Synthesis and aromatase inhibition of 3-cycloalkyl-substituted 3-(4-aminophenyl)piperidine-2,6-diones.

The synthesis of 3-cycloalkyl-substituted 3-(4-aminophenyl)piperidine-2,6-diones is described [cyclopentyl (1), cyclohexyl (2)]. The enantiomers of 2 were separated either by using HPLC on optically active sorbent or by crystallization of the brucine salt of the phthalamic acid of 2. The absolute configuration of the (+)- and (-)-enantiomers of 2 were assigned as S and R, respectively, by comparing the CD spectra to those of the enantiomers of aminoglutethimide (AG, 3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione). The compounds were tested in vitro for inhibition of human placental aromatase, the cytochrome P450-dependent enzyme which is responsible for the conversion of androgens to estrogens. Compounds 1 and 2 inhibited aromatase by 50% at 1.2 and 0.3 microM, respectively (IC50 AG = 37 microM). According to the findings with AG, the (+)-enantiomer of 2 was responsible for the inhibitory activity, being a 240-fold more potent aromatase inhibitor in vitro than racemic AG. On the other hand, (+)-2 displayed a strongly reduced inhibition of desmolase (cholesterol side-chain cleavage enzyme) compared to AG (relative activity = 0.3). Thus (+)-2 is of interest as a potential drug for the treatment of estrogen-dependent diseases, e.g. mammary tumors.     

Inhibitors of aromatase. Synthesis and pharmacologic action of potential mammary tumor-inhibiting 4-alkyl-3-(4-aminophenyl)-3-ethylpiperidine-2,6-diones

Aromatase Inhibitors. Syntheses and Evaluation of Potential Mammary Tumor Inhibiting 4-Alkyl-3-(4-aminophenyl)-3-ethylpiperidine-2,6-diones The 4-alkyl-3-(4-aminophenyl)-3-ethylpiperidine-2,6-diones 1–3 were synthesized. Compared to the parent compound aminoglutethimide (AG), they showed a reduced inhibition of aromatase and desmolase in vitro. In vivo compound 2 like AG led to a strong decrease of the estradiol secretion.     

Potential antiestrogens. Synthesis and evaluation of mammary tumor inhibiting activity of 1,2-dialkyl-1,2-bis(3'-hydroxyphenyl)ethanes

The syntheses of the meso-1,2-dialkyl-1,2-bis(3'-hydroxyphenyl)ethanes [alkyl substituent: CH3 (19), C2H5 (20), C3H7 (22), C4H9 (23), i-C4H9 (24), and C5H11 (25)] and of d,l-3,4-bis(3'-hydroxyphenyl)hexane (21) are described. In vitro these compounds inhibited the [3H]estradiol receptor interaction competitively, exhibiting Ka values between 0.20 x 10(9) (20) and 0.11 x 10(6) M-1 (24). In vivo the meso compounds reduced the estrone-stimulated mouse uterine growth; the most effective compounds were 20, 22, and 23 (53, 50, and 45% inhibition, respectively). Compounds 20 and 22-24 showed weak estrogenic activity in the mouse uterine weight test and in the vaginal cornification test. Compounds 19 (NSC-297169), 20 (NSC-297170), and 22 (NSC-297171) exhibited a dose-dependent growth inhibition on the MCF-7 human breast tumor cell line (10(-6) to 10(-9) M). These compounds also showed a marked dose-dependent inhibition on the DMBA-induced, hormone-dependent mammary carcinoma of the Sprague-Dawley rat corresponding to their association constants.     

Synthesis of some 3-(arylalkylthio)-4-alkyl/aryl-5-(4-aminophenyl)-4H-1,2,4-triazole derivatives and their anticonvulsant activity

A series of novel 3-[[(substituted phenyl)methyl]thio]-4-alkyl/aryl-5-(4-aminophenyl)-4H-1,2,4-triazoles 11-20 and several related Schiff's bases, 3-[[(substituted phenyl)-methyl]thio]-4-alkyl/aryl-5-[[[(substituted phenyl/5-nitro-2-furyl)methylene]amino]-phenyl]-4H-1,2,4-triazoles 21-31 were synthesized for evaluation of their biological properties. Structures of the synthesized compounds were confirmed by the use of their spectral data besides elemental analysis. All compounds were evaluated for their anticonvulsant activity by maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) and neurotoxicity (NT) screens. A number of triazole derivatives, exhibited protection after intraperitoneal administration at the dose of 100 and 300 mg/kg in one or both models employed. Compounds 12, 13 and 14 were subjected to oral MES screening in rats at 30 mg/kg and were observed to protect 50% of the animals employed in the experiment. Antimicrobial and antituberculosis activity of these compounds 11-31 were also screened. Some of the tested compounds showed marginal activity against M. tuberculosis H37 Rv.     

