enzymes. We have developed 8‐halogenated‐7‐deaza‐2′‐deoxyguanosine derivatives that resemble 8‐oxo‐dG in that they adopt the syn conformation. In this study, we investigated their effects on Fpg (formamidopyrimidine DNA glycosylase) and hOGG1 (human 8‐oxoguanine DNA N‐glycosylase 1). Relative to 8‐oxo‐dG, Cl‐ and Br‐deaza‐dG were good substrates for Fpg, whereas they were less efficient substrates for hOGG1. Kinetics and binding experiments indicated that, although hOGG1 effectively binds Cl‐ and Br‐deaza‐dG analogues with low Km values, their lower kcat values result in low glycosylase activities. The benefits of the high binding affinities and low reactivities of 8‐oxo‐dG analogues with hOGG1 have been successfully applied to the competitive inhibition of the excision of 8‐oxoguanine from duplex DNA by hOGG1. 相似文献
AMOP‐H‐OH (sazetidine‐A; 6‐[5‐(azetidin‐2‐ylmethoxy)pyridin‐3‐yl]hex‐5‐yn‐1‐ol) and some sulfur‐bearing analogues were tested for their activities in vitro against human α4β2‐, α4β4‐, α3β4*‐ and α1*‐nicotinic acetylcholine receptors (nAChRs). AMOP‐H‐OH was also assessed in an antidepressant efficacy model. AMOP‐H‐OH and some of its analogues have high potency and selectivity for α4β2‐nAChRs over other nAChR subtypes. Effects are manifested as partial agonism, perhaps reflecting selectivity for high sensitivity (α4)3(β2)2‐nAChRs. More prolonged exposure to AMOP‐H‐OH and its analogues produces inhibition of subsequent responses to acute challenges with full nicotinic agonists, again selectively for α4β2‐nAChRs over other nAChR subtypes. The inhibition is mediated either via antagonism or desensitization of nAChR function, but the degree of inhibition of α4β2‐nAChRs is limited by the partial agonist activity of the drugs. Certain aspects of the in vitro pharmacology suggest that AMOP‐H‐OH and some of its analogues have a set of binding sites on α4β2‐nAChRs that are distinct from those for full agonists. The in vitro pharmacological profile suggests that peripheral side effects of AMOP‐H‐OH or its analogues would be minimal and that their behavioral effects would be dominated by central nAChR actions. AMOP‐H‐OH also has profound and high potency antidepressant‐like effects in the forced swim test. The net action of prolonged exposure to AMOP‐H‐OH or its analogues, as for nicotine, seems to be a selective decrease in α4β2‐nAChR function. Inactivation of nAChRs may be a common neurochemical endpoint for nicotine dependence, its treatment, and some of its manifestations, including relief from depression.相似文献
Herein we describe the synthesis and structure–activity relationships of 3‐aminocyclohex‐2‐en‐1‐one derivatives as novel chemokine receptor 2 (CXCR2) antagonists. Thirteen out of 44 derivatives were found to inhibit CXCR2 downstream signaling in a Tango assay specific for CXCR2, with IC50 values less than 10 μm . In silico ADMET prediction suggests that all active compounds possess drug‐like properties. None of these compounds show significant cytotoxicity, suggesting their potential application in inflammatory mediated diseases. A structure–activity relationship (SAR) map has been generated to gain better understanding of their binding mechanism to guide further optimization of these new CXCR2 antagonists. 相似文献
In recent years, DAPK‐related apoptosis‐inducing protein kinase 2 (DRAK2) has emerged as a promising target for the treatment of a variety of autoimmune diseases and for the prevention of graft rejection after organ transplantation. However, medicinal chemistry optimization campaigns for the discovery of novel small‐molecule inhibitors of DRAK2 have not yet been published. Screening of a proprietary compound library led to the discovery of a benzothiophene analogue that displays an affinity constant (Kd) value of 0.25 μM . Variation of the core scaffold and of the substitution pattern afforded a series of 5‐arylthieno[2,3‐b]pyridines with strong binding affinity (Kd=0.008 μM for the most potent representative). These compounds also show promising activity in a functional biochemical DRAK2 enzyme assay, with an IC50 value of 0.029 μM for the most potent congener. Selectivity profiling of the most potent compounds revealed that they lack selectivity within the DAPK family of kinases. However, one of the less potent analogues is a selective ligand for DRAK2 and can be used as starting point for the synthesis of selective and potent DRAK2 inhibitors. 相似文献
