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1.
《Bioorganic & medicinal chemistry》2016,24(12):2823-2831
In this work, new potent steroidal aromatase inhibitors both in microsomes and in breast cancer cells have been found. The synthesis of the 3,4-(ethylenedioxy)androsta-3,5-dien-17-one (12), a new steroid containing a heterocycle dioxene fused in the A-ring, led to the discovery of a new reaction for which a mechanism is proposed. New structure–activity relationships were established. Some 5β-steroids, such as compound 4β,5β-epoxyandrostan-17-one (9), showed aromatase inhibitory activity, because they adopt a similar A-ring conformation as those of androstenedione, the natural substrate of aromatase. Moreover, new chemical features to increase planarity were disclosed, specifically the 3α,4α-cyclopropane ring, as in 3α,4α-methylen-5α-androstan-17-one (5) (IC50 = 0.11 μM), and the Δ9–11 double bond in the C-ring, as in androsta-4,9(11)-diene-3,17-dione (13) (IC50 = 0.25 μM). In addition, induced-fit docking (IFD) simulations and site of metabolism (SoM) predictions helped to explain the recognition of new potent steroidal aromatase inhibitors within the enzyme. These insights can be valuable tools for the understanding of the molecular recognition process by the aromatase and for the future design of new steroidal inhibitors. 相似文献
2.
Jong Taik Moon Ji Young Jeon Hang Ah Park Young-Soo Noh Kyung-Tae Lee Jungahn Kim Dong Joon Choo Jae Yeol Lee 《Bioorganic & medicinal chemistry letters》2010,20(2):734-737
3,4-Diphenyl-substituted 1H-furan-2,5-dione and 1H-pyrrole-2,5-dione derivatives were synthesized and evaluated for the inhibitory activities on LPS-induced PGE2 production in RAW 264.7 macrophage cells. Both 1H-furan-2,5-dione and 1H-pyrrole-2,5-dione rings as main scaffolds were easily obtained using one of three synthetic methods. Among the compounds investigated, 1H-3-(4-sulfamoylphenyl)-4-phenyl-pyrrole-2,5-dione (6l) showed a strong inhibitory activity (IC50 = 0.61 μM) of PGE2 production. 相似文献
3.
《Bioorganic & medicinal chemistry letters》2014,24(8):1958-1962
As a continuous research for discovery of new COX-2 inhibitors, we present the simple chemical synthesis, in vitro biological screening, and molecular docking study of 1H-pyrrole-2,5-dione derivatives. New synthetic compounds were evaluated for the inhibitory activities on LPS-induced PGE2 production in RAW 264.7 macrophage cells as well as the COX-1 and COX-2 inhibitory potency. Among them, compound 9d (MPO-0029) was identified as more potent and selective COX-2 inhibitor [PGE2 IC50 = 8.7 nM, COX-2 IC50 = 6.0 nM; COX-2 selectivity index (SI) = >168] than celecoxib. Molecular docking experiments were further performed against COX-2 and COX-1 isozymes to determine their probable binding models. Results of molecular docking studies revealed that compound 9d (MPO-0029) has stronger binding interaction with COX-2 than with COX-1 isozyme, and provided successfully complementary theoretical support for the obtained experimental biological data. 相似文献
4.
Evelyn L. Bonifazi Carla Ríos-Luci Leticia G. León Gerardo Burton José M. Padrón Rosana I. Misico 《Bioorganic & medicinal chemistry》2010,18(7):2621-2630
A series of 5-hydroxy-1,4-naphthoquinones analogues was synthesized from juglone (6) and their antiproliferative activity against a representative panel of six human solid tumor cell lines has been investigated. The 2,5-dihydroxy-3-(3-methylbut-2-enyl)naphthalene-1,4-dione (4) and 2,3-dihydro-5-hydroxy-2-(prop-1-en-2-yl)naphtho[2,3-b]furan-4,9-dione (27) were the most potent antiproliferative agents with GI50 values of 0.42–8.1 and 0.80–2.2 μM, respectively. The results provide insight into the correlation between some structural properties of 5-hydroxynaphthoquinones and their antiproliferative activity. 相似文献
5.