Novel steroid sulfatase inhibitors based on N-thiophosphorylated 3-(4-aminophenyl)-coumarin-7-O-sulfamates

In the present work, we described convenient methods for the synthesis of N-thiophosphorylated 3-(4-aminophenyl)-coumarin-7-O-sulfamates as steroid sulfatase (STS) inhibitors. To design the structures of the potential STS inhibitors, molecular modeling techniques were used. A computational docking method was used to determine the binding modes of the synthesized inhibitors as well as to identify potential interactions between specified functional groups on the inhibitors and the amino acid residues present in the active site of the enzyme. The inhibitory activities of the synthesized compounds were tested in an enzymatic assay with STS isolated from a human placenta. Within the set of newly synthesized compounds, 9e demonstrated the highest inhibitory activity in the enzymatic assay with an IC₅₀ value of 0.201 μM (the IC₅₀ value of 667-COUMATE in the same test was 0.062 μM). Furthermore, we tried to verify if the obtained STS inhibitors are able to pass through the cellular membrane effectively in cell line experiments. In the course of our study, we determined the STS activity in the MCF-7 cell line after incubation in the presence of the inhibitors (at 100 nM concentration). For this evaluation, we included newly synthesized compounds 9a-g and their N-phosphorylated analogs 6a-h , whose synthesis has been previously described. We found that the lowest STS activities were measured in the presence of N-phosphorylated derivatives 6e (0.1% of STS activity) and 6f (0.2% of STS activity). The measured STS activity in the presence of 667-COUMATE (used as a reference) was 0.1%. Moreover, at concentrations up to 1 μM, the most active compounds ( 6e , 6f , 9b , and 9e ) did not exert any toxic effects on zebrafish embryos.     

Synthesis and cardiovascular activity of new 8-alkylamino-1,3-dimethyl-7-(2-hydroxy-3- piperazinopropyl)-3,7-dihydro-1H-purine-2,6-diones

7-{2-Hydroxy-3-[4-(2-phenoxyethyl)-piperazinyl-1-yl]-propyl}-1,3-di-methyl-3,7-dihydro-1H-purine-2,6-dione dihydrochloride (2), and several of its 8-alkylamino substituted derivatives (11-17) were synthesized and tested for electrocardiographic, antiarrhythmic and hypotensive activity. Also their alpha(1)- and alpha(2)-adrenoreceptor affinities were determined. It was found that compound 2, and its analogue 15 with 8-(2-morpholin-4-yl-ethylamino) substituent displayed a strong prophylactic antiarrhythmic activity in experimentally induced arrhythmia (LD50/ED50 = 54.9 and 55.0, respectively). The hypotensive activity was observed for 8-benzylamino (11) or 8-(pyridin-2-yl-methylamino) (12) analogues. All the new derivatives (11-17) and 2 showed a weak affinity for alpha1-(Ki = 0.225-1.400 microM) and alpha2-(Ki = 0.152-4.299 microM) receptors.     

Conformational analysis of the aromatase inhibitor 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione (rogletimide) and discovery of potent 5-alkyl derivatives.

Analysis of the proton NMR spectra of 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione (rogletimide, 1) shows that it exists in solution with the aromatic ring in an axial position; the same conformation was found for aminoglutethimide. Excess lithium diisopropylamide treatment of 1 formed a dianion which methylated at C-5. The major product with the methyl group trans to the pyridyl ring retained this ring in an axial position and had higher aromatase inhibitory potency than 1. The minor diastereoisomer with an equatorial pyridyl ring had low potency. Upon elongating the alkyl chain, particularly high inhibitory activity was found for the major product isomer having a C-5 octyl, coinciding with the high activity in C-3 and N-1 octyl derivatives of 1, but there was only a small difference in the activity between the enantiomers of 5-octyl-1 and activity was reduced rather than increased when octyl also replaced ethyl at C-3. The results partially support a previously described model comparing binding of androstenedione to aromatase in as much as an axial pyridyl ring is needed to mimic the axial C-19 methyl group of the steroid and bind to the heme component of the enzyme, but for the derivatives bearing a C-5 octyl, the function of the glutarimide ring seems to be simply as a spacer between the hydrophobic chain and the pyridyl ring.     

