Promising carboranylquinazolines for boron neutron capture therapy: synthesis, characterization, and in vitro toxicity evaluation

Novel classes of structurally different boronated quinazolines were designed bearing 22-37% boron by weight for potential application in BNCT of tumors. Firstly, the o-carborane cage was linked to quinazoline at C-2 position via thioether linker: 2-S-(1,2-dicarba-closo-dodecaboran(12)-1-ylmethyl)-3-phenylquinazolin-4(3H)-one. Secondly, the o-carborane cage connected to quinazoline moiety at C-4 position through an ether linkage: 4-O-(o-carboran-1-ylmethyl)-2-methylquinazoline. Finally, carborane moieties were also linked to the C-6 position of quinazoline: 6-[N-{3-(2-methyl-1,2-dicarba-closo-dodecaboran(12)-1-yl)methyl}benzylidinamino]quinazolin-4(3H)-one and 6-[N-{3,5-di(2-methyl-1,2-dicarba-closo-dodecaboran(12)-1-yl)methyl}benzylidinamino]quinazolin-4(3H)-one. The water solubility was achieved by the degradative conversion of the o-carboranylquinazolines to the corresponding potassium nido-carboranyl quinazolines: 2-S-(1,2-dicarba-nido-undecacarborate-1-ylmethyl)-3-phenylquinazolin-4(3H)-one, 4-O-(1,2-dicarba-nido-undecacarborate-1-ylmethyl)-2-methylquinazoline, 6-[N-{3-(2-methyl-1,2-dicarba-nido-undecacarborate-1-yl)methyl}benzylidinamino]quinazolin-4(3H)-one and 6-[N-{3,5-di(2-methyl-1,2-dicarba-nido-undecacarborate-1-yl)methyl}benzylidinamino]quinazolin-4(3H)-one. The products were confirmed by NMR, elemental analysis, IR, and mass spectrometry. In vitro toxicity was performed with B16 melanoma cells and showed that the connection of hydrophilic nido-carborane to quinazoline moiety decreases the compound's toxicity. This cytotoxicity effect was not observed in the nido-carborane containing two cluster units which was relatively nontoxic and did not inhibit colony formation up to concentrations of 300microg boron ml(-1). The compounds described here can be considered as new candidates for BNCT.     

New acyclic nucleosides analogues as potential analgesic, anti-inflammatory, anti-oxidant and anti-microbial derived from pyrimido[4,5-b]quinolines

Synthesis of 2-thioxopyrimido[4,5-b]quinoline 3a-c by microwave oven was used as a base to synthesis acyclic nucleosides analogue of types, 3-(penta-O-acetyl-glycosyl)-6-(4-chlorophenyl)-10-(4-chlorophenylmethylene)-7,8,9,10-tetrahydro[1,2,4]triazolo[4',3':1,2]-pyrimido[4,5-b]quinolin-4-ones (7a-c), 2-tetra-O-acetyl-glycosylhydrazon-N3-acetyl-5-(4-chlorophenyl)-9-(4-chlorophenylmethylene)-6,7,8,9-pentahydro-1H-pyrimido[4,5-b]-quinolin-4-ones (10a-c) and 3-(glycosyl)-6-(4-chlorophenyl)-10-(4-chlorophenylmethylene)-7,8,9,10-tetrahydro[1,2,4]triazolo[4',3':1,2]pyrimido[4,5-b]quinolin-4-ones (8a-c), (12a-c). The title compounds were investigated for analgesic, anti-inflammatory, anti-oxidant and anti-microbial activities. Compounds 8a,b and 12a,b exhibited highly significant activity towards gram-negative and gram-positive bacteria, showed more potent anti-inflammatory and analgesic activities than the acetylated glycoside derivatives 7a,b and 10a,b and exhibited high anti-oxidant activity when compared to the ascorbic acid.     