《Bioorganic & medicinal chemistry》2016,24(16):3624-3635
Dihydropyrimidones 1–37 were synthesized via a ‘one-pot’ three component reaction according to well-known Biginelli reaction by utilizing Cu(NO3)2·3H2O as catalyst, and screened for their in vitro β-glucuronidase inhibitory activity. It is worth mentioning that amongst the active molecules, compounds 8 (IC50 = 28.16 ± .056 μM), 9 (IC50 = 18.16 ± 0.41 μM), 10 (IC50 = 22.14 ± 0.43 μM), 13 (IC50 = 34.16 ± 0.65 μM), 14 (IC50 = 17.60 ± 0.35 μM), 15 (IC50 = 15.19 ± 0.30 μM), 16 (IC50 = 27.16 ± 0.48 μM), 17 (IC50 = 48.16 ± 1.06 μM), 22 (IC50 = 40.16 ± 0.85 μM), 23 (IC50 = 44.16 ± 0.86 μM), 24 (IC50 = 47.16 ± 0.92 μM), 25 (IC50 = 18.19 ± 0.34 μM), 26 (IC50 = 33.14 ± 0.68 μM), 27 (IC50 = 44.16 ± 0.94 μM), 28 (IC50 = 24.16 ± 0.50 μM), 29 (IC50 = 34.24 ± 0.47 μM), 31 (IC50 = 14.11 ± 0.21 μM) and 32 (IC50 = 9.38 ± 0.15 μM) found to be more potent than the standard d-saccharic acid 1,4-lactone (IC50 = 48.4 ± 1.25 μM). Molecular docking study was conducted to establish the structure–activity relationship (SAR) which demonstrated that a number of structural features of dihydropyrimidone derivatives were involved to exhibit the inhibitory potential. All compounds were characterized by spectroscopic techniques such as 1H, 13C NMR, EIMS and HREI-MS. 相似文献
6.
《Bioorganic & medicinal chemistry letters》2014,24(7):1825-1829
Bisindole analogs 1–17 were synthesized and evaluated for their in vitro β-glucuronidase inhibitory potential. Out of seventeen compounds, the analog 1 (IC50 = 1.62 ± 0.04 μM), 6 (IC50 = 1.86 ± 0.05 μM), 10 (IC50 = 2.80 ± 0.29 μM), 9 (IC50 = 3.10 ± 0.28 μM), 14 (IC50 = 4.30 ± 0.08 μM), 2 (IC50 = 18.40 ± 0.09 μM), 19 (IC50 = 19.90 ± 1.05 μM), 4 (IC50 = 20.90 ± 0.62 μM), 7 (IC50 = 21.50 ± 0.77 μM), and 3 (IC50 = 22.30 ± 0.02 μM) showed superior β-glucuronidase inhibitory activity than the standard (d-saccharic acid 1,4-lactone, IC50 = 48.40 ± 1.25 μM). In addition, molecular docking studies were performed to investigate the binding interactions of bisindole derivatives with the enzyme. This study has identified a new class of potent β-glucouronidase inhibitors. 相似文献
7.
《Bioorganic & medicinal chemistry》2014,22(8):2403-2408
We synthesized four types of arginine-based amphipathic nonapeptides, including two homochiral peptides, R-(l-Arg-l-Arg-Aib)3-NH2 (R = 6-FAM-β-Ala: FAM-1; R = Ac: Ac-1) and R-(d-Arg-d-Arg-Aib)3-NH2 (R = 6-FAM-β-Ala: ent-FAM-1; R = Ac: ent-Ac-1); a heterochiral peptide, R-(l-Arg-d-Arg-Aib)3-NH2 (R = 6-FAM-β-Ala: FAM-2; R = Ac: Ac-2); and a racemic mixture of diastereomeric peptides, R-(rac-Arg-rac-Arg-Aib)3-NH2 (R = 6-FAM-β-Ala: FAM-3; R = Ac: Ac-3), and then investigated the relationship between their secondary structures and their ability to pass through cell membranes. Peptides 1 and ent-1 formed stable one-handed α-helical structures and were more effective at penetrating HeLa cells than the non-helical peptides 2 and 3. 相似文献
8.
