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1.
Three heterocyclic systems were selected as potential bioisosteres of the amide linker for a series of 1,6-disubstituted-4-quinolone-3-carboxamides, which are potent and selective CB2 ligands that exhibit poor water solubility, with the aim of improving their physicochemical profile and also of clarifying properties of importance for amide bond mimicry. Among the newly synthesized compounds, a 1,2,3-triazole derivative (1-(adamantan-1-yl)-4-[6-(furan-2-yl)-1,4-dihydro-4-oxo-1-pentylquinolin-3-yl]-1H-1,2,3-triazole) emerged as the most promising in terms of both physicochemical and pharmacodynamic properties. When assayed in vitro, this derivative exhibited inverse agonist activity, whereas, in the formalin test in mice, it produced analgesic effects antagonized by a well-established inverse agonist. Metabolic studies allowed the identification of a side chain hydroxylated derivative as its only metabolite, which, in its racemic form, still showed appreciable CB2 selectivity, but was 150-fold less potent than the parent compound.  相似文献   

2.
3.
Among the twelve catalytically active carbonic anhydrase isozymes present in the human body, the CAIX is highly overexpressed in various solid tumors. The enzyme acidifies the tumor microenvironment enabling invasion and metastatic processes. Therefore, many attempts have been made to design chemical compounds that would exhibit high affinity and selective binding to CAIX over the remaining eleven catalytically active CA isozymes to limit undesired side effects. It has been postulated that such drugs may have anticancer properties and could be used in tumor treatment. Here we have designed a series of compounds, methyl 5-sulfamoyl-benzoates, which bear a primary sulfonamide group, a well-known marker of CA inhibitors, and determined their affinities for all twelve CA isozymes. Variations of substituents on the benzenesulfonamide ring led to compound 4b, which exhibited an extremely high observed binding affinity to CAIX; the Kd was 0.12 nM. The intrinsic dissociation constant, where the binding-linked protonation reactions have been subtracted, reached 0.08 pM. The compound also exhibited more than 100-fold selectivity over the remaining CA isozymes. The X-ray crystallographic structure of compound 3b bound to CAIX showed the structural position, while several structures of compounds bound to other CA isozymes showed structural reasons for compound selectivity towards CAIX. Since this series of compounds possess physicochemical properties suitable for drugs, they may be developed for anticancer therapeutic purposes.  相似文献   

4.
The MT2-selective melatonin receptor ligand UCM765 (N-(2-((3-methoxyphenyl)(phenyl)amino)ethyl)acetamide), showed interesting sleep inducing, analgesic and anxiolytic properties in rodents, but suffers from low water solubility and modest metabolic stability. To overcome these limitations, different strategies were investigated, including modification of metabolically liable sites, introduction of hydrophilic substituents and design of more basic derivatives. Thermodynamic solubility, microsomal stability and lipophilicity of new compounds were experimentally evaluated, together with their MT1 and MT2 binding affinities. Introduction of a m-hydroxymethyl substituent on the phenyl ring of UCM765 and replacement of the replacement of the N,N-diphenyl-amino scaffold with a N-methyl-N-phenyl-amino one led to highly soluble compounds with good microsomal stability and receptor binding affinity. Docking studies into the receptor crystal structure provided a rationale for their binding affinity. Pharmacokinetic characterization in rats highlighted higher plasma concentrations for the N-methyl-N-phenyl-amino derivative, consistent with its improved microsomal stability and makes this compound worthy of consideration for further pharmacological investigation.  相似文献   

5.
Different Mannich base derivatives have been studied with the aim of addressing the poor aqueous solubility of the recently disclosed 6-phenethyl-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one ( 1 ), a human butyrylcholinesterase inhibitor (hBChE, IC5013 nM) and protective agent in NMDA-induced neurotoxicity, in in vivo assays. The N-(4-methylpiperazin-1-yl)methyl derivative 2 c showed a 50-fold increase in solubility in pH 7.4-buffered solution, high stability in serum and (half-life >24 h) and rapid (<3 min) conversion to 1 at acidic pH. Although less active than 1 , 2 c retained moderate hBChE inhibition (IC50=3.35 μM) and a significant protective effect against NMDA-induced neurotoxicity at 0.1 μM. Moreover, 2 c resulted a weaker serum albumin binder than 1 , could pass the blood–brain barrier, and exerted negligible cytotoxicity on HepG2 cells. These findings suggest that 2 c could be a water-soluble prodrug candidate of 1 for oral administration or a slow-release injectable derivative in in vivoAlzheimer's disease models.  相似文献   