The involvement of the serotonin 5‐HT1A receptor (5‐HT1A‐R) in the antidepressant effect of allyphenyline and its analogues indicates that ligands bearing the 2‐substituted imidazoline nucleus as a structural motif interact with 5‐HT1A‐R. Therefore, we examined the 5‐HT1A‐R profile of several imidazoline molecules endowed with a common scaffold consisting of an aromatic moiety linked to the 2‐position of an imidazoline nucleus by a biatomic bridge. Our aim was to discover other ligands targeting 5‐HT1A‐R and to identify the structural features favoring 5‐HT1A‐R interaction. Structure–activity relationships, supported by modeling studies, suggested that some structural cliché such as a polar function and a methyl group in the bridge, as well as proper steric hindrance in the aromatic area of the above scaffold, favored 5‐HT1A‐R recognition and activation. We also highlighted the potent antidepressant‐like effect (mouse forced swimming test) of (S)‐(+)‐ 19 [(S)‐(+)‐naphtyline] at very low dose (0.01 mg kg?1). This effect was clearly mediated by 5‐HT1A, as it was significantly reduced by pretreatment with the 5‐HT1A antagonist WAY100635. 相似文献
9‐cis‐Retinoic acid was identified and claimed to be the endogenous ligand of the retinoid X receptors (RXRs) in 1992. Since then, the endogenous presence of this compound has never been rigorously confirmed. Instead, concerns have been raised by other groups that have reported that 9‐cis‐retinoic acid is undetectable or that its presence occurs at very low levels. Furthermore, these low levels could not satisfactorily explain the physiological activation of RXR. Alternative ligands, among them various lipids, have also been identified, but also did not fulfill criteria for rigorous endogenous relevance, and their consideration as bona fide endogenous mammalian RXR ligand has likewise been questioned. Recently, novel studies claim that the saturated analogue 9‐cis‐13,14‐dihydroretinoic acid functions as an endogenous physiologically relevant mammalian RXR ligand. 相似文献
The four stereoisomers of azetidine‐2,3‐dicaroxylic acid (L ‐trans‐ADC, L ‐cis‐ADC, D ‐trans‐ADC, and D ‐cis‐ADC) were synthesized in a stereocontrolled fashion following two distinct strategies: one providing the two cis‐ADC enantiomers and one giving access to the two trans‐ADC enantiomers. The four azetidinic amino acids were characterized in a radioligand binding assay ([3H]CGP39653) at native NMDA receptors: L ‐trans‐ADC showed the highest affinity (Ki=10μM ) followed by the D ‐cis‐ADC stereoisomer (21μM ). In contrast, the two analogues L ‐cis‐ADC and D ‐trans‐ADC were low‐affinity ligands (>100 and 90μM , respectively). Electrophysiological characterization of the ADC compounds at the four NMDA receptor subtypes NR1/NR2A, NR1/NR2B, NR1/NR2C, and NR1/NR2D expressed in Xenopus oocytes showed that L ‐trans‐ADC displayed the highest agonist potency at NR1/NR2D (EC50=50μM ), which was 9.4‐, 3.4‐, and 1.9‐fold higher than the respective potencies at NR1/NR2A–C. D ‐cis‐ADC was shown to be a partial agonist at NR1/NR2C and NR1/NR2D with medium‐range micromolar potencies (EC50=720 and 230μM , respectively). A subsequent in silico ligand–protein docking study suggested an unusual binding mode for these amino acids in the agonist binding site. 相似文献
4‐{[(4‐Cyanophenyl)(4H‐1,2,4‐triazol‐4‐yl)amino]methyl}phenyl sulfamate and its ortho‐halogenated (F, Cl, Br) derivatives are first‐generation dual aromatase and sulfatase inhibitors (DASIs). Structure–activity relationship studies were performed on these compounds, and various modifications were made to their structures involving relocation of the halogen atom, introduction of more halogen atoms, replacement of the halogen with another group, replacement of the methylene linker with a difluoromethylene linker, replacement of the para‐cyanophenyl ring with other ring structures, and replacement of the triazolyl group with an imidazolyl group. The most potent in vitro DASI discovered is an imidazole derivative with IC50 values against aromatase and steroid sulfatase in a JEG‐3 cell preparation of 0.2 and 2.5 nM , respectively. The parent phenol of this compound inhibits aromatase with an IC50 value of 0.028 nM in the same assay. 相似文献
Ruthenium complexes are currently considered to be among the most promising alternatives to platinum anticancer drugs. In this work, thirteen structural analogues and organelle/receptor‐targeting peptide bioconjugates of a cytotoxic bis(dppz)‐RuII complex [Ru(dppz)2(CppH)](PF6)2 ( 1 ) were prepared, characterized, and assessed for their cytotoxicity and cellular localization (CppH=2‐(2′‐pyridyl)pyrimidine‐4‐carboxylic acid; dppz=dipyrido[3,2‐a:2′,3′‐c]phenazine). It was observed that structural modifications (lipophilicity, charge, and size‐based) result in the cytotoxic potency of 1 being compromised. Confocal microscopy studies revealed that unlike 1 , the screened complexes/bioconjugates do not have a preferential accumulation in mitochondria. The results of this important structure–activity relationship strongly support our initial hypothesis that accumulation in mitochondria is crucial for 1 to exert its cytotoxic action. 相似文献