1-(4-Aminobenzyl)-and 1-(4-aminophenyl)isoquinoline derivatives: synthesis and evaluation as potential irreversible cyclic nucleotide phosphodiesterase inhibitors

In an effort to increase the specificity of the potent phosphodiesterase inhibitor papaverine, we synthesized two series of novel 1-(4-aminobenzyl)- and 1-(4-aminophenyl)isoquinoline derivatives, incorporating alkylating moieties on the amine substituents. These compounds were evaluated for their inhibitory action on phosphodiesterase preparations from bovine heart and rat cerebral cortex. Studies were also conducted to determine whether these compounds were reacting with the enzymes in an irreversible manner. The compounds were potent inhibitors of the phosphodiesterases; however, no evidence was found for an irreversible inhibition.     

Synthesis and Biological Evaluation of New 3-Phenyl-1-[(4-arylpiperazin-1-yl)alkyl]-piperidine-2,6-diones

A set of 13 alkyl derivatives of 3-phenylpiperidine-2,6-dione were synthesized. Newly obtained compounds were investigated in vitro against HIV-1 and other selected viruses. The benzyl 3f and fluorophenyl 3g derivatives showed moderate protection against CVB-2 and the compound 3g also against HSV-1. Derivatives were tested also for their antibacterial and antifungal activity. The molecular structures of 3a and 3d were determined by an X-ray analysis.     

2-Alkyl-substituted 1,1-bis(4-acetoxyphenyl)-2-phenylethenes. Estrogen receptor affinity, estrogenic and antiestrogenic properties, and mammary tumor inhibiting activity

1,1-Bis(4-acetoxyphenyl)-2-phenylethenes that are substituted with H, CH3, C2H5, n-C3H7, i-C3H7, or CH2CF3 in position 2 were synthesized in order to study the influence of the alkyl side chain on estradiol receptor affinity, estrogenic and antiestrogenic properties, and inhibition of the hormone-dependent MXT mammary carcinoma of the mouse. Furthermore, the double bond of 1,1-bis(4-acetoxyphenyl)-2-phenylbut-1-ene was hydrogenated or epoxidated to yield the corresponding ethane and oxirane derivative. Compounds 14 (R = H), 15 (R = CH3), and 16 (R = C2H5) had the best binding affinities. Lengthening the side chain, hydrogenation, or epoxidation decreased the RBA values. In the immature mouse assay, 15 (R = CH3) and 19 (R = CH2CF3) had the highest uterotrophic activity. There was no correlation between receptor affinity and estrogenic properties. Compounds 14 (R = H), 17 (R = n-C3H7), the ethane 20, and the oxirane 21 had some antiuterotrophic activity in a low dosage. The MXT tumor was best inhibited by compounds 15 (R = CH3), 16 (R = C2H5), and 18 (R = i-C3H7) without significant elevation of the uterine weight determined at the end of the experiment. The antitumor effect of 15, 16, and 18 was significantly better than that of tamoxifen. In this series, a certain estrogenic potency in the immature mouse test seems to be necessary for a good antitumor activity, as all compounds with antiuterotrophic and low uterotrophic properties did not exert any significant tumor-inhibiting effect.     

Synthesis and activity of 3-(isoxazolin-5-yl)- and 3-(isoxazol-4-yl)cephalosporins.

The 1,3-dipolar cycloaddition of nitrile oxide with 3-vinylcephalosporin provided diastereomeric isomers of 3-(isoxazolin-5-yl)cephalosporin. Cycloaddition of nitrile oxide with 3-(dimethylamino-vinyl)cephalosporin gave 3-(isoxazol-4-yl)cephalosporin. These semisynthetic cephalosporins with an aminothiazole in the C-7 side chain showed moderate antibacterial activities.     

