Synthesis and antiproliferative evaluation of amide-containing flavone and isoflavone derivatives

Certain amide-containing flavone and isoflavone derivatives were synthesized and evaluated for their antiproliferative activities. These compounds were synthesized via alkylation of hydroxyl precursors followed by the reaction with H(2)SO(4) and NaN(3) (Schmidt reaction). The preliminary assays indicated that the inhibitory activity against the growth of NCI-H661 decreased in an order of linked chromophore flavone-6-yl 16a-d>flavone-7-yl 17a-d>flavone-3-yl 15a-d and isoflavone-7-yl 18a-d. Among these flavone-6-yl derivatives, N-(4-methoxyphenyl)-2-(4-oxo-2-phenyl-4H-chromen-6-yloxy)acetamide (16c) was the most potent with a GI(50) value of 0.84 microM. The inhibitory activity against the growth of NPC-TW01 decreased in an order of linked chromophore flavone-6-yl 16a-d>isoflavone-7-yl 18a-d>flavone-7-yl 17a-d>flavone-3-yl 15a-d. Flavone-6-yl derivatives 16a-d demonstrated significant inhibitory activities against the growth of NPC-TW01 cell with an average GI(50) value of 0.84 microM. The oxime derivatives 1 and 2 caused accumulation of NPC-TW01 cell in G(2)/M phase which were distinct from that of their amide isomers 16b and 16c, respectively, which induced cell-cycle arrest in G(0)/G(1) phase followed by apoptosis. Therefore, the antiproliferative mechanism of flavone derivatives was affected not only by the phenyl benzopyran-4-one pharmacophore but also by the peripheral substituents.     

Synthesis and antiproliferative evaluation of certain indeno[1,2-c]quinoline derivatives

Although the quinoline ring is found in a wide variety of biologically active compounds and is frequently condensed with various heterocycles, synthesis and biological evaluation of the indenoquinoline skeleton attracts only very limited attention. We report herein the synthesis and antiproliferative evaluation of certain indeno[1,2-c]quinoline derivatives against the growth of six cancer cell lines including human cervical epithelioid carcinoma (HeLa), oral squamous cell carcinoma (SAS), hepatocellular carcinoma (SKHep), human stomach adenocarcinoma (AGS), prostate cancer (PC-3), and non-small cell lung cancer (A549). The results indicated that 9-methoxy-6-(piperazin-1-yl)-11H-indeno[1,2-c]quinolin-11-one (17b) is more active than its C(6)-amino derivative 17a, C(6)-morpholine and C(6)-piperidine isomers, 17c and 17d, respectively. Treatment of 17b with NH(2)OH afforded its hydroxyimino derivative 20 which is more active than the carbonyl precursor 17b. More potent agents were obtained by further derivatization of 20. Thus, antiproliferative activities decreased in an order of aminoalkoxyimino 22a-d>hydroxyimino 20>alkoxyimino 21, 22e>carbonyl 17b. Both AGS and A549 were resistant to camptothecin with GI(50) values of 23.76 and 2.80 microM, respectively, while GI(50) values for 22a-d were in the range of 5.93-7.11 microM and 0.38-0.87 microM, respectively. Among them, 22b was the most potent with GI(50) values of 0.52, 0.74, 6.76, and 0.64 microM against the growth of HeLa, SKHep, AGS, and A549 cells, respectively. Flowcytometric analysis indicated 22c can induce cell cycle arrest in S phase, and DNA polyploidy (>4n) followed by apoptosis.     

Synthesis, antiproliferative, and antiplatelet activities of oxime- and amide-containing quinolin-2(1H)-one derivatives

