共查询到20条相似文献,搜索用时 15 毫秒
1.
Ha HJ Hong MC Ko SW Kim YW Lee WK Park J 《Bioorganic & medicinal chemistry letters》2006,16(7):1880-1883
Constrained ceramide analogs were designed and synthesized by binding terminal alcohol and amine of ceramide with additional carbonyl functional group as 3-acetyl (3), 3-propionyl (4), 3-benzoyl (5), and 3-hexadecanoyl-4-(1-hydroxyhexadec-2-enyl)-oxazolidin-2-ones (6). Compounds 4 and 5 showed potent antileukemic activities against human leukemia HL-60 cells with good correlation between cell death and DNA fragmentation. 相似文献
2.
《Bioorganic & medicinal chemistry》2019,27(12):2629-2636
Our previous study has revealed 4-(4-(4-chlorophenyl)-1,4-diazepan-1-yl)-1-(4-fluorophenyl)butan-1-one·2HCl (SYA013) 1 as a sigma ligand with moderate selectivity for the sigma-2 receptor. Given the overexpression of sigma receptors in solid tumors and reports of sigma ligands with anticancer activities, we selected 1 for evaluation in several solid tumor cell lines. In addition, we have synthesized new analogs of 1 and now report that several of them bind preferentially at the sigma-2 receptor and have shown inhibition of several cancer cell lines including MDA-MB-231, MDA-MB-486, A549, PC-3, MIA PaCa-2 and Panc-1 cells. In particular, compounds 1 and 12 have demonstrated sub-micromolar activity against the Panc-1 cell line. It has also been observed that several of these compounds demonstrate selective toxicity toward cancer cells, when compared to normal cells. 相似文献
3.
Bouleghlem H Berredjem M Lecouvey M Aouf NE 《Nucleosides, nucleotides & nucleic acids》2007,26(10-12):1539-1542
A series of chiral cyclosulfamides and oxazolidinon-2-ones have been synthesized starting from aminoacids. Regioselective substitution of these pseudopyrimidic heterocyles was carried out under Mitsunobu conditions. Best substitution results were obtained by preliminary deprotection of cyclosulfamides and their condensation with beta-D-ribofuranose. Chiral oxazolidin-2-ones were coupled directly with D-ribofuranose. All compounds were tested against HSV-2, VV and SV viruses. Two compounds 6b and 6e showed significant activities against HSV-type 1. 相似文献
4.
The growth factor receptor-bound protein 2 (Grb2) plays an important role in the Ras signaling pathway. Several proteins were found to be overexpressed by oncogenes in the Ras signaling pathway, rendering Grb2 a potential target for the design of antitumor agents. Blocking the interaction between the phosphotyrosine-containing activated receptor and the Src-homology 2 (SH2) domain of Grb2 thus constitutes an important strategy for the development of potential anticancer agents. X-ray, NMR structural investigations, and molecular modeling studies have provided the target structure of Grb2 SH2 domain-alone or complexed with a phosphotyrosine-containing peptide-which is useful for the structure-based design of peptides or peptidomimetics with high affinity for the Grb2 SH2 domain. We review here the variety of approaches to Grb2 SH2 pepide inhibitors developed with the aim of interrupting Grb2 recognition. Inhibitory effects of peptide analogs on the Grb2 SH2 domain and their binding affinities for Grb2 SH2 were determined by ELISA, cell-based assays, or Surface Plasman Resonance (SPR) technology. Results of theses studies provide important information for further modifications of lead peptides, and should lead to the discovery of potent peptides as anticancer agents. 相似文献
5.
Four new chiral 4-substituted 5,5-diethyl oxazolidin-2-ones (5a-5d) as potential effective chiral auxiliaries were synthesized from readily available amino acids via asymmetric etherification, Boc protection, Grignard reaction and cyclization reactions in four steps with overall yields of 50-60%. 相似文献
6.
7.
Yuelong Ma Sangkil Nam Richard Jove Kenichi Yakushijin David A. Horne 《Bioorganic & medicinal chemistry letters》2010,20(1):83-86
A series of ageladine A analogs that include 2-aminoimidazo[4,5-c]azepines (seven-membered rings) and 2-amino-3H-imidazo[4,5-c]pyridine (six-membered rings) derivatives were synthesized and evaluated for their anticancer effects against several human cancer cell lines and MMP-2 inhibition in vitro. Only compounds possessing the aromatic azepine (seven-membered ring) core showed anticancer activity with IC50 values in the low micromolar range. 相似文献
8.
Zong-Ying Liu Yue-Ming Wang Zhuo-Rong Li Jian-Dong Jiang David W. Boykin 《Bioorganic & medicinal chemistry letters》2009,19(19):5661-5664
A series of 3,4-diarylthiazol-2(3H)-ones and three 3,4-diarylthiazol-2(3H)-imines were synthesized and evaluated for their cytotoxicity in a panel of human cancer cell lines. Compounds 21 and 22 showed potential anticancer activity against human CEM cells with IC50 values of 0.12 and 0.24 μM, respectively. 相似文献
9.