Regioselective synthesis of dispiro[1H-indene-2,3'-pyrrolidine-2',3'-[3H]indole]-1,2'(1'H)-diones of potential anti-tumor properties

1,3-Dipolar cycloaddition reaction of 2-(arylmethylene)-2,3-dihydro-1H-inden-1-ones 1a-g with non-stabilized azomethine ylides, generated in situ via decarboxylative condensation of isatins 2a,b and sarcosine (3) afforded dispiro[1H-indene-2,3'-pyrrolidine-2',3'-[3H]indole]-1,2'(1'H)-diones 4a-n and not the isomeric forms dispiro[1H-indene-2,4'-pyrrolidine-2',3'-[3H]indole]-1,2'(1'H)-diones 5 in a highly regioselective manner. Anti-tumor activity screening for the synthesized compounds (4c,d,i-l) at a dose of 10 microM utilizing 56 different human tumor cell lines representing, leukemia, melanoma and cancers of the lung, colon, brain, ovary, breast, prostate and kidney was carried out. All the tested compounds exhibit promising anti-tumor activity against SK-MEL-2 (melanoma) cell line. Anti-inflammatory activity of the prepared compounds was determined in vivo by the acute carrageenan-induced paw oedema in rats. Many of the prepared compounds exhibit considerable anti-inflammatory properties "at a dose of 50 mg/kg body weight", especially 4a and 4m which reveal remarkable activities relative to indomethacin which was used as a reference standard in this study.     

Microwave assisted synthesis and structure-activity relationship of 4-hydroxy-N'-[1-phenylethylidene]-2H/2-methyl-1,2-benzothiazine-3-carbohydrazide 1,1-dioxides as anti-microbial agents

A series of 4-hydroxy-N'-[1-phenylethylidene]-2H/2-methyl, 1,2-benzothiazine-3-carbohydrazide 1,1-dioxides was synthesized from commercially available sodium saccharin. Base catalyzed ring expansion of methyl (1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)acetate followed by ultrasound mediated hydrazinolysis and subsequent reaction with 1-phenylethanones under the influence of microwaves yielded the title compounds. Besides, microwave assisted synthesis of 1,4-dihydropyrazolo[4,3-c][1,2]benzothiazin-3-ol 5,5-dioxide and 4-methyl-1,4-dihydropyrazolo[4,3-c][1,2]benzothiazin-3-ol 5,5-dioxide is also discussed. Most of the synthesized compounds were found to possess moderate to significant anti-microbial (anti-bacterial and anti-fungal) activities. It is found that compounds with greater lipophilicity (N-methyl analogues) possessed higher anti-bacterial activities.     

永生化人晶状体上皮细胞的体外培养

目的:建立永生化人晶状体上皮细胞(Human lens epithelial cell,HLEC)培养、冻存与复苏技术。方法:传代培养人晶状体上皮细胞系B-3,并进行细胞冻存与复苏,台盼蓝染色法判断细胞活力。结果:接种后的HLEC在短时间内即可贴壁及延伸,12～24 h后大部分细胞贴壁生长,具有上皮细胞的形态特点,约3～4 d细胞基本融合。冻存后复苏的HLEC活力超过90%,保持正常的细胞形态,并可长期传代培养。结论:成功建立永生化HLEC培养、冻存与复苏技术,为白内障相关研究提供理想的细胞材料。     

Synthesis and anti-cholinergic activity of aminoalkyl 2-cyclic amino-2-(1,2-benzisoxazol-3-yl)acetates and their quaternary ammonium salts

A series of aminoalkyl 2-cyclic amino-2-(1,2-benzisoxazol-3-yl)acetates 1 and 2 and their quaternary ammonium derivatives 3 and 4 has been prepared and tested for anti-cholinergic activity. Among these compounds, 1-alkyl-1-methyl-4-[2-cyclic amino-2-(1,2-benzisoxazol-3-yl)acetoxy]piperidinium salts 3 showed potent anti-cholinergic activity in the in vitro studies. The structure—activity relationships of these compounds are discussed.     