Certain oxime- and amide-containing quinolin-2(1H)-one derivatives were synthesized and evaluated for their antiproliferative and antiplatelet activities. These compounds were synthesized via alkylation of hydroxyl precursors followed by the reaction with NH(2)OH or NaN(3) (Schmidt reaction). The preliminary assays indicated that amide derivatives are either weakly active or inactive while the oxime counterparts exhibited potent inhibitory activities against platelet aggregation induced by collagen, AA (arachidonic acid), and U46619 (the stable thromboxan A(2) receptor agonist). Among them, (Z)-6-[2-(4-methoxyphenyl)-2-hydroxyiminoethoxy]quinolin-2(1H)-one (7c) was the most active against AA induced platelet aggregation with an IC(50) of 0.58microM and was inactive against cell proliferation. For the inhibition of U46619 induced aggregation, 7a and 8a-c exhibited very potent activities with IC(50) values in a range between 0.54 and 0.74microM. For the antiproliferative evaluation, N-(biphenyl-4-yl)-2-(2-oxo-1,2-dihydroquinolin-7-yloxy)acetamide (11d) was the most potent with GI(50) values of <10, 10.8, and <10microM against the growth of MT-2, NCI-H661, and NPC-Tw01, respectively, and possessed only a weak antiplatelet activity. Further evaluation of 11d as a potential anticancer agent is on-going.     

Three isoflavanones with cannabinoid-like moieties from Desmodium canum

Three further derivatives of 5,7,2',4'-tetrahydroxy-6-methyl isoflavanone have been isolated from the root extract of Desmodium canum and assigned the structures 2,3-dihydro-5,7-dihydroxy-6-methyl-3-(1a,2,3,3a,8b,8c-hexahydro-6-hydroxy-1,1,3a-trimethyl-1H-4-oxabenzo[f]cyclobut[c,d]inden-7-yl)-4H-1-benzopyran-4-one (1) 2,3-dihydro-5,7-dihydroxy-6-methyl-3-(6a,7,8,10a-tetrahydro-3-hydroxy-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-2-yl)-4H-1-benzopyran-4-one (2) 2,3-dihydro-5,7-dihydroxy-6-methyl-3-(3-hydroxy-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-2-yl) 4H-1-benzopyran-4-one (3). The three compounds and the previously isolated chromene 4 all derive from the geranylated precursor 5 by a series of cannabinoid-like oxidative rearrangements.     

Nitrogen-containing flavonoid analogues as CDK1/cyclin B inhibitors: synthesis, SAR analysis, and biological activity

A series of nitrogen-containing flavonoid analogues were designed and synthesized by Mannich reaction, and screened for the inhibitory activities of cyclin-dependent kinases using a FRET-based biochemical assay method. The results showed that C-8 nitrogen-containing baicalein analogues 3a-3f exhibited potent CDK1/Cyclin B inhibitory activities. 5,6,7-Trihydroxy-8-(dimethylaminomethyl)-2-phenyl-4H-chromen-4-one 3a, 5,6,7-trihydroxy-8-(pyrrolid inylmethyl)-2-phenyl-4H-chromen-4-one 3b, and 5,6,7-trihydroxy-8-(piperidinylmethyl)-2-phenyl-4H-chromen-4-one 3c (IC(50) 1.05-1.28 microM) were about sixfold more potent than baicalein 2 (IC(50) 6.53 microM). 5,6,7-Trihydroxy-8-(morpholinomethyl)-2-phenyl-4H-chromen-4-one 3d, 5,6,7-trihydroxy-8-(thiomorpholinomethy)-2-phenyl-4H-chrom en-4-one 3e, and 5,6,7-trihydroxy-8-(4-methylpiperazinylmethyl)-2-phenyl-4H-chromen-4-one 3f (IC(50) 0.27-0.38 microM) were about 20-fold more potent than baicalein, and were at the same level as flavopiridol (IC(50) 0.33 microM).     

Synthesis and potent antimicrobial activity of some novel 2-phenyl or methyl-4H-1-benzopyran-4-ones carrying amidinobenzimidazoles

Series of flavones and methyl-4H-1-benzopyran-4-ones carrying mono or diamidinobenzimidazoles at different positions were synthesized and evaluated for antibacterial and antifungal activities against E. coli, S. aureus, MRSA (methicillin-resistant S. aureus), MRSE (methicillin-resistant S. epidermidis), S. faecalis and C. albicans, C. krusei. The results showed that while all diamidines are inactive, the compounds having monoamidinobenzimidazoles at the C-6 position of the 2-phenyl-4H-1-benzopyran-4-one have potent antibacterial activities, particularly, against Gram-positive bacteria. Compounds 23 and 22 exhibited the best inhibitory activity with MIC values of 1.56 microg/ml against S. aureus, MRSA, MRSE and 3.12 microg/ml against C. albicans, respectively.     