6-(4-氨基苯基)-2,3,4,5-四氢哒嗪-3-酮衍生物的合成及生物活性

目的合成6-(4-氨基苯基)-2,3,4,5-四氢哒嗪-3-酮结构的衍生物,探讨其生物活性.方法对6-(4-氨基苯基)-2,3,4,5-四氢哒嗪-3-酮进行结构修饰,考察此类化合物对心血管系统和肿瘤细胞生长两方面的作用.结果设计并合成了2个系列共8个新化合物,所有新化合物结构均经IR、1H-NMR、MS及元素分析确证;8个目标化合物对大鼠离体心房肌收缩频率影响较小,而正性肌力作用明显,其中化合物I d和Ⅱa活性较高;在体外对肿瘤细胞(人肺癌细胞A549、人低分化胃腺癌细胞BGC-823、人原髓细胞白血病细胞HL-60和人肝癌细胞SMMC-7721)的生长具有不同程度的抑制作用,且对HL-60的抑制作用具有一定的专一性,化合物Ⅰ b和Ⅱc对人肺癌细胞A549的抑制作用较强.结论6-(4-氨基苯基)-2,3,4,5-四氢哒嗪-3-酮衍生物除了具有强心作用外,在体外对肿瘤细胞生长还具有抑制作用.     

Synthesis and biological activity of 5-(4-[2-(Methyl-p-substituted phenylamino)ethoxy]benzyl)thiazolidine-2,4-diones

Thiazolidinedione derivatives are potential antidiabetic drugs that bind and activate peroxisome proliferator activated receptor gamma (PPARgamma), which is a member of the nuclear hormone receptor superfamily and enhances insulin sensitivity. In an effort to develop a novel and effective thiazolidindione derivative, 5-{4-[2-(methyl-p-substituted phenylamino) ethoxy] benzyl} thiazolidine-2,4-diones 7 have been prepared by Mitsunobu reaction of the hydrophobic segment, methyl-p-substituted phenylaminoethanol 4 with hydroxybenzylthiazolidinedione 5 and their ability to activate PPARgamma and inhibit LPS-induced NO production were evaluated.     

Synthesis and biological activity of 3-methyl-3-(3′-aminothiazol-4-yl)-8-alkoxymethyl-2,7-dioxaspiro[4,4]nonane-1,6-diones

A method for obtaining derivatives of γ-dilactones, 3-methyl-3-(3′-amino[or substituted amino]thiazol-4-yl)-8-alkoxymethyl-2,7-dioxaspiro[4, 4]nonane-1,6-diones, has been developed. Their antibacterial and antitumor properties have been evaluated. Compounds possessing low toxicity and weak antitumor activity have been found in the series of γ-dilactone derivatives. Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 42, No. 9, pp. 12–14, September, 2008.     

Structure-activity relationship in ring-opened serotonin analogs: 3-(2-aminophenyl)-propanamine and 1-(N-piperidino)-3-(2-aminophenyl)-3-oxopropane

The complete reduction of the carbonyl group of the 5-HT agonist 3-(2-amino-5-hydroxy-phenyl)-3-oxo-propanamine results in a drastic loss of activity: as investigations on the isolated gastric fundus of the rat showed, the affinity to the D receptor of serotonin is reduced by a factor of 100 whereas the relative intrinsic activity also decreases from 0.83 to values less than 0.3. The additional suppression of the phenolic hydroxyl group causes only a relatively unimportant decrease of the affinity while the relative intrinsic activity increases again up to 0.65. These results support the postulate according to which the active conformation of serotonin shows a stretched side chain, as its logical interpretation is only possible under this assumption. Inside the 1-(N-piperidino)-3-(2-amino-phenyl)-3-oxo-propanes the derivative methoxylated at C-5 of the benzene nucleus with a pA2 value of 7.39 proved to be the most effective 5-HT antagonist the mechanism being a purely competitive one.     

Synthesis of 1-(4-((E)-3-arylacryloyl) phenyl)-3,4-dibromo-1H-pyrrole-2,5-diones and screening for anti-Candida and antituberculosis activity

A series of eleven 1-(4-((E)-3-arylacryloyl) phenyl)-3,4 dibromo-1H-pyrrole-2,5-diones (4′-aminochalcone-based dibromomaleimides) were synthesized using maleic anhydride and p-aminoacetophenone as starting material. Furthermore, there has been some additional work investigating the effect of these derivatives on biological activity. They were characterized using FTIR, ¹H NMR, ¹³C NMR, ESI mass spectroscopy, and elemental analysis. The compounds show anti-Candida & antituberculosis activity.