New ferrocenic pyrrolo[1,2-a]quinoxaline derivatives: synthesis, and in vitro antimalarial activity--Part II

Following our search for antimalarial compounds, novel series of ferrocenyl-substituted pyrrolo[1,2-a]quinoxalines 1-2 were synthesized from ferrocene-carboxaldehyde and tested for their in vitro activity upon the erythrocytic development of Plasmodium falciparum strains with different chloroquine-resistance status. The ferrocenic pyrrolo[1,2-a]quinoxalines 1-2 were prepared in 6 or 9 steps through a Barton-Zard reaction. Promising pharmacological results against FcB1, K1 and F32 strains were obtained with ferrocenyl pyrrolo[1,2-a]quinoxalines 1j-l linked by a bis-(3-aminopropyl)piperazine linker substituted by a nitrobenzyl moiety.     

Design and synthesis of azolopyrimidoquinolines, pyrimidoquinazolines as anti-oxidant, anti-inflammatory and analgesic activities

The 5,10-dihydro-2-thioxo-pyrimido[4,5-b]quinolines (2a-c) and its oxidized form 3 were prepared and used as key intermediates for the synthesis of thiazolo[3',2':1,2]pyrimido[4,5-b]-quinolines (5a-c), isoxazolo[5',4':4',5']thiazolo[3',2':1,2]pyrimido[4,5-b]quinolines (6a-c), 4-chloro-2-methylthio-pyrimido[4,5-b]quinoline, its amino derivatives (19-21) and 10,11,12,13-tetrahydro-5H-quino[2',3':4,5]pyrimido[6,1-b]quinazoline (22). The newly synthesized compounds were characterized by IR, NMR (1H, 13C) and mass spectral studies. Representative of the synthesized compounds was tested and evaluated for anti-oxidant, anti-inflammatory and analgesic activities. Compounds 2a-c showed the highest inhibitory anti-oxidant activity either using erythrocyte hemolysis or ABTS methods. Compounds 2a, 10b, 16, and 17a manifested the best protective effect against DNA damage induced by bleomycin. Compounds 2c, 5a, 20a, 2a, and 2b exhibited a potent anti-inflammatory activity using carrageenan-induced paw edema test in rats.     

Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity, part 1

A series of new derivatives of 4-aryl-pyrido[1,2-c]pyrimidine containing the 3-(4-piperidyl)-1H-indole residue or its 5-methoxy derivative were synthesized. They were characterized (i) in vitro by binding to 5-HT(1A) receptors and 5-HT transporter proteins in rat brain cortex membranes and (ii) in vivo in the mouse by induced hypothermia and forced swimming models for antagonist/agonist activity against the 5-HT(1A) autoreceptors and postsynaptic 5-HT(1A) receptors, respectively. Structure activity relationship evaluation indicated that the presence of the 3-(4-piperidyl)-1H-indole residue and ortho- or para-substituents with -F or -CH(3) groups in the aryl ring as well as an unsubstituted aryl in the 4-aryl-pyrido[1,2-c]pyrimidine moiety promoted low K(i) values for both receptors. In contrast, the presence of a 5-methoxy-3-(4-piperidyl)-1H-indole residue as well as -Cl or -OCH(3) substituents at the para position markedly reduced the receptor affinity.     

Cytotoxic effects,alkylating properties and molecular modelling of coumarin derivatives and their phosphonic analogues

