Formation of thieno[3,2-g]pterines from the molybdenum cofactor

A fluorescent oxidation product of the molybdenum cofactor was isolated from Escherichia coli nitrate reductase (EC 1.9.6.1) and bovine milk xanthine oxidase (EC 1.2.3.2), which showed a visible absorption band at 395 nm and was dephosphorylated by alkaline phosphatase but not by phosphodiesterase I. The dephosphorylated species was oxidized by periodate to thieno[3,2-g]pterin-2-carbaldehyde which was quantitatively converted to thieno[3,2-g]pterin-2-carboxylic acid by subsequent treatment with Ag2O in 2 N NaOH. These results indicate that the oxidation product of the molybdenum cofactor is a thieno[3,2-g]pterin derivative with an unidentified side chain in the 2 position.     

Synthesis of new 4-[2-(alkylamino) ethylthio]pyrrolo[1,2-a]quinoxaline and 5-[2-(alkylamino) ethylthio]pyrrolo[1,2-a]thieno[3,2-e]pyrazine derivatives, as potential bacterial multidrug resistance pump inhibitors

The synthesis of new 4-[2-(alkylamino)ethylthio]pyrrolo[1,2-a]quinoxaline derivatives la-1 is described in five or six steps starting from various substituted nitroanilines 2a-e. The bioisostere 5-[2-(alkylamino)ethylthio]pyrrolo[1,2- a]thieno[3,2-e]pyrazine 1m was also prepared. The new derivatives were evaluated as efflux pump inhibitors (EPIs) in a model targeting the NorA system of Staphylococcus aureus. The antibiotic susceptibility of two strains overproducing NorA, SA-1199B and SA-1, was determined alone and in combination with the neo-synthesised compounds by the agar diffusion method and MIC determination, in comparison with reserpine and omeprazole taken as reference EPIs. A preliminary structure-activity relationship study firstly allowed to clarify the influence of the substituents at positions 7 and/or 8 of the pyrrolo[1,2-a]quinoxaline nucleus. Methoxy substituted compounds, 1b and 1g, were more potent EPIs than the unsubstituted compounds (1a and 1f), followed by chlorinated derivatives (1c-d and 1h). Moreover, the replacement of the N,N-diethylamino group (compounds 1a-e) by a bioisostere such as pyrrolidine (compounds 1f-h) enhanced the EPI activity, in contrast with the replacement by a piperidine moiety (compounds 1i-k). Finally, the pyrrolo[1,2-a]thieno[3,2-e]pyrazine compound 1m exhibited a higher EPI activity than its pyrrolo[1,2-a]quinoxaline analogue la, opening the way to further pharmacomodulation.     

Synthesis of New Aromatic Pyrrolo[2,1- c] [1,4]benzodiazepines and Pyrrolo[1,2- a] thieno[3,2- e] [1,4]diazepines as Anti-tumoral Agents

Diazepine analogs of thieno[2,3- b] pyrrolizin-8-ones were synthesized by aromatization of 2-hydroxypyrrolo[1,2- a] thieno[3,2- e] [1,4]diazepines. These compounds were evaluated in vitro for their antiproliferative activity against the L1210 leukemia cell line. The activity of these compounds was in the micromolar range, the best result being for the mixture of the isomers 5 and 6 which showed a 0.35 μM IC 50 against cell growth.     

A facile synthesis of cis-9-[4-(1,2-dihydroxyethyl)-cyclopent-2-enyl]guanine and its derivative

The synthesis of carbocyclic nucleosides, cis-9-[4-(1,2-dihydroxyethyl)-cyclopent-2-enyl]guanine (3) and cis-2-amino-6-cyclopropylamino-9-[4-(1,2-dihydroxyethyl)- cyclopent-2- enyl]purine (4), was achieved from cyclopentadiene (5) in five and six steps, respectively. This route involves a hetero Diels-Alder reaction and a Pd(0)-catalyzed coupling reaction.     

Synthesis of new aromatic pyrrolo[2,1-c] [1,4]benzodiazepines and pyrrolo[1,2-a]thieno[3,2-e] [1,4]diazepines as anti-tumoral agents

Diazepine analogs of thieno[2,3-b]pyrrolizin-8-ones were synthesized by aromatization of 2-hydroxypyrrolo[1,2-a]thieno[3,2-e][1,4]diazepines. These compounds were evaluated in vitro for their antiproliferative activity against the L1210 leukemia cell line. The activity of these compounds was in the micromolar range, the best result being for the mixture of the isomers 5 and 6 which showed a 0.35 microM IC50 against cell growth.     