6.
Quartz crystal microbalance (QCM) was used as an in situ detector to investigate the potential application in the phase equilibrium determination of supercritical CO2-drug-polymer systems. CO2 solubility in two biodegradable polymers, poly(d,l-lactic acid) (d,l-PLA) and poly(l-lactic acid) (l-PLA) was primarily measured at 313.15 K and pressures up to 10.0 MPa. d,l-PLA showed a better CO2 absorption ability due to its amorphous structure. Four drug model compounds of poor solubility in water, ibuprofen, aspirin, salicylic acid and naphthalene were selected as representatives for the examination of drug uptake in PLA matrices, as well as partition coefficient during supercritical impregnation. It was found that partition coefficients of drugs can reach as high as 103-104 orders of magnitude and greatly affected by the intermolecular interactions between drugs and PLA. Aspirin exhibited the best partitioning during the supercritical impregnation at pressures of 8.0-10.0 MPa due to the existence of carboxylic acid and acetyl groups. Drug partitioning is additionally related to the drug concentration in ScCO2, i.e. salicylic acid showed little absorption in PLA according to its poor solubility in ScCO2 at 7.5-8.0 MPa, whereas the well CO2-soluble compound, naphthalene, exhibited a moderate partition coefficient although its polarity was different from l-PLA.  相似文献   

7.
The natural product piperlonguminine (PL) has been shown to exert potential anticancer activity against several types of cancer via elevation of reactive oxidative species (ROS). However, the application of PL has been limited due to its poor water solubility and moderate activity. To improve PL's potency, we designed and synthesized a series of 17 novel phenylmethylenecyclohexenone derivatives and evaluated their pharmacological properties. Most of them exerted antiproliferative activities against four cancer cell lines with IC50 values lower than PL. Among these, compound 10 e not only showed good water solubility and exerted the most potent antiproliferative activity against HGC27 cells (IC50=0.76 μM), which was 10-fold lower than PL (IC50=7.53 μM), but also exhibited lower cytotoxicity in human normal gastric epithelial cells GES-1 compared with HGC27 cells. Mechanistically, compound 10 e inhibited thioredoxin reductase (TrxR) activity, increased ROS levels, and diminished mitochondrial transmembrane potential (MTP) in HGC27 cells. Furthermore, 10 e also induced G2/M cell-cycle arrest, and triggered cancer cell apoptosis through the regulation of apoptotic proteins. Finally, 10 e promoted DNA damage in HGC27 cells via the activation of the H2AX(S139ph) and p53 signaling. In conclusion, 10 e , with prominent tumor selectivity and water solubility, could be a promising candidate for the treatment of cancer and, as such, warrants further investigation.  相似文献   

8.
Halogenated pyrrolo[3,2‐d]pyrimidine analogues have shown antiproliferative activity in recent studies, with cell accumulation occurring in the G2/M stage without apoptosis. However, the mechanism of action and pharmacokinetic (PK) profile of these compounds has yet to be determined. To investigate the PK profile of these compounds, a series of halogenated pyrrolo[3,2‐d]pyrimidine compounds was synthesized and first tested for activity in various cancer cell lines followed by a mouse model. EC50 values ranged from 0.014 to 14.5 μm , and maximum tolerated doses (MTD) in mice were between 5 and 10 mg kg?1. This indicates a wide variance in activity and toxicity that necessitates further study. To decrease toxicity, a second series of compounds was synthesized with N5‐alkyl substitutions in an effort to slow the rate of metabolism, which was thought to be leading to the toxicity. The N‐substituted compounds demonstrated comparable cell line activity (EC50 values between 0.83–7.3 μm ) with significantly decreased toxicity (MTD=40 mg kg?1). Finally, the PK profile of the active N5‐substituted compound shows a plasma half‐life of 32.7 minutes, and rapid conversion into the parent unsubstituted analogue. Together, these data indicate that halogenated pyrrolo[3,2‐d]pyrimidines present a promising lead into potent antiproliferative agents with tunable activity and toxicity, and rapid metabolism.  相似文献   

