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1.
Titov IY Sagamanova IK Gritsenko RT Karmanova IB Atamanenko OP Semenova MN Semenov VV 《Bioorganic & medicinal chemistry letters》2011,21(6):1578-1581
Phenstatin and its derivatives with the modified ring A have been synthesized, using plant allylpolyalkoxybenzenes as a starting material. The targeted molecules were evaluated in a phenotypic sea urchin embryo assay for antiproliferative activity. It was found that phenstatin ring A modifications yielded antimitotic compounds. The most effective myristicin derivative 7d (combretastatin A-2 analogue) was determined to be ca. 10 times more potent than phenstatin, displaying antimitotic tubulin-destabilizing activity at the same concentration range as combretastatins. In contrast to combretastatins, 7d featured the steric stability with potential for further design as anticancer agent. 相似文献
2.
Romagnoli R Baraldi PG Jung MK Iaconinoto MA Carrion MD Remusat V Preti D Tabrizi MA Francesca F De Clercq E Balzarini J Hamel E 《Bioorganic & medicinal chemistry letters》2005,15(18):4048-4052
A new series of compounds, in which the 2-amino-4-methoxyphenyl ring of phenstatin analogue 5 was replaced with 2- or 3-amino-benzoheterocycles, was synthesized and evaluated for antiproliferative activity and inhibition of colchicine binding. The lack of activity of 3',4'-dimethoxy- and 4'-methoxy-benzoyl derivatives (8 and 9, respectively) indicates that the 3',4',5'-trimethoxybenzoyl moiety is critical for the activity. Two compounds, 7 and 11, displayed potent antiproliferative activity, with IC50 values ranging from 25 to 100 nM against a variety of cancer cell lines. Derivative 11 was more active than CA-4 as an inhibitor of tubulin polymerization. The results demonstrated that the antiproliferative activity was correlated with inhibition of tubulin polymerization. 相似文献
3.
《Bioorganic & medicinal chemistry》2016,24(10):2307-2317
New phenothiazine derivatives 6–20 have been designed, synthesized and evaluated in vitro for their ability to inhibit tubulin polymerization and antiproliferative activity against 60 cancer cell lines, including several multi-drug resistant (MDR) tumor cell lines. The phenothiazine unit may successfully replace the classical 3,4,5-trimethoxyphenyle A ring of parent combretastatin A-4 or phenstatin, confirming previous studies. The most promising structural modulations have been realized on the B ring, the 2′-fluoro-4′-methoxy substitution in compound 6 and the 2′-trifluoromethyl-4′-methoxy substitution in compound 7 providing the best antitubulin and antitumor activity in the current study. Compounds 6–8 and 16 exhibited more important cell growth inhibition than parent phenstatin 2 on human colon Duke’s type D, colorectal adenocarcinoma COLO 205 and on human kidney adenocarcinoma A498 cell lines. 10-Methylphenothiazine derivatives 19 and 20 did not show biological activity but exerted bright fluorescence and solvatochromism effects. These molecules deserve further chemical efforts in order to provide valuable tools for biophysical studies. 相似文献
4.
Ghinet A Rigo B Hénichart JP Le Broc-Ryckewaert D Pommery J Pommery N Thuru X Quesnel B Gautret P 《Bioorganic & medicinal chemistry》2011,19(20):6042-6054
Previous investigations on the incubation of phenstatin with rat and human microsomal fractions revealed the formation of nine main metabolites. The structures of eight of these metabolites have been now confirmed by synthesis and their biological properties have been reported. Eaton's reagent was utilized as a convenient condensing agent, allowing, among others, a simple multigram scale preparation of phenstatin. Synthesized metabolites and related compounds were evaluated for their antiproliferative activity in the NCI-60 cancer cell line panel, and for their effect on microtubule assembly. Metabolite 23 (2'-methoxyphenstatin) exhibited the most potent in vitro cytotoxic activity: inhibition of the growth of K-562, NCI-H322M, NCI-H522, KM12, M14, MDA-MB-435, NCI/ADR-RES, and HS 578T cell lines with GI(50) values <10nM. It also showed more significant tubulin polymerization inhibitory activity than parent phenstatin (3) (IC(50)=3.2 μM vs 15.0 μM) and induced G2/M arrest in murine leukemia DA1-3b cells. The identification of this active metabolite led to the design and synthesis of analogs with potent in vitro cytotoxicity and inhibition of microtubule assembly. 相似文献
5.