Y. Thirupathi Reddy P. Narsimha Reddy Srinivas Koduru Chendil Damodaran Peter A. Crooks 《Bioorganic & medicinal chemistry》2010,18(10):3570-3574
A series of substituted (Z)-5-(N-benzylindol-3-ylmethylene)imidazolidine-2,4-dione (3) analogs structurally related to aplysinopsin, and that incorporate a variety of substituents in both the indole and N-benzyl moieties have been synthesized under microwave irradiation and conventional heating methods These analogs were evaluated for their anti-proliferative activity against MCF-7 and MDA-231 breast cancer cell lines, and A549 and H460 lung cancer cell lines. Two analogs, 3f and 3j had IC50 values of 4.4 and 5.2 μM, respectively, compared to 5-fluorouracil (IC50 = 15.2 μM) against MCF-7 cells. 相似文献
9.
A new series of pyrazole-hydrazone derivatives 4a-i were designed and synthesized, their chemical structures were confirmed by IR, 1H NMR, 13C NMR, MS spectral data and elemental analysis. IC50 values for all prepared compounds to inhibit COX-1, COX-2 and 5-LOX enzymes were determined in vitro. Compounds 4a (IC50 = 0.67 μM) and 4b (IC50 = 0.58 μM) showed better COX-2 inhibitory activity than celecoxib (IC50 = 0.87 μM) with selectivity index (SI = 8.41, 10.55 in sequent) relative to celecoxib (SI = 8.85). Also, compound 4a and 4b exhibited superior inhibitory activity against 5-LOX (IC50 = 1.92, 2.31 μM) higher than zileuton (IC50 = 2.43 μM). All target pyrazoles were screened for their ability to reduce nitric oxide production in LPS stimulated peritoneal macrophages. Compounds 4a, 4b, 4f and 4i displayed concentration dependent reduction and were screened for in vivo anti-inflammatory activity using carrageenan-induced rat paw edema assay. Compound 4f showed the highest anti-inflammatory activity (% edema inhibition = 15–20%) at all doses when compared to reference drug celecoxib (% edema inhibition = 15.7–17.5%). Docking studies were carried out to investigate the interaction of target compounds with COX-2 enzyme active site. 相似文献
10.
《Inorganica chimica acta》2006,359(11):3699-3708
Synthesis of a series of heterodinuclear phenylpalladium–molybdenum(or -tungsten) complexes having a bidentate nitrogen ligand, L2PhPd–MCp(CO)3 (M = Mo, L2 = tmeda (12), bpy (13), phen (14); M = W, L2 = tmeda (15)) by metathetical reactions of PdPhIL2 with Na[MCp(CO)3] and acylplatinum–molybdenum(or -tungsten) complex having a 1,2-bis(diphenylphosphino)ethane ligand, (dppe)(RCO)Pt–MCp(CO)3 (M = Mo, R = Et (16), CH2CMe3 (18); M = W, R = Et (17)) by CO insertion into Pt–C bond in corresponding alkyl analogues (dppe)RPt–MCp(CO)3 (M = Mo, R = Et (6), CH2CMe3, M = W, R = Et (8)) are described. These complexes are characterized by NMR and IR spectroscopies and elemental analyses, and the molecular structures of 12, 13, 17 and 18 are determined by X-ray structure analysis. The geometry at Pt (or Pd) is square planar and the MCp(CO)3 moiety has three-leg piano-stool geometries in these complex expect the propionylplatinum–tungsten complex 17, which shows apparent but unexpected structural deformation at Pt and W, giving twisted square-planar and four-leg piano-stool geometries for platinum and tungsten, respectively. 相似文献
11.
