Conversion of indanone oximes into isocarbostyrils

New and effective method for the Beckmann rearrangement of indanone oxime mesylate is described, in which a selective and controlled production of the isomeric isocarbostyrils is achieved.     

A study on the conversion of indanones into carbostyrils

We have surveyed the utility of Beckmann rearrangement for the conversion of indanones into carbostyrils. Initial attempts at the conversion of 6-methoxy indanone oxime under classical conditions resulted in the formation of the two unusual products: 2-sulfonyloxyindanone and the dimeric product. This unusual rearrangement was also observed by the treatment of some metal triflates species. Further investigation has led to the development of reliable conditions starting from oxime mesylate (not oxime tosylate), in which some strong Lewis acid catalyst (ZrCl(4)) was employed in either a conventional or non-conventional solvent system. The advantage of the new protocol is highlighted by the simple work up and direct isolation of the product in 65% isolated yield.     

Aryltetralone and arylindanone neolignans from Virola sebifera

The fruits of Virola sebifera contain several tetralone neolignans, including 2,4-dihydroxy-6,7-methylenedioxy-2,3-dimethyl-4-veratryltetralin-1-one. The 3-hydroxylated derivative of this compound may undergo a biosynthetic pinacol-pinacolone rearrangement to give 2-acetyl-3-hydroxy-2-methyl-5,6-methylenedioxy-3-veratrylindan-1-one which, together with other indanone neolignans, was also isolated.     

Synthesis and SAR studies of bicyclic amine series GPR119 agonists

We disclosed a novel series of G-protein coupled receptor 119 (GPR119) agonists based on a bicyclic amine scaffold. Through the optimization of hit compound 1, we discovered that the basic nitrogen atom of bicyclic amine played an important role in GPR119 agonist activity expression and that an indanone in various bicyclic rings was suitable in this series of compounds. The indanone derivative 2 showed the effect of plasma glucose control in oGTT and scGTT in the rodent model.     

Synthesis and antitumor activity of 5-bromo-1-mesyluracil

Large-scale preparation of 5-bromo-1-mesyluracil (BMsU) 4 has been optimized. BMsU was synthesized by condensation of silylated 5-bromouracil and MsCl in acetonitrile or by the reaction of 5-bromouracil with MsCl in pyridine. The same product was obtained by bromination of 1-mesyluracil. The purpose of this study was to elucidate the effects of BMsU on the biosynthetic activity of tumor cell enzymes involved in DNA, RNA and protein syntheses, and in de novo and salvage pyrimidine and purine syntheses. Investigations were performed in vitro on human cervix carcinoma cells (HeLa). BMsU displayed inhibitory effects on DNA and RNA syntheses in HeLa cells after 24 h of treatment. De nova biosynthesis of pyrimidine and purine was also affected. Antitumor activity of BMsU is closely associated with its inhibitory activity on the enzymes that play an important role in the metabolism of tumor cells. In vivo antitumor activity of BMsU was also investigated. The model used in investigations was a mouse anaplastic mammary carcinoma transplanted into the thigh of the right leg of CBA mice. Significant reduction in tumor growth time was achieved with BmsU administered at a dose of 50 mg/kg.     

Synthesis of rigid trichostatin A analogs as HDAC inhibitors

New inhibitors of histone deacetylase (HDAC) have been synthesized and evaluated for their activity toward non small lung cancer cell line H661. Their design is based on indanone (or tetralone) systems leading to trichostatin A (TSA) analogs with limited conformational mobility. Molecular modelization at the AM1 level revealed that the conformations of indane-based analogs and TSA bound to HDAC like protein are similar. The synthesis of these new analogs was achieved by alkylation of an appropriate indanone (or tetralone) to introduce the side chain bearing a terminal ester group, the latter being a precursor of hydroxamic acid and aminobenzamide derivatives. Hydroxamic acids with the TSA side chain were found to be the most active compounds and the presence of the dimethylamino group on the phenyl ring turned out to be essential to achieve low micromolar activities against H661 cancer cells.     

SYNTHESIS AND ANTITUMOR ACTIVITY OF 5-BROMO-1-MESYLURACIL

Large-scale preparation of 5-bromo-1-mesyluracil (BMsU) 4 has been optimized. BMsU was synthesized by condensation of silylated 5-bromouracil and MsCl in acetonitrile or by the reaction of 5-bromouracil with MsCl in pyridine. The same product was obtained by bromination of 1-mesyluracil. The purpose of this study was to elucidate the effects of BMsU on the biosynthetic activity of tumor cell enzymes involved in DNA, RNA and protein syntheses, and in de novo and salvage pyrimidine and purine syntheses. Investigations were performed in vitro on human cervix carcinoma cells (HeLa). BMsU displayed inhibitory effects on DNA and RNA syntheses in HeLa cells after 24 h of treatment. De nova biosynthesis of pyrimidine and purine was also affected. Antitumor activity of BMsU is closely associated with its inhibitory activity on the enzymes that play an important role in the metabolism of tumor cells. In vivo antitumor activity of BMsU was also investigated. The model used in investigations was a mouse anaplastic mammary carcinoma transplanted into the thigh of the right leg of CBA mice. Significant reduction in tumor growth time was achieved with BmsU administered at a dose of 50 mg/kg.     