Raquel lvarez Concepcin lvarez Faustino Mollinedo Beatriz G. Sierra Manuel Medarde Rafael Pelez 《Bioorganic & medicinal chemistry》2009,17(17):6422-6431
Isocombretastatins A are 1,1-diarylethene isomers of combretastatins A. We have synthesized the isomers of combretastatin A-4, deoxycombretastatin A-4, 3-amino-deoxycombretastatin A-4 (AVE-8063), naphthylcombretastatin and the N-methyl- and N-ethyl-5-indolyl analogues of combretastatin A-4. Analogues with a 2,3,4-trimethoxyphenyl ring instead of the 3,4,5-trimethoxyphenyl ring have also been prepared. The isocombretastatins A strongly inhibit tubulin polymerization and are potent cytotoxic compounds, some of them with IC50s in the nanomolar range. This new family of tubulin inhibitors shows higher or comparable potency when compared to phenstatin or combretastatin analogues. These results suggest that one carbon bridges with a geminal diaryl substitution can successfully replace the two carbon bridge of combretastatins and that the carbonyl group of phenstatins is not essential for high potency. 相似文献
6.
Biaryls, 7-naphthyl-5-s-amino-2,3-dihydrobenzo[b]thiophene-4-carbonitriles (3a-e), 8-(1-naphthyl)-6-s-amino-isothiochroman-5-carbonitriles (6a-d), 4-(1-naphthyl)-2-s-aminobezocycloalkene-1-carbonitriles (6e-j), 8-naphthyl-6-s-amino-2-ethyl-1,2,3,4-tetrahydro-isoquinoline-5-carbonitrle (6k-n), 1-naphthyl-3-s-amino-10H-9-thia-phenantherene-4-carbonitriles (8a-e) and 1-(1-naphthyl)-3-s-amino-9,10-dihydrophenantherene-4-carbonitriles (8f-i) have been prepared through carbanion induced ring transformation reactions of 6-naphthyl-3-cyano-4-s-amino-2H-pyran-2-ones (1) from respective ketones (2, 5, and 7). These compounds have been evaluated for their glucose-6-phosphatase inhibitory activity and only 6a, c, j, m, c, d, h displayed significant inhibition of the glucose-6-phosphatase. 相似文献
7.
Blake A. Winn Zhe Shi Graham J. Carlson Yifan Wang Benson L. Nguyen Evan M. Kelly R. David Ross Ernest Hamel David J. Chaplin Mary L. Trawick Kevin G. Pinney 《Bioorganic & medicinal chemistry letters》2017,27(3):636-641
A variety of solid tumor cancers contain significant regions of hypoxia, which provide unique challenges for targeting by potent anticancer agents. Bioreductively activatable prodrug conjugates (BAPCs) represent a promising strategy for therapeutic intervention. BAPCs are designed to be biologically inert until they come into contact with low oxygen tension, at which point reductase enzyme mediated cleavage releases the parent anticancer agent in a tumor-specific manner. Phenstatin is a potent inhibitor of tubulin polymerization, mimicking the chemical structure and biological activity of the natural product combretastatin A-4. Synthetic approaches have been established for nitrobenzyl, nitroimidazole, nitrofuranyl, and nitrothienyl prodrugs of phenstatin incorporating nor-methyl, mono-methyl, and gem-dimethyl variants of the attached nitro compounds. A series of BAPCs based on phenstatin have been prepared by chemical synthesis and evaluated against the tubulin-microtubule protein system. In a preliminary study using anaerobic conditions, the gem-dimethyl nitrothiophene and gem-dimethyl nitrofuran analogues were shown to undergo efficient enzymatic cleavage in the presence of NADPH cytochrome P450 oxidoreductase. Each of the eleven BAPCs evaluated in this study demonstrated significantly reduced inhibitory activity against tubulin in comparison to the parent anti-cancer agent phenstatin (IC50 = 1.0 μM). In fact, the majority of the BAPCs (seven of the eleven analogues) were not inhibitors of tubulin polymerization (IC50 > 20 μM), which represents an anticipated (and desirable) attribute for these prodrugs, since they are intended to be biologically inactive prior to enzyme-mediated cleavage to release phenstatin. 相似文献
8.