The cytotoxic effects and alkylating activity of a series of 3-[1-(alkylamino)-ethylidene]-chroman-2,4-dione (4a-4c), 2-methoxy-3-[1-(alkylamino)-ethylidene]-2,3-dihydro-2,4-dioxo-2lambda(5)-benzo[e][1,2] oxaphosphinane (5a-5c) and [2-oxo-4-phenyl(alkyl)-2H-chromen-3-yl]-phosphonic acids dimethyl ester (6a-6c) on the two leukemia cell lines HL-60 and NALM-6 have been determined. The test compounds are much more toxic to NALM-6 cells than to HL-60 cells. IC(50) data are up to nine times lower for the NALM-6 than for the HL-60 cell lines. As determined in an in vitro Preussmann test phosphonic derivatives 6a-6c possess very high (+++) alkylating activity, phosphoric derivatives 5a-5c are less active (++) while the derivatives 4a-4c can be included in the group of low activity (+) alkylating agents. Using regression analysis QSAR we found a relationship between biological activity and the physicochemical properties of the test compounds. Their cytotoxic effect increases with an increase of the hydrophobic parameters in the region of the substituents at the 2-, 3- and 4-positions of the benzopyrone skeleton of 4-6.     

3-Pyrazolone analogues of the 3-isoxazolol metabotropic excitatory amino acid receptor agonist homo-AMPA. Synthesis and pharmacological testing

We have previously shown that the higher homologue of (S)-glutamic acid [(S)-Glu], (S)-alpha-aminoadipic acid [(S)-alpha-AA] is selectively recognized by the mGlu(2) and mGlu(6) subtypes of the family of metabotropic glutamic acid (mGlu) receptors. Furthermore, a number of analogues of (S)-alpha-AA, in which the terminal carboxyl group has been replaced by various bioisosteric groups, such as phosphonic acid or 3-isoxazolol groups, have been shown to interact selectively with different subtypes of mGlu receptors. In this paper we report the synthesis of the 3-pyrazolone bioisosteres of alpha-AA, compounds (RS)-2-amino-4-(1,2-dihydro-5-methyl-3-oxo-3H-pyrazol-4-yl)butyric acid (1) and (RS)-2-amino-4-(1,2-dihydro-1,5-dimethyl-3-oxo-3H-pyrazol-4-yl)butyric acid (2). At a number of steps in the reaction sequences used, the reactions took unexpected courses and provided products which could not be transformed into the target compounds, and attempts to synthesize the 2,5-dimethyl isomer of 2, compound 3, failed. An X-ray crystallographic analysis of the intermediate 1,2-dihydro-4-(2-hydroxyethyl)-2,5-dimethyl-3H-pyrazol-3-one (5b) confirmed the expected regioselectivity of the reaction between methylhydrazine and alpha-acetylbutyrolactone (4). Neither 1 nor 2 showed significant effects at the different types of ionotropic glutamic acid receptors or at mGlu(1a) (group I), mGlu(2) (group II), and mGlu(4a) and mGlu(6) (group III) receptors, representing the three indicated groups of mGlu receptors.     

Orthopedic,ophthalmic, and psychiatric diseases primarily affect activity limitation for Japanese males and females: Based on the Comprehensive Survey of Living Conditions

Background

Healthy life expectancy (HLE) is used as one of the primary objectives of fundamental health promotion plans and social development plans. Activity limitation is used to calculate HLE, but little study has been done to identify determinants of activity limitation in order to extend HLE. The purpose of this study is to identify diseases and injuries that commonly lead to activity limitation to prioritize countermeasures against activity limitation.

1,5-benzodiazepines. Part XIII. Substituted 4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-5-amines and 4H-imidazo[1,2-a][1,5]benzodiazepin-5-amines as analgesic,anti-inflammatory and/or antipyretic agents with low acute toxicity

The reaction of proper N,N-dialkyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-5-amines (1) with N-chlorosuccinimide afforded their 4-chloroderivatives 3 which in turn were treated with cyclic amines to give the corresponding 4,5-diaminoderivatives 4. The N,N-dialkyl-4H-imidazo[1,2-a][1,5]benzodiazepin-5-amines (5) were prepared starting from suitable 4-(dialkylamino)-1,3-dihydro-2H-1,5-benzodiazepin-2-ones (8), through multistep synthetic routes. At the 200 mg kg(-1) os dose, some compounds 3 and 4 showed notable analgesic or anti-inflammatory activity but no antipyretic properties, whereas the 5-(dibutylamino) derivatives 5b and 5f proved to be significantly endowed with all these activities. Almost all the compounds 3, 4 and 5 did not show acute toxicity in mice up to 800 mg kg(-1) os dose.     