Microbial production of isoquinoline from indene

A purified microbial isolate, identified as a strain of Rhodococcus sp., metabolized indene primarily to iso quinoline and lesser amounts of indandiol and indanone. Isoquinoline production was dependent on the presence of microbial culture, indene, and ammonium ions as the source of nitrogen in the molecule. The ability to produce isoquinoline was induced by growth on benzene or naphthalene and by the presence of indene itself. The culture produced compounds tentatively identified as 3-methylisoquinoline and 3-ethylisoquinoline from 2-methylindene and from 2-ethylindene, respectively. Deuterated indene was converted to deuterated isoquinoline, deuterated indanone, and deuterated indandiol. Experiments with [15N]ammonium nitrate and ammonium [15N]nitrate confirmed ammonium as the source of nitrogen in the isoquinoline products.     

Total Synthesis of Sclerotinin A

Sclerotinin A (3,6,8-trihydroxy-3,4,5,7-tetramethyl-3,4-dihyroisocoumarin: 1), a metabolite of Sclerotinia sclerotiorum, was first totally synthesized. The pentenone ring of 2,3,4,6-tetramethyl-5,7-dimethoxyindanone (VII_a) which was obtained from 2,4-dimethylresorcinol dimethyl ether (VI) through a new synthetic process, was cleavaged oxidatively, and demethylated to I. Sclerotinin A was also yielded from indanone dibenzyl ether (VII_b) by the same method and reductive debenzylation.     

Gallic acid-based indanone derivatives as anticancer agents

Gallic acid-based indanone derivatives have been synthesised. Some of the indanones showed very good anticancer activity in MTT assay. Compounds 10, 11, 12 and 14 possessed potent anticancer activity against various human cancer cell lines. The most potent indanone (10, IC₅₀ = 2.2 μM), against MCF-7, that is, hormone-dependent breast cancer cell line, showed no toxicity to human erythrocytes even at higher concentrations (100 μg/ml, 258 μM). While, indanones 11, 12 and 14 showed toxicities to erythrocytes at higher concentrations.     

Chemoenzymatic synthesis of (1S,2R)-1-amino-2-indanol, a key intermediate of HIV protease inhibitor, indinavir

The synthesis of (1S,2R)-1-amino-2-indanol, a key component of HIV protease inhibitor is accomplished in four steps starting from indanone efficiently and with high levels of diastereo- and enantioselectivity. The starting material is converted into 2-acetoxy-1-indanone involving Manganese (III) acetate oxidation . The 2-acetoxyketone is hydrolyzed to 2-hydroxy-1-indanone enantioselectively using Rhizopus oryzae. Selective reduction of 2-hydroxyoxime derivative, derived from the 2-hydroxyketone, gives the amino alcohol up to 98% diastereo- and enantioselectivity.     

Experiments Directed toward the Total Syntheses of Polycyclic Terpenes

A synthetic sequence for the conversion of 2-methoxycarbonyl-methyl-3-methoxy-carbonyl-4-methylindanone to (±)-7-deoxyepiallo-gibberic acid methyl ester norketone is described.

A synthetic sequence for conversion of m-methoxy benzaldehyde to 2-methoxycarbonyl-methyl-3-methoxycarbonyl-5-methoxy indanone and its reaction with methyl vinyl ketone are described.     

Design, synthesis, and evaluation of indanone derivatives as acetylcholinesterase inhibitors and metal-chelating agents

A series of novel indanone derivatives was designed, synthesised and evaluated as potential agents for Alzheimer's disease. Among them, compound 6a, with a piperidine group linked to indone by a two-carbon spacer, exhibited the most potent inhibitor activity, with an IC(50) of 0.0018 μM for AChE; the inhibitory activity of this compound was 14-fold more potent than that of donepezil. Furthermore, these compounds also exhibited good metal-chelating ability.     

Indanone and mellein derivatives from the Garcinia-derived fungus Xylaria sp. PSU-G12

Two new compounds, one indanone (1) and one mellein (2), along with 3-hydroxy-4-methyl-1-indanone (3), griseofulvin (4), dechlorogriseofulvin (5), cytochalasin D (6) and three mellein derivatives (7–9) were isolated from the broth extract of the Garcinia-derived fungus Xylaria sp. PSU-G12. The structures were elucidated by spectroscopic analysis. This is the first report on the isolation of indanone derivatives from the genus Xylaria. The isolated compounds were evaluated for antioxidant activity in DPPH assay.     