《Bioorganic & medicinal chemistry letters》2014,24(6):1452-1457
A small library of monovalent Smac mimics with general structure NMeAla-Tle-(4R)-4-Benzyl-Pro-Xaa-cysteamide, was synthesized (Xaa = hydrophobic residue). The library was screened in vitro against human breast cancer cell lines MCF-7 and MDA-MB-231, and two most active compounds oligomerized via S-alkylation giving bivalent and trivalent derivatives. The most active bivalent analogue SMAC17-2X was tested in vivo and in physiological conditions (mouse model) it exerted a potent anticancer effect resulting in ∼23.4 days of tumor growth delay at 7.5 mg/kg dose. Collectively, our findings suggest that bivalent Smac analogs obtained via S-alkylation protocol may be a suitable platform for the development of new anticancer therapeutics. 相似文献
10.
Brown DG Maier DL Sylvester MA Hoerter TN Menhaji-Klotz E Lasota CC Hirata LT Wilkins DE Scott CW Trivedi S Chen T McCarthy DJ Maciag CM Sutton EJ Cumberledge J Mathisen D Roberts J Gupta A Liu F Elmore CS Alhambra C Krumrine JR Wang X Ciaccio PJ Wood MW Campbell JB Johansson MJ Xia J Wen X Jiang J Wang X Peng Z Hu T Wang J 《Bioorganic & medicinal chemistry letters》2011,21(11):3399-3403
Herein we describe the discovery of compounds that are competitive antagonists of the CP101-606 binding site within the NR2B subtype of the NMDA receptor. The compounds identified do not possess phenolic functional groups such as those in ifenprodil and related analogs. Initial identification of hits in this series focused on a basic, secondary amine side chain which led to good potency, but also presented a hERG liability. Further modifications led to examples of non-basic replacements which demonstrated much less liability in this regard. Finally, one compound in the series, 6a, was tested in the mouse forced swim depression assay and found to show activity (sc 60 mg/kg). 相似文献
11.
12.
A simple, efficient procedure and improved conditions have been found to carry out the Biginelli reaction for the synthesis of 3,4-dihydropyrimidin-2(1H)-one derivatives. This synthesis was performed using CuBr2 as the catalyst in ethanol solution. The optimum conditions were as follows: the molar ratio of aldehyde to alpha,beta-diketone to urea or thiourea is 1:1:1:0.5, the molar ratio of catalyst to aldehyde is 25%, and the reaction time is 4 h.Under the above conditions, the highest yield of dihydropyrimidinones was up to 95%. Compared with the classical Biginelli reaction conditions, this new method has the advantage of excellent yields and short reaction times. 相似文献
13.
Andong Zhou Lei Yan Fangfang Lai Xiaoguang Chen Masuo Goto Kuo-Hsiung Lee Zhiyan Xiao 《Bioorganic & medicinal chemistry letters》2017,27(15):3326-3331
The indolin-2-one core is a privileged structure for antitumor agents, especially kinase inhibitors. Twenty-three novel indolin-2-ones were designed by molecular dissection of the anticancer drug indirubin. Seventeen of them exhibited significant inhibition against the tested cell lines, and two of them (1c and 1h) showed IC50 values at the submicromolar level against HCT-116 cells. Compounds 1c and 2c were also potent inhibitors of the triple-negative breast cancer (TNBC) cell line MDA-MB-231. Flow cytometry was utilized to explore the antitumor mechanism of 1c and 2c with MDA-MB-231 cells, and distinct effects were observed on 2c. Furthermore, immunocytochemical examination of 1c suggested a destabilization of microtubules, which was significantly different from the effect of IM, an indirubin derivative. 相似文献
14.
Alexander S. Kiselyov Marina Semenova Victor V. Semenov 《Bioorganic & medicinal chemistry letters》2009,19(4):1195-1198
Novel derivatives of isothiazoles are described as potent ATP-competitive inhibitors of vascular endothelial growth factor receptors I and II (VEGFR-1/2). A number of compounds exhibited VEGFR-2 inhibitory activity comparable to that of Vatalanib? in both HTRF enzymatic and cellular assays. Several derivatives featuring bulky meta-substituents in the amide portion of the molecule displayed 4- to 8-fold specificity for VEGFR-2 versus VEGFR-1. Active molecules also showed high intrinsic permeability (>30 × 10?5 cm/min) across Caco-2 cell monolayer. 相似文献
15.
