Synthesis and cytotoxicity of 2-methyl-1-substituted-imidazo [4,5-g]quinoline-4,9-dione and 7,8-dihydro-10H-[1,4]oxazino[3',4':2,3]imidazo[4,5-g]quinoline-5,12-dio ne derivatives

2-Methyl-1-substituted-imidazo[4,5-g]quinoline-4,9-diones and 7,8-dihydro-10H-[1,4]oxazino-[3',4':2,3]imidazo[4,5-g]quinoline-5, 12-dione (19) derivatives have been synthesized from 6,7-dichloro-5,8-quinolinedione for developing the new anticancer drugs. Our study on the cytotoxicity of imidazoquinolinedione derivatives has revealed that 7,8-dihydro-10H-[1,4]oxazino-[3',4':2,3]imidazo[4,5-g]quinoline-5, 12-dione (19), a tetracyclic heteroquinone analogue, exhibited high cytotoxicity on human colon tumor cell (HCT 15) in vitro SRB assay. The IC50 value of this compound was 0.026 microg/mL whereas those of doxorubicin and cisplatin were 0.023 microg/mL and 1.482 microg/mL, respectively. Meanwhile compounds 5-7 and 12 in the series of 1-substituted-imidazoquinolinediones showed relatively good activity on human brain tumor cell lines (XF 498).     

Discovery and in vitro evaluation of potent kinase inhibitors: Pyrido[1',2':1,5]pyrazolo[3,4-d]pyrimidines

The discovery, synthesis, potential binding mode, and in vitro kinase profile of several pyrido[1',2':1,5]pyrazolo[3,4-d]pyrimidines as potent kinase inhibitors are discussed.     

Synthesis and biological evaluation of novel hexahydro-pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazines as potent and selective 5-HT(2C) receptor agonists

Further lead optimization efforts on previously described 1,2,3,4,10,10a-hexahydro-1H-pyrazino[1,2-a]indoles led to the new class of 5,5a,6,7,8,9-hexahydro-pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazines culminating in the discovery of (5aR,9R)-2-[(cyclopropylmethoxy)methyl]-5,5a,6,7,8,9-hexahydro-9-methyl-pyrido[3', 2':4,5]pyrrolo[1,2-a]pyrazine 18 as a potent, full 5-HT(2C) receptor agonist with an outstanding selectivity profile and excellent hERG and phospholipidosis properties.     

Synthesis and cytotoxic activity of pyridazino[1',6':1,2]pyrido[3,4-b]indol-5-inium derivatives as anti-cancer agents

Several new pyridazino[1',6':1,2]pyrido[3,4-b]indol-5-inium derivatives were synthesised from beta-carboline derivatives and their cytotoxic activity and effect on the cell cycle were evaluated against L1210 cancer cells.     

Synthesis and biological evaluation of pyrido[3',2':4,5]furo[3,2-d]pyrimidine derivatives as novel PI3 kinase p110alpha inhibitors

4-Morpholin-4-ylpyrido[3',2':4,5]thieno[3,2-d]pyrimidine 2a was discovered in our chemical library as a novel p110alpha inhibitor with an IC(50) of 1.4 microM. By structural modification of 2a, the 2-aryl-4-morpholinopyrido[3',2':4,5]furo[3,2-d]pyrimidine derivative 10e was discovered as a p110alpha inhibitor with approximately 400-fold greater potency than 2a. Evaluation of isoform selectivity showed that 10e is a potent inhibitor of p110beta. Furthermore, 10e showed anti-proliferative activity in various cell lines, including multi-drug resistant MCF7/ADR-res cells, and was effective against HeLa human cervical tumor xenografts in nude mice.     

Synthesis and antitumoral evaluation of indole alkaloid analogues containing an hexahydropyrrolo[1',2',3':1,9a,9]imidazo[1,2-a]indole skeleton

The scope of acid-mediated cyclative additions of electrophiles to tryptophan-derived alpha-amino nitriles for the synthesis of 10b-substituted-1,2,4,5,10b,10c-hexahydropyrrolo[1',2',3':1,9a,9]imidazo[1,2-a]indoles analogues of indole alkaloids has been studied. The results demonstrate the high potential of the methodology for the synthesis of 10b-bromo-derivatives, by bromination with NBS, 10b-allyl-derivatives, by bromo-allyl exchange, and 10b-prenyl-derivatives, by reaction with prenyl bromide in the presence of Mg(NO(3))(2).6H(2)0. Some of the new pyrroloimidazoindole derivatives displayed moderate microM cytotoxicities in human cancer cell lines and at 10 microg/mL inhibited more than 50% EGFR or HIF-1alpha.     