J W Tilley W Danho S J Shiuey I Kulesha R Sarabu J Swistok R Makofske G L Olson E Chiang V K Rusiecki 《International journal of peptide and protein research》1992,39(4):322-336
Previous work indicates that both the C-terminal phenylalanine amide and the tryptophan moieties of cholecystokinin (CCK) are critical pharmacophores for interaction with either the A or B receptor subtypes. We have examined a series of analogs of Ac-CCK-7 [Ac-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe33-NH2] (2) in which the phenyl ring of the C-terminal Phe-NH2 has been modified. Compounds were assessed in binding assays using homogenated rat pancreatic membranes and bovine striatum as the source of CCK-A and CCK-B receptors respectively and for anorectic activity after intraperitoneal administration to rats. Substitution of a number of cycloalkyl or bicyclic aryl moieties for the phenyl ring of phenylalanine33 including cyclopentyl (20), cyclohexyl (21), cyclooctyl (23), 2-(5,6,7,8-tetrahydro)naphthyl (26), 2-naphthyl (27), and 1-naphthyl (29) led to analogs with 10-70 times the anorectic potency of 2. The anorectic activity of 21 was blocked by the specific CCK-A receptor antagonist MK-329. Other bulky aliphatic groups in place of the phenylalanine33 aromatic ring such as isopropyl, 2-adamantyl and cyclohexylmethyl gave derivatives similar to 2 in potency. While most of the new compounds were comparable to CCK in binding assays, 23, 26, 27 and 29 were exceptionally potent with IC50s 10(-11)-10(-14) M in the pancreas. Compounds 23 and 29 were further evaluated for their ability to stimulate amylase secretion and found to have potencies similar to that of CCK. The dissociation between potency in the binding and amylase secretion assays suggests that they may interact with a high affinity binding site which is not coupled to amylase secretion. We conclude that CCK receptors possess a generous hydrophobic pocket capable of accommodating large alkyl groups in place of the side chain of phenylalanine33 and that the pharmacological profile of CCK analogs can be tailored by appropriate exploitation of this finding. 相似文献
9.
Jia ZJ Wu Y Huang W Goldman E Zhang P Woolfrey J Wong P Huang B Sinha U Park G Reed A Scarborough RM Zhu BY 《Bioorganic & medicinal chemistry letters》2002,12(12):1651-1655
Based on DuPont Pharmaceuticals' monobenzamidine lead structure SN429, we have designed the biphenyl 1-(2-naphthyl)-1H-pyrazole-5-carboxylamides as a novel series of non-basic factor Xa inhibitors. We have discovered that the displacement of the benzamidine moiety with substituted 2-naphthyl structures not only results in highly potent factor Xa inhibitors, but also significantly increases their enzyme specificity and oral bioavailability. 相似文献
10.
Jinhui Chen David P. Brown Yi-Jun Wang Zhe-Sheng Chen 《Bioorganic & medicinal chemistry letters》2013,23(18):5119-5122
New phenstatin–fatty acid conjugates have been synthesized and tested against the KB-3-1, H460, MCF-7 and HEK293 cell lines, with an increase in anti-proliferative activity being observed at the micro-molar level paralleling an increase in un-saturation in the fatty acid component. 相似文献
11.
Synthesis, dopamine and serotonin transporter binding affinities of novel analogues of meperidine 总被引:1,自引:0,他引:1
Lomenzo SA Izenwasser S Gerdes RM Katz JL Kopajtic T Trudell ML 《Bioorganic & medicinal chemistry letters》1999,9(23):3273-3276
A series of meperidine analogues was synthesized and the binding affinities for the dopamine and serotonin transporters were determined. The substituents on the phenyl ring greatly influenced the potency and selectivity of these compounds for the transporter binding sites. In general, meperidine (3) and its analogues were more selective for serotonin transporter binding sites and the esters 9 were more potent than the corresponding nitriles 8. The 3,4-dichloro derivative 9e was the most potent ligand of the series for dopamine transporter binding sites while the 2-naphthyl derivative 9g exhibited the most potent binding affinity and was highly selective for serotonin transporter binding sites. 相似文献
12.