9.
A new type of double prodrug of the antiviral family of bicyclic nucleoside analogues (BCNA) bearing cyclization self-cleavage spacers between the Val-Pro dipeptide sequence as well as the parent compound were synthesized and evaluated with regard to activation by the DPPIV/CD26 enzyme and for their stability in human and bovine serum. In buffer solution, carbamate and ester prodrugs were found to be chemically stable. Most prodrugs containing a dipeptidyl linker efficiently converted into the BCNA parent drug. In contrast, the Val-Pro alkyldiamino prodrugs converted predominantly into their alkyldiamino prodrug intermediates in the presence of CD26 and human serum. A marked increase in water solubility was observed for all prodrugs. In contrast to the parent compound, a tetrapeptide prodrug containing the Val-Val dipeptide as a self-cleavage spacer released substantial amounts of the BCNA parent drug at the basolateral side of Caco-2 cell cultures and exhibited 15- to 20-fold increased bioavailability in mice relative to the poorly bioavailable parent compound.  相似文献   

10.
Quinoline dicarboxylic anhydride ( 1 ) reacted with p-aminoacetophenone to give a pyrrolopyridine derivative ( 2 ). The compound produced ( 2 ) reacted with hydrazine hydrate, hydroxyl amine hydrochloride, semicarbazide and thiosemicarbazide to produce pyrrolopyridine derivatives ( 3-6 ). Compound 3 reacted with aromatic aldehyde, PhNCS or PhNCO to produce compounds 7-9 . Compound 4 reacted with PhNCO to give the carbamate ester 10 . When compound 5 was boiled with SOC12, the thiadiazolo compound ( 11 ) was obtained. When compound 6 was allowed to react with α-haloesters and α-haloketones, the thiazolo compounds ( 12-14 ) were produced. All the synthesized compounds were tested against some Gram-positive and some Gram-negative bacteria and they gave satisfactory results.  相似文献   

11.
In this study, we designed and synthesized twelve bitopic ligands as dopamine D2 receptor (D2R) agonists. The forskolin-induced cAMP accumulation assay revealed that all the finial compounds are able to activate D2R. Furthermore, bitopic ligand N-((trans)-4-(((2,3-dihydro-1H-inden-2-yl)(propyl)amino)methyl)cyclo-hexyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide ( 11 b ) showed 21-fold higher potency than lead compound propyl aminoindane ( 2 ) and 17-fold higher subtype selectivity for D2R over D4R, indicating that the optimal length of spacer affects the D2R functionality. Molecular modeling study exhibited that 11 b formed an electrostatic interaction and two H-bonds with amino acid Asp114, which contributes significantly to the D2R functional activity. Taken together, we discovered a bitopic ligand 11 b as potent D2R agonist, which may be used as a tool compound for further study.  相似文献   

12.
A series of 38 2‐naphthyl‐substituted diarylpyrimidine (DAPY) analogues, characterized by various substitution patterns on the pyrimidine and naphthalene rings, was synthesized in a straightforward fashion by means of parallel synthesis and evaluated as inhibitors of the HIV‐1 wild‐type and double mutant (K103N+Y181C) strains. Most of the compounds displayed strong activity against wild‐type HIV‐1. The most active compound, with a cyano group at position C6 on the naphthalene ring, exhibited activity against wild‐type HIV‐1 with an EC50 value of 0.002 μM and against the double mutant strain with an EC50 value of 0.24 μM ; the selectivity index (SI) against wild‐type is >180 000, the highest SI value among DAPY analogues. The structure–activity relationship (SAR) of the newly synthesized DAPYs is presented herein.  相似文献   

13.
The concise synthesis and structure-activity relationship (SAR) studies of 3-aroylindoles were carried out in an effort to improve the potency and solubility of anticancer drug candidate BPR0L075 (8) by exploring structure modifications through three regimens: substitution of the B ring, at the N1 position, and of the 3-carbonyl linker. The SAR information revealed that the methoxy group of the B ring could be replaced with an electron-donating group such as methyl (in compound 9) or N,N-dimethylamino (in compound 13) while retaining both strong cytotoxic and antitubulin activities. The introduction of amide (compounds 30-33) and carbamate (compounds 34-37) functionalities at the N1 position of 8 gave analogues with potent antiproliferative activities. The cytotoxic potency of 8 was improved by replacing the carbonyl group with sulfide (compound 41) or oxygen (compound 43), indicating that the carbonyl moiety is important but not essential. The N,N-dimethylamino derivative 13 not only displayed potent cytotoxicity and antitubulin activity, but also showed a markedly improved physicochemical profile relative to the parent compound.  相似文献   