《Bioorganic & medicinal chemistry letters》2014,24(9):2202-2205
Fifteen novel hybrids containing diterpene skeleton and nitric oxide (NO) donor were prepared from isosteviol. All the compounds were tested on preliminary cytotoxicity, and the results showed that six target compounds (8c, 10b, 14a, 14c, 18c, and 18d) exhibited anti-proliferation activity on HepG2 cells, with 8c (IC50 = 4.24 μM) and 18d (IC50 = 2.75 μM) superior to the positive control CDDO-Me (2-cyano-3,12-dioxooleana-1,9(11)-dien-28-acid methyl ester, IC50 = 4.99 μM); eleven target compounds (8a–c, 9a–c, 10a–b, 14a, 14c, 18d) exhibited anti-proliferation activities on B16F10 cells at different levels, among them, seven compounds were more potent than comptothecin (IC50 = 2.78 μM) and CDDO-Me (IC50 = 5.85 μM), particularly, 10b (IC50 = 0.02 μM) presented the strongest effect, which was selected as a candidate for further study. 相似文献
12.
《Bioorganic & medicinal chemistry》2016,24(16):3456-3463
Herein, we report the synthesis and screening of cyano substituted biaryl analogs 5(a–m) as Peptide deformylase (PDF) enzyme inhibitors. The compounds 5a (IC50 value = 13.16 μM), 5d (IC50 value = 15.66 μM) and 5j (IC50 value = 19.16 μM) had shown good PDF inhibition activity. The compounds 5a (MIC range = 11.00–15.83 μg/mL), 5b (MIC range = 23.75–28.50 μg/mL) and 5j (MIC range = 7.66–16.91 μg/mL) had also shown potent antibacterial activity when compared with ciprofloxacin (MIC range = 25–50 μg/mL). Thus, the active derivatives were not only potent PDF inhibitors but also efficient antibacterial agents. In order to gain more insight on the binding mode of the compounds with PDF, the synthesized compounds 5(a–m) were docked against PDF enzyme of Escherichia coli and compounds exhibited good binding properties. In silico ADME properties of synthesized compounds were also analyzed and showed potential to develop as good oral drug candidates. 相似文献
13.
Coumarin sulfonates 4–43 were synthesized by reacting 3-hydroxy coumarin 1, 4-hydroxy coumarin 2 and 6-hydroxy coumarin 3 with different substituted sulfonyl chlorides and subjected to evaluate for their in vitro immunomodulatory potential. The compounds were investigated for their effect on oxidative burst activity of zymosan stimulated whole blood phagocytes using a luminol enhanced chemiluminescence technique. Ibuprofen was used as standard drug (IC50 = 54.2 ± 9.2 μM). Eleven compounds 6 (IC50 = 46.60 ± 14.6 μM), 8 (IC50 = 11.50 ± 6.5 μM), 15 (IC50 = 21.40 ± 12.2 μM), 19 (IC50 = 5.75 ± 0.86 μM), 22 (IC50 = 10.27 ± 1.06 μM), 23 (IC50 = 33.09 ± 5.61 μM), 24 (IC50 = 4.93 ± 0.58 μM), 25 (IC50 = 21.96 ± 14.74 μM), 29 (IC50 = 12.47 ± 9.2 μM), 35 (IC50 = 20.20 ± 13.4 μM) and 37 (IC50 = 14.47 ± 5.02 μM) out of forty demonstrated their potential suppressive effect on production of reactive oxygen species (ROS) as compared to ibuprofen. All the synthetic derivatives 4–43 were characterized by different available spectroscopic techniques such as 1H NMR, 13C NMR, EIMS and HRMS. CHN analysis was also performed. 相似文献
14.
《Bioorganic & medicinal chemistry》2014,22(15):4109-4118
Twenty four pyrazoline derivatives modified from Celecoxib were designed and synthesized as bi-inhibitor of COX-2 and B-Raf. They were evaluated for their COX-1/COX-2/B-Raf inhibitory and anti-proliferation activities. Compound A3 displayed the most potent activity against COX-2 and HeLa cell line (IC50 = 0.008 μM; GI50 = 19.86 μM) and showed superb COX-1/COX-2 selectivity (>500), being more potent and selective than positive control Celecoxib or 5-fluorouracil. Compounds A5 and B5 were introduced best B-Raf inhibitory activities (IC50 = 0.15 μM and 0.12 μM, respectively). Compound A4 retained superb bioactivity against COX-2 and HeLa cell line (IC50 = 0.015 μM; GI50 = 23.82 μM) and displayed moderate B-Raf inhibitory activity (IC50 = 3.84 μM). Docking simulation was conducted to give binding patterns. QSAR models were built using bioactivity data and optimized conformations to provide a future modification of COX-2/B-Raf inhibitors. 相似文献
15.