We describe herein the investigation of the stereodynamic processes occurring in a series of 1-aryl-2,2-dimethylindanols, by dynamic NMR. When the aryl moiety is a mesityl or a 2-methyl-1-naphthyl, the rotational barrier exceeds the 25 kcal/mol, so that stable atropisomers are observed. In two cases, all the chiral-atropisomeric species have been separated by enantioselective HPLC, and the comparison between theoretical and experimental electronic circular dichroism spectra allowed the absolute configuration assignment of all the isolated species to be obtained. 相似文献
13.
O'Boyle NM Greene LM Bergin O Fichet JB McCabe T Lloyd DG Zisterer DM Meegan MJ 《Bioorganic & medicinal chemistry》2011,19(7):2306-2325
A series of azetidin-2-ones substituted at positions 1, 3 and 4 of the azetidinone ring scaffold were synthesised and evaluated for antiproliferative, cytotoxic and tubulin-binding activity. In these compounds, the cis double bond of the vascular targeting agent combretastatin A-4 is replaced with the azetidinone ring in order to enhance the antiproliferative effects displayed by combretastatin A-4 and prevent the cis/trans isomerisation that is associated with inactivation of combretastatin A-4. The series of azetidinones was synthetically accessible via the Staudinger and Reformatsky reactions. Of a diverse range of heterocyclic derivatives, 3-(2-thienyl) analogue 28 and 3-(3-thienyl) analogue 29 displayed the highest potency in human MCF-7 breast cancer cells with IC(50) values of 7 nM and 10nM, respectively, comparable to combretastatin A-4. Compounds from this series also exhibited potent activity in MDA-MB-231 breast cancer cells and in the NCI60 cell line panel. No significant toxicity was observed in normal murine breast epithelial cells. The presence of larger, bulkier groups at the 3-position, for example, 3-naphthyl derivative 21 and 3-benzothienyl derivative 26, resulted in relatively lower antiproliferative activity in the micromolar range. Tubulin-binding studies of 28 (IC(50)=1.37 μM) confirmed that the molecular target of this series of compounds is tubulin. These novel 3-(thienyl) β-lactam antiproliferative agents are useful scaffolds for the development of tubulin-targeting drugs. 相似文献
14.
Cristina-Maria Abuhaie Elena Bîcu Benoît Rigo Philippe Gautret Dalila Belei Amaury Farce Joëlle Dubois Alina Ghinet 《Bioorganic & medicinal chemistry letters》2013,23(1):147-152
A new family of microtubule-targeting agents with a phenothiazine A-ring was synthesized and evaluated for anti-proliferative activity and interaction with tubulin. These new derivatives showed significant activities against cellular proliferation and tubulin polymerization, rather similar to those of phenstatin. Phenothiazine derivative 21 proved to be the most potent compound synthesized with GI50 values ranging from 29 to 93 nM on different cell lines. The same compound showed a better inhibition of COLO 205, A498, and MCF7 cell lines than the parent phenstatin. 相似文献
15.
A series of substituted-isoxazole derivatives was prepared as candidate farnesoid X receptor (FXR) antagonists, based on our previously proposed ligand superfamily concept. Structure-activity relationship studies indicated that the shape and the structural bulkiness of the substituent at the 5-position of the isoxazole ring affected FXR-antagonistic activity. Compounds 15 g (5-substituent: 2-naphthyl) and 15 h (5-substituent: 4-biphenyl) were identified as potent antagonists with higher selectivity for FXR over progesterone receptor than the naturally occurring FXR antagonist GS. The 5-substituent is also a critical determinant of the characteristic corepressor recruitment profile of this class of FXR antagonists, though distinct mechanisms appear to be involved: 15 h stabilizes the corepressor-nuclear receptor interaction, while 15 g inhibits coactivator recruitment. 相似文献
16.
Roggen H Kehler J Stensbøl TB Hansen T 《Bioorganic & medicinal chemistry letters》2007,17(10):2834-2837
A series of Milnacipran analogs with variation in the aromatic moiety were prepared in high enantiomeric excess. Structure-activity relationships for two parallel enantiomeric series are described. The (-)-(1R,2S)-naphthyl analog (8h) showed the highest potency in the two series and is a triple reuptake inhibitor of the SERT, NET, and DAT. 相似文献
17.