Kaempferol inhibits myosin light chain kinase

Kaempferol, 3,5,7-trihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one, was found to inhibit bovine aorta myosin light chain kinase with a Ki of 0.3-0.5 microM. It was found to be competitive with ATP and non-competitive with isolated myosin light chains. The specificity of this inhibitor was studied relative to protein kinase C and cAMP dependent protein kinase (IC50 = 15 microM and 150 microM, respectively). It appears not to interact strongly with calmodulin binding proteins, such as Ca2+-calmodulin dependent phosphodiesterase (IC50 = 45 microM), and had little effect on actin-activated myosin subfragment-1 ATPase activity (IC50 greater than 100 microM) or smooth muscle phosphatase activities (IC50 greater than 100 microM).     

Synthesis and antiproliferative evaluation of certain 4-anilino-8-methoxy-2-phenylquinoline and 4-anilino-8-hydroxy-2-phenylquinoline derivatives

The present report describes the synthesis and antiproliferative evaluation of certain 4-anilino-8-methoxy-2-phenylquinoline and 4-anilino-8-hydroxy-2-phenylquinoline derivatives. The antiproliferative activity of 4'-COMe-substituted derivatives decreased in an order of 6-OMe (1, 3.89 microM) > 8-OMe (8, 10.47 microM) > 8-OH (9, 14.45 microM), indicating that the position of substitution at the quinoline ring is crucial. For 3'-COMe derivatives, the antiproliferative activity of 8-OH (11, 1.20 microM) is more potent than its 8-OMe counterpart (10, 8.91 microM), indicating that a H-bonding donating substituent is more favorable than that of a H-bonding accepting group. Comparison of 8-OH derivatives, the antiproliferative effect of COMe (11) is more potent than its oxime derivative (15a, 2.88 microM), which in turn is more potent than the methyloxime counterpart (15b, 5.50 microM). Compound 11 is especially active against the growth of certain solid cancer cells such as HCT-116 (colon cancer), MCF7, and MDA-MB-435 (breast cancer) with GI50 values of 0.07, <0.01, and <0.01 microM, respectively. Flow cytometric analyses revealed that growth inhibition by 11 and 15a was due to accumulation in S-phase. This result is interesting because 2-phenylquinolone derivatives have been reported to be antimitotic agents which induced cell cycle arrest in G2/M phase.     

Synthesis, spectroscopy (IR, multinuclear NMR, ESI-MS), diffraction, density functional study and in vitro antiproliferative activity of pyrazole-beta-diketone dihalotin(IV) compounds on 5 melanoma cell lines

Novel 4-acylpyrazolon-5-ato-dihalotin(IV) complexes, [Q2SnX2], (X = F, Cl, Br or I); HQ = HQ(CHPh2) (1,2-dihydro-3-methyl-1-phenyl-4-(2,2-diphenylacetyl)pyrazol-5-one), HQ(Bn) (1,2-dihydro-3-methyl-1-phenyl-4-(2-phenylacetyl)pyrazol-5-one) or HQ(CF3,py) (4-(2,2,2-trifluoroacetyl)-1,2-dihydro-3-methyl-1-(pyridin-2-yl)pyrazol-5-one) have been synthesized and characterized by spectroscopic (IR, 1H, 13C, 19F and 119Sn NMR, electrospray ionisation mass spectrometry (ESI-MS)), analytical and structural methods (X-ray and density functional theory). 119Sn chemical shifts depend on the nature of the halides bonded to tin. Isomer conversion, detected in solution by NMR spectroscopy, is related to the acyl moiety bulkiness while the cis(Cl)-cis(acyl)-trans(pyrazolonato) scheme is found in the solid state. The in vitro antiproliferative tests of three derivatives on three human melanoma cell lines (JR8, SK-MEL-5, MEL501) and two melanoma cell clones (2/21 and 2/60) show dose-dependent decrease of cell proliferation in all cell lines. The activity correlates with the nature of the substituent on position 1 of pyrazole, decreasing in the order pyridyl>Ph>methyl. The activity for (Q(CF3,py))2SnCl2 on the SK-MEL-5 cell line is IC50 = 50 microM.     