Pyridazine derivatives and related compounds. Part 13: Synthesis and antimicrobial activity of some pyridazino[3',4':3,4]pyrazolo[5,1-c]-1,2,4-triazines

A general method for the preparation of substituted pyridazinopyrazolotriazines is reported. 3-Aminopyrazolo[3,4-d]pyridazine was diazotized and coupled with active methylene reagents to afford the tricyclic pyridazino[3',4':3,4]pyrazolo[5,1-c]-1,2,4-triazines with substituents such as methyl, phenyl, ethoxycarbonyl, acetyl or benzoyl, depending on the methylene reagent used. In addition several condensation reactions with hydrazines gave the corresponding acid hydrazide and/or hydrazones. Reactions of 3 with aromatic aldehydes afforded hydrazones. The products were screened for their antimicrobial activity against five microorganisms.     

QSAR studies in substituted 1,2,3,4,6,7,12,12a-octa-hydropyrazino[2',1':6,1]pyrido[3,4-b]indoles--a potent class of neuroleptics

A series of nineteen substituted 1,2,3,4,6,7,12,12a-octahydropyrazino[2',1':6,1]pyrido[3, 4-b]indoles analogues of neuroleptic drug, Centbutindole have been studied using quantitative structure-activity relationship analysis. The derived models display good fits to the experimental data (r>or=0.75) having good predictive power (r(cv)>or=0.688). The best model describes a high correlation between predicted and experimental activity data (r=0.967). Statistical analysis of the equation populations indicates that hydrophobicity (as measured by pi(R), logP(o/w) and SlogP_VSA8), dipole y and structural parameters in terms of indicator variable, (In(1)) and globularity are important variables in describing the variation in the neuroleptic activity in the series.     

Molecular structure of the core-modified siRNA duplexes containing diastereomeric pair of [C6'(R)-OH]- versus [C6'(S)-OH]-carba-LNAs suggests a model for RNAi action

Molecular structures of native and a pair of modified small interfering RNA-RNA duplexes containing carbocyclic [6?'-(R)-OH/7?'-(S)-methyl]- and [6?'-(S)-OH/7?'-(S)-methyl]-carba-LNA-thymine nucleotides, which are two diastereomeric analogs of the native T nucleotide, incorporated at position 13 in the antisense (AS) strand of siRNA, have been simulated using molecular mechanics/dynamics techniques. The main aim of the project has been to find a plausible structural explanation of why modification of siRNA at T(13) position by the [6?'(R)-O-(p-Toluoyl)-7?'(S)-methyl]-carba-LNA-Thymine [IC(50) of 3.32 ± 0.17 nM] is ca 24 times more active as an RNA silencing agent against the target HIV-1 TAR RNA than the [6?'(S)-O-(p-Toluoyl)-7?'(S)-methyl]-counterpart [IC(50) of 79.8 ± 17 nM] [1]. The simulations reveal that introduction of both C6?'(R)-OH and C6?'(S)-OH stereoisomers does not lead even to local perturbation of the siRNA-RNA duplex structures compared to the native, and the only significant difference between 6?'(S)- and 6?'(R)-diastereomers found is the exposure of the 6?'-OH group of the 6?'(R)-diastereoisomer toward the edge of the duplex while the 6?'-hydroxyl group of the 6?'(S)-diastereoisomer is somewhat buried in the minor groove of the duplex. This rules out a hypothesis about any possible local distortion by the nature of chemical modification of the siRNA-target the RNA duplex, which might have influenced the formation of the effective RNA silencing complex (RISC) and puts some weight on the hypothesis about the 6?'-hydroxy group being directly involved with most probably Ago protein, since it is known from exhaustive X-ray studies [2, 3] that the core residues are indeed involved with hydrogen bonding with the internucleotidyl phosphates. Further systematic investigation is in progress to map the position-dependent functional and nonfunctional interactions of the modified [6?'(R or S)-O-(p-Toluoyl)-7?'(S)-methyl]-carba-LNA-T with the Ago2 protein of the RISC.     