14.
Four new fullero-steroids were synthesized starting from γ-aminobutyric acid (GABA)-incorporated fulleropyrrolidine and corresponding sterols. The synthesis, characterization, preliminary study on in vitro antioxidant activity as well as the steady state photophysical properties are presented. All synthesized compounds showed antioxidant activity 2-3-fold higher than the parent fullerene. The most active compound appeared to be as potent as standard antioxidant BHT (2,6-di-tert-butyl-4-methylphenol). Also, all of them fluoresce 6-8-fold stronger than C60, thus representing potential irradiation assisted pro-oxidants. With significantly increased lipophilicity, it could be expected that attached steroidal subunit enables better penetration of C60 to living cell membranes, thus facilitating its antioxidant activity. Based on all obtained results, newly synthesized covalent fullero-steroidal conjugates represent good candidates for potential antioxidants as well as pro-oxidants.  相似文献   

15.
4H‐1,2,4‐Benzothiadiazine‐1,1‐dioxides with various substituents in positions 3, 5, and 7 were synthesized and tested as KATP channel agonists in artificial cell systems (CHO cells transfected with SUR1/Kir6.2, and HEK 293 transfected with SUR2B/Kir6.1) as model systems for insulin‐secreting pancreatic β‐cells and for smooth muscle cells, respectively. The effects of agonists were tested in intact cells using DiBAC4(3) [bis‐(1,3‐dibarbituric acid)trimethine oxanol] as a membrane potential dye, and the results compared with their binding affinity for the SUR2B‐type KATP channels using the radioligand [3H]P1075. Compounds with cycloalkyl and (cycloalkyl)methyl side chains in position 3 had higher affinities towards the SUR2B/Kir6.1 receptor compared with the parent compound diazoxide ( 1 a ). Compounds with bulky, nonpolar residues in position 3 exhibited remarkable selectivity for SUR2B‐type KATP channels. The compound substituted with a bulky (1‐adamantyl)methyl residue exhibited micromolar affinity and activity on SUR2B‐type KATP channels without being able to activate the SUR1‐type KATP channels.  相似文献   

16.
A series of 4-(substituted)-N-(guanidinyl)benzenesulfonamides bearing biologically active pyrazole, pyrimidine and pyridine moieties were prepared and evaluated for their anticancer activity against human tumor breast cell line (MCF7). These sulfonamides showed promising activity with IC50 values ranging from 49.5 to 70.2 μM. The structure-activity relationship of the synthesized compounds was studied. Interestingly, it was found that the most potent compounds in this study were the corresponding 2-cyanoacrylate 3, 3-oxobutanoate 4, pyrazole 6, pyridine 9 and pyrazole 13. Compounds 7 and 8 are nearly as active as Doxorubicin as reference drug with (IC50 values = 70.2, 68.1 μM), while compounds 5, 10 and 11 exhibited a moderate activity.  相似文献   

17.
Three strains of rats were fed a fish oil diet to verify their ability to incorporate and convert dietary eicosapentaenoic acid (20∶5ω3) into trienoic prostaglandins. Our results show that such conversion indeed occurs in kidney medullae homogenates. Specifically, the presence of prostaglandin E3 (PGE3) was established by gas chromatographic-mass spectrometric (GC-MS) analysis. That compound was conclusively identified by comparison of fragment ions and their relative intensities with those obtained from authentic PGE3. Further evidence was provided by studying the recovery of exogenously added PGE3. The crude ethyl acetate extracts of the medullary homogenates were methylated and cleaned up by liquid-gel chromatography with Lipidex-5000 prior to conversion to PGB3 for GC-MS analysis. The PGE3 was quantified by selected ion monitoring (SIM) with [3,3,4,4-2H4PGE2 as internal standard. The levels of PGE3 were similar, about 3 ng/mg of wet tissue, in the 3 strains of rats. Identical in vivo conversion of the 20∶5ω3 fatty acid to PGE3 could not be positively established by analysis of pooled urine specimens.  相似文献   