Structure and vasorelaxant activity of floranol, a flavonoid isolated from the roots of Dioclea grandiflora

The structure of the prenylated flavanonol, floranol (1=(2R,3R)-3,5,7-trihydroxy-2-(2-hydroxyphenyl)-6-methoxy-8-(3-methylbut-2-enyl)-4H-1-benzopyran-4-one), isolated from the roots of Dioclea grandiflora (Fabaceae), was unambiguously determined by X-ray analysis. The compound was tested for vasorelaxant activity. In endothelium-containing aortic rings, floranol (1) induced a concentration-dependent vasodilator effect in vessels precontracted with 0.1 microM phenylephrine with an IC(50) value of 19.9+/-2.4 microM. The removal of endothelium or pretreatment of vessels with the NO-synthase inhibitor L-NAME did not change the IC(50) and E(max) values for floranol-induced vasorelaxation. We conclude that floranol (1) should be acting directly in the rat-aorta smooth muscle cells to produce its vasorelaxant effect. The structure-activity relationship was discussed in terms of the 3-D floranol structure determined by X-ray crystallography.     

Lipase-catalysed regio- and enantioselective deacetylation of 2,4-diacetoxyphenyl alkyl ketones.

Porcine pancreatic lipase in tetrahydrofuran catalyses the deacetylation of 2,4-diacetoxyphenyl alkyl ketones in a highly regioselective fashion. The strategy of regioselective deacetylation of diacetoxyphenyl alkyl ketones has also resulted in the enantiomeric resolution of a racemic diacetoxyphenyl alkyl ketone, i.e. (+/-)-2,4-diacetoxyphenyl (1-ethyl)pentyl ketone, a precursor for the synthesis of an antifungal coumarin, 7-acetoxy-4-(1-ethyl)pentyl-3-phenyl-2H-1-benzopyran-2-one.     

Iridoid glucosides and flavones from the aerial parts of Avicennia marina

Two new iridoid glucosides, namely, 2'-O-[(2E,4E)-5-phenylpenta-2,4-dienoyl]mussaenosidic acid (1; mussaenosidic acid = [1S-(1alpha,4aalpha,7alpha,7aalpha)]-1-(beta-D-glucopyranosyloxy)-1,4a,5,6,7,7a-hexahydro-7-hydroxy-7-methylcyclopenta[c]pyran-4-carboxylic acid) and 2'-O-(4-methoxycinnamoyl)mussaenosidic acid (2), were isolated from the aerial parts of the mangrove plant Avicennia marina. Beside that, one known iridoid glucoside, 2'-O-coumaroylmussaenosidic acid (3) and four known flavones (flavone = 2-phenyl-4H-1-benzopyran-4-one) including 4',5-dihydroxy-3',7-dimethoxyflavone (4), 4',5-dihydroxy-3',5',7-trimethoxyflavone (5), 4',5,7-trihydroxyflavone (6), and 3',4',5-trihydroxy-7-methoxyflavone (7) were also isolated and identified. The structures of these compounds were elucidated by NMR spectroscopy and by low- and high-resolution mass spectrometry. The chemotaxonomic significance of these findings was discussed. In addition, each isolated compound was evaluated for the ability of alpha,alpha-diphenyl-beta-picrylhydrazyl (DPPH) radical-scavenging activity.     

Antitumor agents. Part 218: Cappamensin A,a new In vitro anticancer principle,from Capparis sikkimensis

A new inhibitor of in vitro tumor cell replication, cappamensin A (1) (2H-1,4-benzoxazin-3(4H)-one, 6-methoxy-2-methyl-4-carbaldehyde), was isolated from the roots of Capparis sikkimensis subsp. formosana using bioactivity-guided fractionation. The structure of 1 was established by spectroscopic methods, including 2D NMR analyses. Compound 1 displayed significant in vitro anticancer activity against ovarian (1A9), lung (A549), ileocecal (HCT-8), breast (MCF-7), nasopharyngeal (KB), and vincristine resistant (KB-VIN) human tumor cell lines with ED(50) values 相似文献   

Synthesis, and cytotoxic and antiplatelet activities of oxime- and methyloxime-containing flavone, isoflavone, and xanthone derivatives