Axially dissymmetric (R)-(+)-5,5',6,6',7,7',8,8' octahydro-[1,1']binaphthyldiimine chiral salen type-ligands for copper-catalyzed asymmetric aziridination

Axially dissymmetric chiral diimine ligand 2 was prepared from the reaction of (R)-(+)-5,5',6,6',7,7',8,8'-octahydro-[1,1']binaphthyl-2,2'-diamine 1 with 2,6-dichlorobenzaldehyde. The catalytic asymmetric aziridination of alkenes was examined using this novel chiral ligand. Excellent enantioselective aziridination of cinnamates was achieved using C(2)-symmetric chiral ligand 2.     

Synthesis and anthelmintic activity of 7-substituted 3,4a-dimethyl-4a,5a,8a,8b-tetrahydro-6H-pyrrolo[3',4':4,5]furo[3,2-b]pyridine-6,8(7H)-diones

The racemic 7-substituted 3,4a-dimethyl-4a,5a,8a,8b-tetrahydro-6H-pyrrolo[3',4':4,5]furo[3,2-b]pyridine-6,8(7H)-diones represent novel tricyclic compounds with strong in vivo efficacy against the parasitic nematode Haemonchus contortus Rudolphi in sheep. Here we report on the synthesis of tricyclic endo-2,3-dihydro[3,2-b]pyridine-type cycloadducts and describe the separation of the racemic 3,4a-dimethyl-7-ethyl-4a,5a,8a,8b-tetrahydro-6H-pyrrolo[3',4':4,5]furo[3,2]pyridine-6,8(7H)-dione into the enantiomers by HPLC. The absolute configuration of the most anthelmintically active (4aS,5aS,8aS,8bR)-enantiomer was determined by single crystal X-ray analysis using its stable (4aS,5aS,8aS,8bR)-enantiomer-CuCl2 (2:1)-complex.     

Pyrazolo[1',5':1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones as selective human A(1) adenosine receptor ligands

A series of pyrazolo[1',5':1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones was synthesized and tested in radioligand binding assays to determine their affinities for the human adenosine A(1), A(2A), A(2B) and A(3) receptors. Results indicated that this scaffold is appropriate for adenosine receptor subtype A(1) ligands and that the best arranged groups around this scaffold are 3- and 4-pyridinyl at position 1, benzyl at position 3, hydrogen at position 6 and 3-thienyl or phenyl at position 9. The most interesting compounds showed K(i) for A1 in the nanomolar range and an appreciable selectivity for other receptor subtypes.     

Discovery and bioactivity of 4-(2-arylpyrido[3',2':3,4]pyrrolo[1,2-f][1,2,4]triazin-4-yl) morpholine derivatives as novel PI3K inhibitors

PI3K is a promising therapeutic target for cancer. With PI-103 as the lead compound, we designed and synthesized 4-(2-arylpyrido[3',2':3,4]pyrrolo[1,2-f][1,2,4]triazin-4-yl)morpholine derivatives. 9, 10a, 10d, 10e had the IC(50) against PI3Kα comparable with PI-103. All of the compounds showed selectivity over 15 tested protein kinases and anti-proliferative activity at micromolar concentration against several cancer cell lines.     

Sequence selective modification of DNA with muta-carcinogenic 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole

2-Acetoxyamino-6-methyldipyrido[1,2-a:3',2'-d]imidazole binds covalently to the 8 position of guanine residues in DNA. Treatment of the modified DNA with aqueous piperidine causes the liberation of the modified nucleic acid base, 2-(C8-guanyl)amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole, and cleavage of DNA at the sites of the modified guanylic acid residues. By use of 5'-end 32P-labelled DNA and sequence analysing gel electrophoresis, we discovered the base sequence specificity of DNA modification with 2-acetoxyamino-6-methyldipyrido[1,2-a:3',2'-d]imidazole. The guanine residues in G-C cluster-like regions are modified more frequently.     

DNA mediated resonance energy transfer from 4',6-diamidino-2-phenylindole to [Ru(1,10-phenanthroline)2L]2+