Wen Yang Yang Hu Yu-Shun Yang Fei Zhang Yan-Bin Zhang Xiao-Liang Wang Jian-Feng Tang Wei-Qing Zhong Hai-Liang Zhu 《Bioorganic & medicinal chemistry》2013,21(5):1050-1063
Two series of novel naphthalin-containing pyrazoline derivatives C1–C14 and D1–D14 have been synthesized and evaluated for their EGFR/HER-2 inhibitory and anti-proliferation activities. Compound D14 displayed the most potent activity against EGFR and A549 cell line (IC50 = 0.05 μM and GI50 = 0.11 μM), being comparable with the positive control Erlotinib (IC50 = 0.03 μM and GI50 = 0.03 μM) and more potent than our previous compounds C0–A (IC50 = 5.31 μM and GI50 = 33.47 μM) and C0–B (IC50 = 0.09 μM and GI50 = 0.34 μM). Meanwhile, compound C14 displayed the most potent activity against HER-2 and MCF-7 cell line (IC50 = 0.88 μM and GI50 = 0.35 μM), being a little less potent than Erlotinib (IC50 = 0.16 μM and GI50 = 0.08 μM) but far more potent than C0–A (IC50 = 6.58 μM and GI50 = 27.62 μM) and C0–B (IC50 = 2.77 μM and GI50 = 3.79 μM). The docking simulation was performed to analyze the probable binding models and the QSAR models were built for reasonable design of EGFR/HER-2 inhibitors at present and in future. The structural modification of introducing naphthalin moiety reinforced the combination of our compounds and the receptor, resulting in progress of bioactivity. Moreover, the replacement of thiourea skeleton by using benzene ring resulted in the slight diversity of the two series towards specific targets. 相似文献
16.
6-Chloro-2-Aryl-1H-imidazo[4,5-b]pyridine derivatives 1–26 were synthesized and characterized by various spectroscopic techniques. All these derivatives were evaluated for their antiglycation, antioxidant and β-glucuronidase potential followed their docking studies. In antiglycation assay, compound 2 (IC50 = 240.10 ± 2.50 μM) and 4 (IC50 = 240.30 ± 2.90 μM) was found to be most active compound of this series, while compounds 3 (IC50 = 260.10 ± 2.50 μM), 6 (IC50 = 290.60 ± 3.60 μM), 13 (IC50 = 288.20 ± 3.00 μM) and 26 (IC50 = 292.10 ± 3.20 μM) also showed better activities than the standard rutin (IC50 = 294.50 ± 1.50 μM). In antioxidant assay, compound 1 (IC50 = 69.45 ± 0.25 μM), 2 (IC50 = 58.10 ± 2.50 μM), 3 (IC50 = 74.25 ± 1.10 μM), and 4 (IC50 = 72.50 ± 3.30 μM) showed good activities. In β-glucuronidase activity, compounds 3 (IC50 = 29.25 ± 0.50 μM), compound 1 (IC50 = 30.10 ± 0.60 μM) and compound 4 (IC50 = 46.10 ± 1.10 μM) showed a significant activity as compared to than standard D-Saccharic acid 1,4-lactonec (IC50 = 48.50 ± 1.25 μM) and their interaction with the enzyme was confirm by docking studies. 相似文献
17.