A series of oxime- and methyloxime-containing flavone, isoflavone, and xanthone derivatives (1-12) were synthesized (Scheme) and evaluated for their cytotoxic (Table 1) and antiplatelet activities (Table 2). The in vitro anticancer assay indicated that the cytotoxicity of structurally related compounds decreases in the order isoflavones (7a-7c) > flavones (8a-8c) > xanthones (9a-9c), electron-releasing substituents (R) on the Ph ring being favorable (mean GI50 values of 2.84, 12.3, and 20.9 microM for 7c, 8c, and 9c, resp.). The inhibition of platelet aggregation induced by arachidonic acid (AA) similarly decreased from the isoflavone 1 (IC50 = 2.97 microM) to the flavone 2 (7.70 microM) to the xanthone 3 (inactive). Thereby, compound 1 seems to be a promising lead, since it was not only the most-potent aggregation inhibitor (IC50 = 2.97 microM), but was also found to be noncytotoxic at a concentration of 100 microM.     

Anti-neoplastic activity of two flavone isomers derived from Gnaphalium elegans and Achyrocline bogotensis

Over 4000 flavonoids have been identified so far and among these, many are known to have antitumor activities. The basis of the relationships between chemical structures, type and position of substituent groups and the effects these compounds exert specifically on cancer cells are not completely elucidated. Here we report the differential cytotoxic effects of two flavone isomers on human cancer cells from breast (MCF7, SK-BR-3), colon (Caco-2, HCT116), pancreas (MIA PaCa, Panc 28), and prostate (PC3, LNCaP) that vary in differentiation status and tumorigenic potential. These flavones are derived from plants of the family Asteraceae, genera Gnaphalium and Achyrocline reputed to have anti-cancer properties. Our studies indicate that 5,7-dihydroxy-3,6,8-trimethoxy-2-phenyl-4H-chromen-4-one (5,7-dihydroxy-3,6,8-trimethoxy flavone) displays potent activity against more differentiated carcinomas of the colon (Caco-2), and pancreas (Panc28), whereas 3,5-dihydroxy-6,7,8-trimethoxy-2-phenyl-4H-chromen-4-one (3,5-dihydroxy-6,7,8-trimethoxy flavone) cytototoxic action is observed on poorly differentiated carcinomas of the colon (HCT116), pancreas (Mia PaCa), and breast (SK-BR3). Both flavones induced cell death (>50%) as proven by MTT cell viability assay in these cancer cell lines, all of which are regarded as highly tumorigenic. At the concentrations studied (5-80 μM), neither flavone demonstrated activity against the less tumorigenic cell lines, breast cancer MCF-7 cells, androgen-responsive LNCaP human prostate cancer line, and androgen-unresponsive PC3 prostate cancer cells. 5,7-dihydroxy-3,6,8-trimethoxy-2-phenyl-4H-chromen-4-one (5,7-dihydroxy-3,6,8-trimethoxy flavone) displays activity against more differentiated carcinomas of the colon and pancreas, but minimal cytotoxicity on poorly differentiated carcinomas of these organs. On the contrary, 3,5-dihydroxy-6,7,8-trimethoxy-2-phenyl-4H-chromen-4-one (3,5-dihydroxy-6,7,8-trimethoxy flavone) is highly cytotoxic to poorly differentiated carcinomas of the colon, pancreas, and breast with minimal activity against more differentiated carcinomas of the same organs. These differential effects suggest activation of distinct apoptotic pathways. In conclusion, the specific chemical properties of these two flavone isomers dictate mechanistic properties which may be relevant when evaluating biological responses to flavones.     

Coumarins from the Malagasy Cedrelopsis rakotozafyi Cheek and Lescot (Rutaceae)

A phytochemical analysis of the bark of the Malagasy Cedrelopsis rakotozafyi Cheek and Lescot (Rutaceae) yielded the novel 8-hydroxy-7-methoxy-6-(2R-hydroxy-3-methylbut-3-enoxy)-2H-1-benzopyran-2-one, and 7-hydroxy-6-(2R-hydroxy-3-methylbut-3-enoxy)-2H-1-benzopyran-2-one, 5,6,7-trimethoxy-2H-1-benzopyran-2-one, scoparone, scopoletin, lupeol and β-amyrin. The placement of Cedrelopsis within the Rutaceae is supported phytochemically by the typically Rutaceous coumarins isolated.     