Synthesis, molecular structure, and in vitro antitumor activity of new 4-chloro-2-mercaptobenzenesulfonamide derivatives

The reaction of 3-amino-2-(2-alkylthio-4-chlorobenzenesulfonyl)guanidines 2a-j with 1,2-dicarbonyl compounds are described. Depending on structure of 1,2-dicarbonyl reagent novel 2-alkylthio-5-chloro-N-(1,2,4-triazin-3-yl)benzenesulfonamides 3-15, 1-(2-alkylthio-4-chlorobenzenesulfonyl)-3-(2-oxobutane-3-ylidenoimino)guanidines 16-18 and 2-alkylthio-4-chloro-N-(1,2-dihydroxycyclobuta[e]1,2,4-triazin-3-yl)benzenesulfonamides 19-21 are obtained. The structures of these compounds were confirmed on the basis of elemental analysis, spectral data and X-ray analysis. The compounds 4, 5, 7, 9, 10, 12-15, 17, 18 and 20 were screened at the National Cancer Institute (NCI) for their in vitro activities against a panel of 56 tumor cell lines and relationship between structure and antitumor activity are discussed. The compounds 10, 12, 17 and 20 were inactive, whereas the other compounds exhibited reasonable activity against one or more human tumor cell lines. The prominent compound 18 showed significant activity against cell lines of colon cancer (HCT-116), renal cancer (786-0) and melanoma (M14) (GI50 in the range 0.33-1.08 microM) as well as good selectivity toward non-small cell lung cancer (HOP-62) cells (GI50 = 0.05 microM, TGI = 0.38 microM and LC50 = 4.83 microM).     

Heterocyclic 1,2-epoxyalkan-3-ones as cytotoxic agents

A series of 1-{2-(3-,4-)[1-oxidopyridinyl]}-1,2-epoxybutan-3-ones 13 and 1-[2-(3-,4-)pyridinyl]-1,2-epoxy-alkan-3-ones 12, 16 and 17 was synthesized. In vitro screening against L1210 leukemic cells indicated that thes tereochemistry of the oxiranyl substituents and/or size of the R² alkyl substituents are determinants of cytotoxic activity. Increasing the length of the R² alkyl substituent for trans-16 decreased activity. The lipophilic effect of the R² substituent does not appear to be a significant determinant of activity. Some structure—activity correlations are described.     

A facile synthesis of novel biologically active 4-hydroxy-N'-(benzylidene)-2H-benzo[e][1,2]thiazine-3-carbohydrazide 1,1-dioxides

A novel series of potentially biologically active 4-hydroxy-N'-(benzylidene)-2H-benzo[e][1,2]thiazine-3-carbohydrazide 1,1-dioxides were synthesized starting from ultrasonic mediated N-alkylation of sodium saccharin with methyl chloroacetate. Ring expansion of methyl(1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)acetate followed by its hydrazinolysis afforded 4-hydroxy-2H-1,2-benzothiazine-3-carbohydrazide 1,1-dioxide which was reacted in a straight forward manner with various benzaldehydes in an ultrasonic bath to get the title compounds. All of the synthesized compounds were subjected to preliminary evaluation for their antibacterial and DPPH radical scavenging activities.     

Simultaneous tritium labelling of two potent 5-HT4 ligands

Two potent and selective 5-HT₄ ligands, [³H]-5-[(N-propylpiperidin-4-yl)methoxy]-1,2,3,4-tetrahydrobenzo[h][1,6] naphthyridine (1a) and [³H]-1-methyl-5-[(N-propylpiperidin-4-yl)methoxy]pyrrolo[1,2-a]thieno[2,3-e]pyrazine (2a) were radiolabelled with tritium. Radioactive labelling was achieved by simultaneous tritium reduction of a mixture of both propargylic precursors (1c–2c). The two tritiated ligands thus obtained were radiochemically pure and possessed high radioactive specific activities. These tritiated 5-HT₄ ligands will allow for binding characterization as an essential tool for their further development.     