The binding site of Delta- and Lambda-[Ru(phenanthroline)2L]2+ (L being phenanthroline (phen), dipyrido[3,2-a:2'3'-c]phenazine (DPPZ), and benzodipyrido[3,2-a:2'3'-c]phenazine (benzoDPPZ)), bound to poly[d(A-T)2] in the presence and absence of 4',6-diamidino-2-phenylindole (DAPI) was investigated by circular dichroism and fluorescence techniques. DAPI binds at the minor groove of poly[d(A-T)2] and blocks the groove. The circular dichroism spectrum of all Ru(II) complexes are essentially unaffected whether the minor groove of poly[d(A-T)2] is blocked by DAPI or not, indicating that the Ru(II) complexes are intercalated from the major groove. When DAPI and Ru(II) complexes simultaneously bound to poly[d(A-T)2], the fluorescence intensity of DAPI decreases upon increasing Ru(II) complex concentrations. The energy of DAPI at excited state transfers to Ru(II) complexes across the DNA via the F?rster type resonance energy transfer. The efficiency of the energy transfer is similar for both [Ru(phen)2DPPZ]2+ and [Ru(phen)2benzoDPPZ]2+ complexes, whereas that of [Ru(phen)3]2+ is significantly lower. The distance between DAPI and [Ru(phen)3]2+ is estimated as 0.38 and 0.64 F?rster distance, respectively, for the Delta- and Lambda-isomer.     

Efficient methods for the synthesis of [2-15N]guanosine and 2'-deoxy[2-15N]guanosine derivatives

The nucleophilic addition-elimination reaction of 2',3',5'-tri-O-acetyl-2-fluoro-O6-[2-(4-nitrophenyl)ethyl]inosine (8) with [15N]benzylamine in the presence of triethylamine afforded the N2-benzyl[2-15N]guanosine derivative (13) in a high yield, which was further converted into the N2-benzoyl[2-15N] guanosine derivative by treatment with ruthenium trichloride and tetrabutylammonium periodate. A similar sequence of reactions of 2',3',5'-tri-O-acetyl-2-fluoro-06-[2-(methylthio)ethyl]inosine (9) and the 6-chloro-2-fluoro-9-(beta-D-ribofuranosyl)-9H-purine derivative (11), which were respectively prepared from guanosine, with potassium [15N]phthalimide afforded the N2-phthaloyl [2-15N]guanosine derivative (15; 62%) and 9-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-6-chloro-2-[15N]phthalimido-9H-purine (17; 64%), respectively. Compounds 15 and 17 were then efficiently converted into 2',3',5'-tri-O-acetyl [2-15N]guanosine. The corresponding 2'-deoxy derivatives (16 and 18) were also synthesized through similar procedures.     

RAPD typing of Aspergillus chevalieri, Aspergillus nidulans, Aspergillus tetrazonus (quadrilineatus) and their teleomorphs using 5'-d[AACGCGCAAC]-3' and 5'-d[CCCGTCAGCA]-3' primers

Sexuality in fungi has long been a matter of concerns and debates that always necessitated extensive analysis of the relationship between organisms assumed to represent different developmental forms of the same organism. Moreover, mating-virulence correlation and the growing worry of opportunistic fungal infections in immunocompromised states associated with AIDS, cancer chemotherapy and organ transplantation protocols have been critically addressed nowadays. In view of that, we genetically characterized Aspergillus chevalieri, Aspergillus nidulans, Aspergillus tetrazonus (quadrilineatus) and their teleomorphs with RAPD analysis using 5'-d[AACGCGCAAC]-3' and 5'-d[CCCGTCAGCA]-3' primers. The reported similarities between the sexual and the asexual forms of the tested species, using Dice coefficient, ranged between 40% and 70% which holds pretty much with the current systematics of the genus. The study presents a rapid consistent method for identification of A. chevalieri, A. nidulans, A. tetrazonus (quadrilineatus) and their teleomorphs based on the banding pattern of RAPD-generated fragments that can be reliably used ahead of further applications on these species.     

Synthesis of 1-(3',4',5'-trimethoxy) phenyl naphtho[2,1b]furan as a novel anticancer agent

3',4',5'-Trimethoxy benzoyl-naphthalene 2-O-acetic acid (5) underwent base catalysed intramolecular condensation to yield exclusively 1-(3',4',5'-trimethoxy) phenyl naphtho[2,1-b]furan 8. The cyclised product 8 has been characterised by spectroscopy. The product 8 showed significant anticancer activity against human cancer cell lines COLO320DM (colon), CaCO2 (colon) and WRL68 (liver) at 0.7, 0.65 and 0.50 microg/ml concentrations, respectively, in the in vitro MTT assay.     

Synthesis of [1'-fluoro-2',2'-bis-(hydroxymethyl)cyclopropylmethyl]purines as antiviral agents

[1'-Fluoro-2',2'-bis-(hydroxymethyl)cyclopropylmethyl]purines were designed, synthesized and their antiviral activity against poliovirus, HSV and HIV was evaluated.