A new series of 1,2-diaryl-4-substituted-benzylidene-5-4H-imidazolone derivatives 10a-h was designed and synthesized for evaluation as selective COX-2 inhibitors, anti-inflammatory agents and as analgesic agents. All compounds were more selective for COX-2 isozyme and showed good in vivo anti-inflammatory activity. Compounds 10a, 10b, 10e and 10f were the most COX-2 selective compounds (S.I. = 10.76, 10.87, 8.69 and 9.14 respectively), the most potent anti-inflammatory derivatives (ED50 = 65.7, 60.2, 76.3 and 107.4 μmol/kg respectively) in comparison with Celecoxib (COX-2 S.I. = 8.61, ED50 = 82.2 μmol/kg) and were less ulcerogenic (ulcer indexes = 1.22–3.02) than Ibuprofen (ulcer index = 20.25) and comparable to Celecoxib (ulcer index = 2.93). The four derivatives (10a, 10b, 10e and 10f) showed considerable analgesic activities which are clearly parallel to their anti-inflammatory activities. 相似文献
18.
Khalid M. Khan Sumayya Saeed Muhammad Ali Madiha Gohar Javariya Zahid Ambreen Khan Shahnaz Perveen M. Iqbal Choudhary 《Bioorganic & medicinal chemistry》2009,17(6):2447-2451
A series of unsymmetrically disubstituted urea derivatives 1–28 has been synthesized and screened for their antiglycation activity in vitro. Compounds 26 (IC50 = 4.26 ± 0.25 μM), 1 (IC50 = 5.8 ± 0.08 μM), 22 (IC50 = 4.26 ± 0.25 μM), 6 (IC50 = 6.4 ± 0.02 μM), 5 (IC50 = 6.6 ± 0.26 μM), 2 (IC50 = 7.02 ± 0.31 μM), 3 (IC50 = 7.14 ± 0.84 μM), 27 (IC50 = 7.27 ± 0.36 μM), 4 (IC50 = 8.16 ± 1.04 μM), 21 (IC50 = 8.4 ± 0.15 μM), 23 (IC50 = 9.0 ± 0.35 μM) and 13 (IC50 = 15.22 ± 6.7 μM) showed an excellent antiglycation activity far better than the standard (rutin, IC50 = 41.9 ± 2.3 μM). This study thus provides a series of potential molecules for further studies of antiglycation agents. 相似文献
19.
《Bioorganic & medicinal chemistry letters》2014,24(1):332-336
Three classes of novel inhibitors of inosine monophosphate dehydrogenase have been prepared and their anti-proliferative properties were evaluated against several cancer cell lines.(1) Mycophenolic adenine dinucleotide analogues (8–13) containing a substituent at the C2 of adenine ring were found to be potent inhibitors of IMPDH (Ki’s in range of 0.6–82 nM) and sub-μM inhibitors of leukemic K562 cell proliferation. (2) Mycophenolic adenosine (d and l) esters (20 and 21) showed a potent inhibition of IMPDH2 (Ki = 102 and Ki = 231 nM, respectively) and inhibition of K562 cell growth (IC50 = 0.5 and IC50 = 1.6 μM). These compounds serve both as inhibitors of the enzyme and as a depot form of mycophenolic acid. The corresponding amide analogue 22, also a potent inhibitor of IMPDH (Ki = 84 nM), did not inhibit cancer cell proliferation. (3) Mycophenolic-(l)- and (d)-valine adenine di-amide derivatives 25 (Ki = 9 nM) and 28 (Ki = 3 nM) were found to be very potent enzymatically, but did not inhibit proliferation of cancer cells. 相似文献
20.
《Bioorganic & medicinal chemistry》2014,22(22):6509-6514
A series of Schiff base triazoles 1–25 was synthesized and evaluated for their nucleotide pyrophosphatase/phosphodiesterase-1 inhibitory activities. Among twenty-five compounds, three compounds 10 (IC50 = 132.20 ± 2.89 μM), 13 (IC50 = 152.83 ± 2.39 μM), and 22 (IC50 = 251.0 ± 6.64 μM) were identified as potent inhibitors with superior activities than the standard EDTA (IC50 = 277.69 ± 2.52 μM). The newly identified inhibitors may open a new avenue for the development of treatment of phosphodiesterase-I related disorders. These compounds were also evaluated for carbonic anhydrase, acetylcholinesterase and butyrylcholinesterase inhibitory potential and were found to be inactive. The compounds showed non-toxic effect towards PC3 cell lines. 相似文献