(R)-Goniothalamin, is a member of styryl lactones, possesses selective cytotoxicity against cancer cell lines. In this work, replacement of styryl substituent with 2-naphthyl and 3-quinoyl gave new analogues which may have less conformational changes compared to the lead compound. Anti-proliferative tests indicated that 2-naphthyl substituted (R)-5,6-dihydro-2H-pyran-2-one has slightly better cytotoxicity than (R)-goniothalamin. To clarify the effect of 2-naphthyl substituent additional aryl substituted (R)-5,6-dihydro-2H-pyran-2-ones have been synthesized enantioselectively and tested against PC-3 and MCF-7 cell lines. 相似文献
18.
《Bioorganic & medicinal chemistry》2016,24(22):6021-6030
The phenothiazine group has been identified as a suitable A ring in the structure of tubulin polymerization inhibitors. In our search to identify more potent inhibitors, a study of different isosteric tricyclic groups as new potential A rings was first realized and permitted to identify 1-azaphenothiazine and iminodibenzyl as favorable modulations providing compounds with improved activity against tubulin. An investigation of the methylene group as the connector between the A and B rings revealed that the “CH2” bridge was tolerated, improving the biological potency when the A unit was of phenothiazine, 1-azaphenothiazine or iminodibenzyl type. Molecules 6–8 and 12 showed increased biological activity in comparison to parent phenstatin 2 on COLO 205 colon cancer cell line. The most antineoplastic agent in the current study was phenothiazine 5 displaying a GI50 of 25 nM against the melanoma MDA-MB-435 cell line. 相似文献
19.
The biochemistry of aromatic amines. 2-Formamido-1-naphthyl hydrogen sulphate, a metabolite of 2-naphthylamine 总被引:2,自引:2,他引:0
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1. 2-Formamido-1-naphthyl hydrogen sulphate is excreted by dogs and rats dosed with 2-naphthylamine or with 2-amino-1-naphthyl hydrogen sulphate and was isolated from dog urine. 2. 2-Formamido-1-naphthol, naphtho[2,1-d]oxazole and N-formyl-2-naphthylhydroxylamine are excreted as (2-formamido-1-naphthyl glucosid)uronic acid. 2-Formamidonaphthalene is converted into conjugates of 2-amino-6-naphthol and 2-amino-8-naphthol, but 2-methylaminonaphthalene is excreted as 2-amino-1-naphthyl hydrogen sulphate and its N-methyl and N-formyl derivatives and (2-amino-1-naphthyl glucosid)uronic acid. 3. 2-Methylamino-1-naphthyl hydrogen sulphate is converted into 2-formamido-1-naphthyl hydrogen sulphate and 2-amino-1-naphthyl hydrogen sulphate on charcoal. 2-Amino-1-naphthyl hydrogen sulphate and formaldehyde react on charcoal to yield 2-methylamino- and 2-formamido-1-naphthyl hydrogen sulphate. 4. 2-Formamido-1-naphthol, 2-formamido-1-naphthyl hydrogen sulphate, N-formyl-2-naphthylhydroxylamine and N-formyl-2-naphthylhydroxylamine-O-sulphonic acid were synthesized. 相似文献
20.
Alina Ghinet Aurélien Tourteau Benoît Rigo Vivien Stocker Marie Leman Amaury Farce Joëlle Dubois Philippe Gautret 《Bioorganic & medicinal chemistry》2013,21(11):2932-2940
With the aim of investigating the influence of fluorine, in particular on the A-ring, a new series of fluoro analogues (7a–l) of phenstatin (3) was synthesized and tested for interactions with tubulin polymerization and evaluated for cytotoxicity on an NCI-60 human cancer cell lines panel. We have shown that the replacement of 3,4,5-trimethoxyphenyl A-ring of phenstatin with 2,4,5-trifluoro-3-methoxyphenyl unit, results in the conservation of both antitubulin and cytotoxic effect. Fluoro isocombretastatin 7k was the most effective anticancer agent in the present study and demonstrated the highest antiproliferative potential on leukemia cell lines SR (GI50 = 15 nM) and HL-60(TB) (GI50 = 23 nM) and on melanoma cell line MDA-MB-435 (GI50 = 19 nM). 相似文献