Synthesis and antimicrobial activity of new 1-alkyl/cyclohexyl-3,3-diaryl-1'-methylspiro[azetidine-2,3'-indoline]-2',4-diones

The paper describes the synthesis of new 1-alkyl/cyclohexyl-3,3-diaryl-1'-methylspiro[azetidine-2,3'-indoline]-2',4-diones from the reactions of the 2-diazo-1,2-diarylethanones with 1-methyl-3-(alkyl/cyclohexylimino)indolin-2-ones under thermal condition. The compounds, characterized by satisfactory analytical and spectral (IR, (1)H NMR and (13)C NMR) data, have been screened for their antibacterial and antifungal activities.     

Novel isatinyl thiosemicarbazones derivatives as potential molecule to combat HIV-TB co-infection

A series of novel 5-substituted-1-(arylmethyl/alkylmethyl)-1H-indole-2,3-dione-3-(N-hydroxy/methoxy thiosemicarbazone) analogues were synthesized and evaluated for their anti-HIV activity and anti-tubercular activity in both log phase and starved cultures. The compound 2-(1-{[4-(4-chlorophenyl)tetrahydropyrazin-1(2H)-yl]methyl}-5-methyl-2-oxo-1,2-dihydro-3H-indol-3-yliden)-N-(methyloxy)hydrazine-1-carbothioamide (B21) displayed promising activity against the replication of HIV-1 cells (EC₅₀ 1.69 μM). In anti-mycobacterial screening B21 proved effective in inhibiting the growth of both log phase (MIC 3.30 μM) and starved (MIC 12.11 μM) MTB cultures. Isocitrate lyase enzyme having momentous implication in persistent TB was shown to be inhibited by 1-cyclopropyl-6-fluoro-7-[4-{[5-methyl-3-((Z)-2-{[(methyloxy)amino]carbothioyl}hydrazono)-2-oxo-1H-indol-1(2H)-yl]methyl}tetrahydropyrazin-1(2H)-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (B30) with 63.44% inhibition at 10 mM.     

Synthesis of some new 4-styryltetrazolo[1,5-a]quinoxaline and 1-substituted-4-styryl[1,2,4]triazolo[4,3-a]quinoxaline derivatives as potent anticonvulsants

4-Methyltetrazolo[1,5-a]quinoxaline (3) was prepared by the azide cyclocondensation of 2-chloro-3-methylquinoxaline (2). The reaction of 3 with aromatic aldehydes furnished 4-styryltetrazolo[1,5-a]quinoxalines (4a-f). Compound 2, on treatment with hydrazine hydrate gave 2-hydrazino-3-methylquinoxaline (5). The ring closure of 5 was achieved by the reaction of orthoesters and trifluoroacetic acid to yield 4-methyl-1-(substituted)[1,2,4]triazolo[4,3-a]quinoxalines (7a-c). Further, reaction of 7a-c with different aromatic aldehydes furnished the title compounds, 4-styryl-1-(substituted)[1,2,4]triazolo[4,3-a]quinoxalines (8a-i) in good yield. In another scheme, the hydrazino compound 5 was treated with different aromatic aldehydes to yield corresponding N-arylidenehydrazino quinoxalines (6a-d). Further, the oxidative cyclization of hydrazones by nitrobenzene yielded 1-aryl-4-methyl[1,2,4]triazolo[4,3-a]quinoxalines (7d-g), which on condensation with aromatic aldehydes gave the title compounds, 1-aryl-4-styryl[1,2,4]triazolo[4,3-a]quinoxalines (8j-u). The newly synthesized compounds have been characterized by FTIR, (1)H NMR, (13)C NMR and mass spectral data, followed by elemental analysis. Some of the compounds were screened for in vivo anticonvulsant activity. Few of them exhibited promising results.