Subtype‐selective ligands are of great interest to the scientific community, as they provide a tool for investigating the function of one receptor or transporter subtype when functioning in its native environment. Several 4‐substituted (S)‐glutamate (Glu) analogues were synthesized, and altogether this approach has provided important insight into the structure–activity relationships (SAR) for ionotropic and metabotropic glutamate receptors (iGluRs and mGluRs), as well as the excitatory amino acid transporters (EAATs). In this work, three 4,4‐disubstituted Glu analogues 1 – 3 , which are hybrid structures of important 4‐substituted Glu analogues 4 – 8 , were investigated at iGluRs and EAATs. Collectively, their pharmacological profiles add new and valuable information to the SAR for the iGluRs and EAAT1–3.相似文献
Metabolically stabilized analogues of PtdIns(3,4,5)P3 have shown long‐lived agonist activity for cellular events and selective inhibition of lipid phosphatase activity. We describe an efficient asymmetric synthesis of two 5‐phosphatase‐resistant analogues of PtdIns(3,4,5)P3, the 5‐methylene phosphonate (MP) and 5‐phosphorothioate (PT). Furthermore, we illustrate the biochemical and biological activities of five stabilized PtdIns(3,4,5)P3 analogues in four contexts. First, the relative binding affinities of the 3‐MP, 3‐PT, 5‐MP, 5‐PT, and 3,4,5‐PT3 analogues to the Grp1 PH domain are shown, as determined by NMR spectroscopy. Second, the enzymology of the five analogues is explored, showing the relative efficiency of inhibition of SHIP1, SHIP2, and phosphatase and tensin homologue deleted on chromosome 10 (PTEN), as well as the greatly reduced ability of these phosphatases to process these analogues as substrates as compared to PtdIns(3,4,5)P3. Third, exogenously delivered analogues severely impair complement factor C5a‐mediated polarization and migration of murine neutrophils. Finally, the new analogues show long‐lived agonist activity in mimicking insulin action in sodium transport in A6 cells.相似文献
Thirty two analogues of phencyclidine were synthesised and tested as inhibitors of trypanothione reductase (TryR), a potential drug target in trypanosome and leishmania parasites. The lead compound BTCP ( 1 , 1‐(1‐benzo[b]thiophen‐2‐yl‐cyclohexyl) piperidine) was found to be a competitive inhibitor of the enzyme (Ki=1 μM ) and biologically active against bloodstream T. brucei (EC50=10 μM ), but with poor selectivity against mammalian MRC5 cells (EC50=29 μM ). Analogues with improved enzymatic and biological activity were obtained. The structure–activity relationships of this novel series are discussed.相似文献
P‐glycoprotein (P‐gp)‐mediated multidrug resistance (MDR) is a major obstacle for successful cancer chemotherapy. Based on our previous study, 17 novel compounds with the 6,7‐dimethoxy‐2‐{2‐[4‐(1H‐1,2,3‐triazol‐1‐yl)phenyl]ethyl}‐1,2,3,4‐tetrahydroisoquinoline scaffold were designed and synthesized. Among them, 2‐[(1‐{4‐[2‐(6,7‐dimethoxy‐3,4‐dihydroisoquinolin‐2(1H)‐yl)ethyl]phenyl}‐1H‐1,2,3‐triazol‐4‐yl)methoxy]‐N‐(p‐tolyl)benzamide (compound 7 h ) was identified as a potent modulator of P‐gp‐mediated MDR, with high potency (EC50=127.5±9.1 nM ), low cytotoxicity (TI>784.3), and long duration (>24 h) in reversing doxorubicin (DOX) resistance in K562/A02 cells. Compound 7 h also enhanced the effects of other MDR‐related cytotoxic agents (paclitaxel, vinblastine, and daunorubicin), increased the accumulation of DOX and blocked P‐gp‐mediated rhodamine 123 efflux function in K562/A02 MDR cells. Moreover, 7 h did not have any effect on cytochrome (CYP3A4) activity. These results indicate that 7 h is a relatively safe modulator of P‐gp‐mediated MDR that has good potential for further development. 相似文献
Palladium‐catalyzed C N bond forming reactions of 6‐bromo‐ as well as 6‐chloropurine ribonucleosides and the 2′‐deoxy analogues with arylamines are described. Efficient conversions were observed with palladium(II) acetate/Xantphos/cesium carbonate, in toluene at 100 °C. Reactions of the bromonucleoside derivatives could be conducted at a lowered catalytic loading [5 mol% Pd(OAc)2/7.5 mol% Xantphos], whereas good product yields were obtained with a higher catalyst load [10 mol% Pd(OAc)2/15 mol% Xantphos] when the chloro analogue was employed. Among the examples evaluated, silyl protection for the hydroxy groups appears better as compared to acetyl. The methodology has been evaluated via reactions with a variety of arylamines and by synthesis of biologically relevant deoxyadenosine and adenosine dimers. This is the first detailed analysis of aryl amination reactions of 6‐chloropurine nucleosides, and comparison of the two halogenated nucleoside substrates. 相似文献