Synthesis of 1-(β-D-Ribofuranosyl)Thieno[3,2-d] Pyrimidine-2,4-Dione and 4-Substituted Derivatives

Abstract

Regiospecific ribosylation of the bis(trimethylsilyl) derivative of thieno[3,2-d]pyrimidine-2,4-dione in the presence of a Lewis acid followed by debenzoylation has afforded 1-(β-D-ribofuranosyl)thieno[3,2-d]pyrimidine-2,4-dione, a uridine analogue. The site of ribosylation and anomeric configuration of this N-nucleoside were established by NMR and UV. Thiation of the β-anomer was followed by treatment with methanolic ammonia to afford 4-amino-1-(β-D-ribofuranosyl)thieno [3,2-d]pyrimidin-2-one, a cytidine analogue.     

A Facile Synthesis of cis-9-[4-(1,2-Dihydroxyethyl)-cyclopent-2-enyl]guanine and Its Derivative

Abstract

The synthesis of carbocyclic nucleosides, cis-9-[4-(1,2-dihydroxyethyl)-cyclopent-2-enyl]guanine (3) and cis-2-amino-6-cyclopropylamino-9-[4-(1,2-dihydroxyethyl)-cyclopent-2-enyl]guanine (4), was achieved from cyclopentadiene (5) in five and six steps, respectively. This route involves a hetero Diels-Alder reaction and a Pd(0)-catalyzed coupling reaction.     

Switching androgen receptor antagonists to agonists by modifying C-ring substituents on piperidino[3,2-g]quinolinone

New nonsteroidal human androgen receptor (hAR) agonists were developed from an hAR antagonist pharmacophore, 2(1H)-piperidino[3,2-g]quinolinone. (+/-)-trans-7,8-Diethyl-4-trifluoromethyl-2(H)-piperidino-[3,2-g]quinoli none was synthesized and demonstrated potent hAR agonist activity (EC50=3 nM) in the cell-based cotransfection assay and high binding affinity (Ki=16 nM) in the competitive receptor binding assay.     

The synthesis and vasopressin (AVP) antagonist activity of a novel series of N-aroyl-2,4,5,6-tetrahydropyrazolo[3,4-d]thieno[3,2-b]azepines

Synthesis and SAR of N-[4-[(4,5-dihydropyrazolo[3,4-d]thieno[3,2-b]azepin-6(2H)-y l)carbonyl]phenyl]benzamides as arginine vasopressin (AVP) receptor antagonists are discussed. Potent orally active AVP receptor antagonists are produced when the benzamide moiety contains a phenyl group at the 2-position. Similar analogues of 4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepine and VPA-985 are reported.     

Synthesis and antimicrobial activity of some new substituted pyrido[3′,2′:4,5]thieno[3,2-d]-pyrimidinone derivatives

A series of new 3-substituted-7-(2-chloro-6-ethoxypyridin-4-yl)-9-(2,4-dichlorophenyl)-2-methylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4(3H)-one derivatives were synthesized as antimicrobial agents using 7-(2-chloro-6-ethoxypyridin-4-yl)-9-(2,4-dichlorophenyl)-2-methyl-4H-pyrido[3′,2′:4,5]thieno[3,2-d]-[1,3]oxazin-4-one as a starting compound. Its condensation with substituted aniline derivatives or phenyl hydrazine gave the corresponding N-substituted derivatives. Treatment of the starting compound with hydrazine hydrate afforded the corresponding N-amino derivative, which was reacted with substituted phenylisocyanate and phenylisothiocyanate derivatives to give the corresponding semicarbazides and thiosemicarbazide derivatives. All the newly synthesized compounds were evaluated for their antimicrobial activities in comparison to streptomycin and fusidic acid as positive controls. The structure assignments of the new compounds are based on chemical and spectroscopic evidence.     