18.
Pyrylium Compounds. 41. 7aH-Cyclopenta[b]pyran-7-ones by Ring Transformation of 2,4,6-Triarylpyrylium Salts with Acyclic 1,2-Diketones Reaction of 2,4,6-triarylpyrylium salts 1 with acyclic 1,2-diketones 2 (CH3COCOR, R = Me, Ph) in the presence of an appropriate condensing agent (e.g. piperidine acetate, triethyl-amine/acetic acid, sodium acetate) yields the hitherto unknown 2,4,5,7a-substituted 7aH-cyclopenta[b]pyran-7-ones 3 as a result of a new type of ring transformation (2,5-[C4O+C]/2,3-[C2+C3]). A characteristic feature of compounds 3 is their ability to undergo electrophilic substitutions. Thus, stepwise bromination of the 7a-methyl derivative 3a in acetic acid affords 6-bromo-7a-methyl-2,4,5-triphenyl-cyclopenta[b]pyran-7-one ( 4 ) and 3,6-dibromo-7a-methyl-2,4,5-triphenyl-cyclopenta[b]pyran-7-one ( 5 ); analogously, nitration of 3a leads to 7a-methyl-6-nitro-2,4,5-triphenyl-cyclopenta[b]pyran-7-one ( 6 ), indicating that position 6 is the favoured position for electrophilic substitutions. Contrary to the 3,5-unsubstituted pyrylium salts 1 , the 3,5-dimethyl-2,4,6-triphenyl-pyrylium perchlorate ( 13 ) reacts with 1,2-diketones 2 through a 2,6-[C5+C] transformation to give arylsubstituted 1,2-diones 14 . The structure of the new compounds was determined by spectroscopic methods and by a single crystal X-ray analysis of the dibromo derivative 5 .  相似文献   

19.
A C18 1-pyrroline fatty ester, methyl 8-(5-hexyl-2-pyrrolin-1-yl)octanoate (1), was prepared from methyliso-ricinoleate. The C=N bond of the pyrroline ring was oxidized bym-chloroperoxy-benzoic acid to yield a mixture of oxaziridine isomers 2a,2b, which decomposed during gas chromatographic analysis to a 2,5-disubstituted pyrrole derivative, methyl 8-(5-hexyl-1H-pyrrole-2-)octanoate (3). Compound 3 was also obtained by reaction of 2a,2b with dilute HCl in methanol. Reaction of compound 1 with iodo-methane formed anN-methyl iminium iodide intermediate 4, which on reduction with sodium borohydride furnished a mixture ofcis/trans-N-methyl-2,5-disubstituted pyrrolidine derivatives, methyl 8-(cis/trans-5-hexyl-N-methyl-pyrrolidine-2-)octanoates 5a,5b. Reduction of compound 1 with NaBH4 gave a mixture ofcis/trans-isomers of 2,5-disubstituted pyrrolidine derivatives, methyl 8-(5-hexyl-pyrrolidine-2-)octanoates 6a,6b. Acetylation of compounds 6a,6b with acetic anhydride furnished the correspondingN-acetyl pyrrolidines 7a,7b. When compound 1 was treated with perchloric acid, the corresponding iminium perchlorate derivative, methyl 8-(5-hexyl-1-pyrrolinium perchlorate-2-)octanoate 8 was obtained. The structures of the various derivatives were characterized by a combination of chromatographic, mass spectral and spectroscopic techniques.  相似文献   

20.
In this study, galactose conjugated new magnesium and zinc porphyrazines were synthesized by the cyclotetramerization reaction of 2,3-bis[1-(2,2,7,7-tetramethyltetra-hydro-bis[1,3]dioxolo[4,5-b;4′,5′-d]pyran-5,methyl)-1H-[1,2,3]triazol-4-yl methylsulfanyl]-but 2-enedinitrile. This substituted dicyano compound was prepared via two different routes. One started from cis-1,2-dicyano-1,2-ethylenedithiolate disodium, [1-(2, 2, 7,7-tetramethyltetrahydrobis[1,3]dioxolo[4,5-b;4′,5′-d]pyran-5-yl-methyl)-1H-[1,2,3]triazo-l-4-yl]methanol and ended in a multi-step reaction sequence via Click procedures. The other reaction was between 5-azidomethyl-2,2,7,7-tetramethyltetrahydro-bis[1,3]dioxolo[4,5-b;4′,5′-d]pyran and (2Z)-2,3-bis(prop-2-yl-1-yl-thio)but-2-enedinitrile. A very soluble galactose linked magnesium porphyrazine derivative in common polar solvents and water was achieved by the deprotected isopropylidene groups in TFA and water media. It is first time, zinc porphyrazine complex has been achieved at one-step reaction by using Zn(BuO)2 as template agent. The new compounds have been characterized by a combination of elemental analysis, 1H, 13C NMR, IR, UV–vis and MS spectral data.  相似文献   

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