Ternary Organic Solar Cells With 12.8% Efficiency Using Two Nonfullerene Acceptors With Complementary Absorptions

A new small‐molecule acceptor (2,9‐bis(2‐methylene‐(3(1,1‐dicyanomethylene)benz[f]indanone))7,12‐dihydro‐(4,4,10,10‐tetrakis(4‐hexylphenyl)‐5,11‐diocthylthieno[3′,2′:4,5]cyclopenta[1,2‐b]thieno[2″,3″:3′,4′]cyclopenta[1′,2′:4,5]thieno[2,3‐f][1]benzothiophene) (NNBDT) based on naphthyl‐fused indanone ending units is reported. This molecule shows a narrow optical bandgap of 1.43 eV and effective absorption in the range of 700–870 nm. The devices based on poly[(2,6‐(4,8‐bis(5‐(2‐ethylhexyl)thiophen‐2‐yl)‐benzo[1,2‐b:4,5‐b′]dithiophene))‐alt‐(5,5‐(1′,3′‐di‐2‐thienyl‐5′,7′‐bis(2‐ethylhexyl)benzo[1′,2′‐c:4′,5′‐c′]dithiophene‐4,8‐dione))] (PBDB‐T):NNBDT yield a power conversion efficiency of 11.7% with a low energy loss of 0.55 eV and a high fill factor (FF) of 71.7%. Another acceptor (2,9‐bis(2‐methylene‐(3(1,1‐dicyanomethylene)benz[f]indanone))7,12‐dihydro‐4,4,7,7,12,12‐hexaoctyl‐4H‐cyclopenta[2″,1″:5,6;3″,4″:5′,6′]diindeno[1,2‐b:1′,2′‐b′]dithiophene (FDNCTF) is introduced as the third component to fabricate ternary devices. The two acceptors (NNBDT and FDNCTF) possess complementary absorption, same molecular orientation, and well‐miscible behavior. It is found that there exists a nonradiative energy transfer process from FDNCTF to NNBDT. The fullerene‐free ternary cells based on PBDB‐T:NNBDT:FDNCTF achieve a high efficiency of 12.8% with an improved short circuit current near 20 mA cm^?2 in contrast to the binary devices. The result represents the best performance for fullerene‐free ternary solar cells reported to date and highlights the potential of ternary solar cells.     

New indanone compounds from Onychium japonicum

A new indanone glucoside pteroside M has been isolated from fronds of Onychium japonicumPteridaceae. The structure of its aglycone pterosin M has been established by ¹³C NMR, PMR spectra and degradation with nitric acid.     

The discovery of furo[2,3-c]pyridine-based indanone oximes as potent and selective B-Raf inhibitors

Virtual and high-throughput screening identified imidazo[1,2-a]pyrazines as inhibitors of B-Raf. We describe the rationale, SAR, and evolution of the initial hits to a series of furo[2,3-c]pyridine indanone oximes as highly potent and selective inhibitors of B-Raf.     

Synthesis of Isochroman-1,3-diones A New Synthesis of (±)Sclerin

(±)Sclerin (4,5,6,7-tetramethyl-8-hydroxyisochroman-1,3-dione), a mycerial extracts of Sclerotinia libertiana, and related compounds were synthesized. Alkylated-7-hydroxyindanones were obtained from alkylated phenols and α-bromobutyrylbromide, and these indanone derivatives were treated with benzaldehyde to give 2-benzylidene-7-hydroxyindanone derivatives. By ozonolysis of these benzylidene-indanones were obtained 8-hydroxyisochroman-1,3-diones.     

In vitro genotoxicity of polycyclic musk fragrances in the micronucleus test

The synthetic polycyclic musk fragrance compounds galaxolide (1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta-(g)-2-benzopyrane), tonalide (7-acetyl-1,1,3,4,4,6-hexamerthyltetraline), celestolide (4-acetyl-1,1-dimethyl-6-tert-butylindane), phantolide (6-acetyl-1,1,2,3,3,5-hexamethylindane), cashmeran (6,7-dihydro-1,1,2,3,3-pentamethyl-4-(5H) indanone) and traseolide (5-acetyl-1,1,2,6-tetramethyl-3-isopropylindane) were examined for their genotoxicity in the micronucleus test (MNT) with human lymphocytes in vitro in the presence and absence of an exogenous metabolizing system containing rat liver S9 and the metabolically competent human hepatoma cell line Hep G2. Compound concentrations were employed up to cytotoxic doses. Galaxolide, tonalide, celestolide, phantolide, cashmeran and traseolide revealed no genotoxicity in the micronucleus test with human lymphocytes and with the human hepatoma cell line Hep G2.     

Synthesis of chalcone derivatives on steroidal framework and their anticancer activities

Chalcone derivatives on estradiol framework have been synthesized. Some of the derivatives showed potent anticancer activity against some human cancer cell lines. Compounds 9 and 19 showed potent activity against MCF-7, a hormone dependent breast cancer cell line. Chalcone 7 was further modified to the corresponding indanone derivative (19) using the Nazarov reaction, which showed better activity than the parent compound against the MCF-7 breast cancer cell line. Active anticancer derivatives were also evaluated for osmotic hemolysis using the erythrocyte as a model system. It was observed that chalcone derivatives showing cytotoxicity against cancer cell lines did not affect the fragility of erythrocytes and hence may be considered as non-toxic to normal cells.