Fumonisins and fumonisin analogs as inhibitors of ceramide synthase and inducers of apoptosis 总被引:5,自引:0,他引:5
Desai K Sullards MC Allegood J Wang E Schmelz EM Hartl M Humpf HU Liotta DC Peng Q Merrill AH 《Biochimica et biophysica acta》2002,1585(2-3):188-192
Sphingoid bases are growth inhibitory and pro-apoptotic for many types of cells when added to cells exogenously, and can be elevated to toxic amounts endogenously when cells are exposed to inhibitors of ceramide synthase. An important category of naturally occurring inhibitors are the fumonisins, which inhibit ceramide synthase through structural similarities with both the sphingoid base and fatty acyl-CoA co-substrates. Fumonisins cause a wide spectrum of disease (liver and renal toxicity and carcinogenesis, neurotoxicity, induction of pulmonary edema, and others), and most-possibly all-of the pathophysiologic effects of fumonisins are attributable to disruption of the sphingolipid metabolism. The products of alkaline hydrolysis of fumonisins (which occurs during the preparation of masa flour for tortillas) are aminopentols that also inhibit ceramide synthase, but more weakly. Nonetheless, the aminopentols (and other 1-deoxy analogs of sphinganine) are acylated to derivatives that inhibit ceramide synthase, perhaps as product analogs, elevate sphinganine, and kill the cells. Somewhat paradoxically, fumonisins sometimes stimulate growth and inhibit apoptosis, possibly due to elevation of sphinganine 1-phosphate, which is known to have these cellular effects. These findings underscore the complexity of sphingolipid metabolism and the difficulty of identifying the pertinent mediators unless a full profile of the potentially bioactive species is evaluated. 相似文献
16.
A simple and effective synthesis of 3,4-dihydropyrimidin-2(1H)-one derivatives from aldehydes, 1,3-dicarbonyl compounds and urea or thiourea using chloroacetic acid as catalyst under solvent-free conditions is described. Compared with the classical Biginelli reaction conditions, this new method has the advantage of good to excellent yields and short reaction time. 相似文献
17.
Thanh Kim Pham Do-Hee Kim Bong-Jin Lee Young-Woo Kim 《Bioorganic & medicinal chemistry letters》2013,23(24):6717-6720
Esculentin-2EM is a 37-residue, cationic, amphipathic, α-helical antimicrobial peptide isolated from a Korean frog, Glandirama emeljanovi. Many studies revealed that truncation of this peptide results in substantial decreases in its antimicrobial activity. Lee and his colleagues have recently reported that a 23-residue esculentin-2EM analog containing a tryptophanyl substitution at position 16 showed a significant recovery of the antimicrobial activity of the parent peptide. Here we report a new series of 15-residue esculentin-2EM analogs which are constrained into an α-helical conformation via an oct-4-enyl cross-link. The resulting ‘stapled’ derivatives displayed remarkable increases not only in antimicrobial activity but also in helical content and protease resistance compared to Lee’s original 23-residue esculentin-2EM analog. The preliminary data obtained in this work strongly supports the potential of our strategy for the development of a new class of peptide antibiotics. 相似文献
18.
Peter W. Schiller Ralf Schmidt Grazyna Weltrowska Irena Berezowska Thi M.-D. Nguyen Sébastien Dupuis Nga N. Chung Carole Lemieux Brian C. Wilkes Katharine A. Carpenter 《Letters in Peptide Science》1998,5(2-3):209-214
Novel conformationally constrained opioid peptide analogs with antagonist, mixed agonist/ antagonist or agonist properties were developed. TIP(P)-related antagonists showed unprecedented antagonist potency and receptor selectivity, and may have potential for use in analgesia in combination with agonists. A definitive model of their receptor-bound conformation was developed. Three prototype mixed agonist/ antagonists were discovered. They represent the only known compounds with this pharmacological profile and, as expected, one of them was shown to be a potent analgesic and to produce no dependence and less tolerance than morphine. Novel dipeptide derivatives turned out to be potent and selective agonists. Because of their low molecular weight and lipophilic character, these compounds may cross the blood-brain barrier and, thus, may have potential as centrally acting analgesics. 相似文献
19.
Peter W. Schiller Ralf Schmidt Grazyna Weltrowska Irena Berezowska Thi M.-D. Nguyen Sébastien Dupuis Nga N. Chung Carole Lemieux Brian C. Wilkes Katharine A. Carpenter 《International journal of peptide research and therapeutics》1998,5(2-3):209-214
Summary Novel conformationally constrained opioid peptide analogs with δ antagonist, mixed μ agonist/δ antagonist or δ agonist properties
were developed. TIP(P)-related δ antagonists showed unprecedented δ antagonist potency and δ receptor selectivity, and may
have potential for use in analgesia in combination with μ agonists. A definitive model of their δ receptor-bound conformation
was developed. Three prototype mixed μ agonist/δ antagonists were discovered. They represent the only known compounds with
this pharmacological profile and, as expected, one of them was shown to be a potent analgesic and to produce no dependence
and less tolerance than morphine. Novel dipeptide derivatives turned out to be potent and selective δ agonists. Because of
their low molecular weight and lipophilic character, these compounds may cross the blood-brain barrier and, thus, may have
potential as centrally acting analgesics. 相似文献
20.
A simple high-yield three-steps route to optically active 4-hydroxymethyl-3-(1H-indolyl)oxazolidin-2-ones from (S)-glycidol is described. The key intermediates (R)-oxiran-2-ylmethyl 1H-indol-4/-5-ylcarbamates are obtained in high yields from (S)-glycidol. These are readily transformed to oxazolidin-2-ones, very interesting building blocks in drug synthesis. 相似文献