Design,synthesis and biological evaluation of 5-amino-4-(1H-benzoimidazol-2-yl)-phenyl-1,2-dihydro-pyrrol-3-ones as inhibitors of protein kinase FGFR1

Fibroblast growth factor receptor 1 (FGFR1) plays an important role in tumorigenesis and is therefore an attractive target for anticancer therapy. Using molecular docking approach we have identified inhibitor of FGFR1 belonging to 5-amino-4-(1H-benzoimidazol-2-yl)-phenyl-1,2-dihydro-pyrrol-3-ones with IC₅₀ value of 3.5 μM. A series of derivatives of this chemical scaffold has been synthesized and evaluated for inhibition of FGFR1 kinase activity. It was revealed that the most promising compounds 5-amino-1-(3-hydroxy-phenyl)-4-(6-methyl-1H-benzoimidazol-2-yl)-1,2-dihydro-pyrrol-3-one and 5-amino-4-(1H-benzoimidazol-2-yl)-1-(3-hydroxy-phenyl)-1,2-dihydro-pyrrol-3-one inhibit FGFR1 with IC₅₀ values of 0.63 and 0.32 μM, respectively, and posses antiproliferative activity against KG1 myeloma cell line with IC₅₀ values of 5.6 and 9.3 μM. Structure–activity relationships have been studied and binding mode of this chemical class has been proposed.     

Metabolites from the endophytic fungus Xylaria sp. PSU-D14

Glucoside derivatives, xylarosides A (1) and B (2), were isolated from the broth extract of the endophytic fungus Xylaria sp. PSU-D14 along with two known compounds, sordaricin (3) and 2,3-dihydro-5-hydroxy-2-methyl-4H-1-benzopyran-4-one (4). The structures were assigned by spectroscopic methods. Sordaricin (3), one of the known metabolites, exhibited moderate antifungal activity against Candida albicans ATCC90028 with a MIC value of 32 microg/ml.     

Synthesis and antiproliferative evaluation of 4-anilino-n-methoxyfuro[2,3-b]quinoline derivatives (n=6, 7). Part 5

A series of 27 differently substituted 4-anilinofuro[2,3-b]quinolines were synthesized and evaluated for their antiproliferative activities against the HeLa, SKHep1, SAS, AGS, A549, and CE81T cell lines, cancers commonly found in Asian countries. Among the compounds tested, 1-{4-[(3-chloro-7-methoxyfuro[2,3-b]quinolin-4-yl)amino]phenyl}ethanone (1) was the most potent, with IC(50) values of 3.1, 3.0, and 4.2 microM, resp., against the growth of HeLa, SKHep, and CE81T cells. Compound 1 was, thus, further evaluated by flow cytometry to evaluate its effect on the cell-cycle distribution of HeLa cells. Our results indicated that 1 readily induces cell-cycle arrest in the G2/M phase, followed by DNA fragmentation and, ultimately, cell death.     

Synthesis, X-ray crystal structural study, antiviral and cytostatic evaluations of the novel unsaturated acyclic and epoxide nucleoside analogues

A series of the novel purine and pyrimidine nucleoside analogues were synthesised in which the sugar moiety was replaced by the 4-amino-2-butenyl (2-6 and 10-18) and oxiranyl (8 and 20) spacer. The Z- (2-6) and E-isomers (10-18) of unsaturated acyclic nucleoside analogues were synthesized by condensation of 2- and 6-substituted purine and 5-substituted uracil bases with Z- (1) or E-phthalimide (9) precursors. The oxiranyl nucleoside analogues (8 and 20) were obtained by epoxidation of 1 and 9 with m-chloroperoxybenzoic acid and subsequent coupling with adenine. The new compounds were evaluated for their antiviral and antitumor cell activities. Among the olefinic nucleoside analogues, Z-isomer of adenine containing 4-amino-2-butenyl side chain (6) exhibited the best cytostatic activities, particularly against colon carcinoma (SW 620, IC50 = 26 microM). Its E-isomer 15 did not show any antiproliferative activity against malignant tumor cell lines, except for a slight inhibition of colon carcinoma (SW 620, IC50 = 56.5 microM) cells. In general, Z-isomers showed better cytostatic activities than the corresponding E-isomers. (Z)-4-Amino-2-butenyl-adenine nucleoside analogue 6 showed albeit modest but selective activity against HIV-1 (EC50 = 4.83 microg mL(-1)).