Synthesis of new 4-[2-(alkylamino)ethylthio]pyrrolo[1,2-a]quinoxaline and 5-[2-(alkylamino)ethylthio]pyrrolo[1,2-a]thieno[3,2-e]pyrazine derivatives,as potential bacterial multidrug resistance pump inhibitors

The synthesis of new 4-[2-(alkylamino)ethylthio]pyrrolo[1,2-a]quinoxaline derivatives 1a-l is described in five or six steps starting from various substituted nitroanilines 2a-e. The bioisostere 5-[2-(alkylamino)ethylthio]pyrrolo[1,2-a]thieno[3,2-e]pyrazine 1m was also prepared. The new derivatives were evaluated as efflux pump inhibitors (EPIs) in a model targeting the NorA system of Staphylococcus aureus. The antibiotic susceptibility of two strains overproducing NorA, SA-1199B and SA-1, was determined alone and in combination with the neo-synthesised compounds by the agar diffusion method and MIC determination, in comparison with reserpine and omeprazole taken as reference EPIs. A preliminary structure-activity relationship study firstly allowed to clarify the influence of the substituents at positions 7 and/or 8 of the pyrrolo[1,2-a]quinoxaline nucleus. Methoxy substituted compounds, 1b and 1g, were more potent EPIs than the unsubstituted compounds (1a and 1f), followed by chlorinated derivatives (1c-d and 1h). Moreover, the replacement of the N,N-diethylamino group (compounds 1a-e) by a bioisostere such as pyrrolidine (compounds 1f-h) enhanced the EPI activity, in contrast with the replacement by a piperidine moiety (compounds 1i-k). Finally, the pyrrolo[1,2-a]thieno[3,2-e]pyrazine compound 1m exhibited a higher EPI activity than its pyrrolo[1,2-a]quinoxaline analogue 1a, opening the way to further pharmacomodulation.     

Dopamine Semiquinone Radical Doped PEDOT:PSS: Enhanced Conductivity,Work Function and Performance in Organic Solar Cells

Poly(3,4‐ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) has been is applied as hole transport material in organic electronic devices for more than 20 years. However, the redundant sulfonic acid group of PEDOT:PSS has often been overlooked. Herein, PEDOT:PSS‐DA is prepared via a facile doping of PEDOT:PSS with dopamine hydrochloride (DA·HCl) which reacts with the redundant sulfonic acid of PSS. The PEDOT:PSS‐DA film exhibits enhanced work function and conductivity compared to those of PEDOT:PSS. PEDOT:PSS‐DA‐based devices show a power conversion efficiency of 16.55% which is the highest in organic solar cells (OSCs) with (poly[(2,6‐(4,8‐bis(5‐(2‐ethylhexyl)‐4‐fluorothiophen‐2‐yl)benzo[1,2‐b:4,5‐b′]dithio‐phene))‐co‐(1,3‐di(5‐thiophene‐2‐yl)‐5,7‐bis(2‐ethylhexyl)‐benzo[1,2‐c:4,5‐c′]dithiophene‐4,8‐dione))] (PM6):(2,2′‐((2Z,2′Z)‐((12,13‐bis(2‐ethylhexyl)‐3,9‐diundecyl‐12,13‐dihydro‐[1,2,5]thiadiazolo[3,4‐e]thieno[2′′,3′:4′,5′]thieno[2′,3′:4,5]pyrrolo[3,2‐g]thieno[2′,3′:4,5]thieno[3,2‐b]indole‐2,10‐diyl)bis(methanylylidene))bis(5,6‐difluoro‐3‐oxo‐2,3‐dihydro‐1H‐indene‐2,1‐diylidene))dimalononitrile) (Y6) as the active layer. Furthermore, PEDOT:PSS‐DA also exhibits enhanced performance in three other donor/acceptor systems, exhibiting high compatibility in OSCs. This work demonstrates that doping PEDOT:PSS with various amino derivatives is a potentially efficient strategy to enhance the performance of PEDOT:PSS in organic electronic devices.     

Novel cyano- and amidino-substituted derivatives of thieno[2,3-b]- and thieno[3,2-b]thiophene-2-carboxanilides and thieno[3',2':4,5]thieno- and thieno[2',3':4,5]thieno [2,3-c]quinolones: synthesis, photochemical synthesis, DNA binding, and antitumor evaluation

A series of cyano- and amidino-substituted derivatives of thieno[2,3-b]- and thieno[3,2-b]thiophene-2-carboxanilides and their 'cyclic' derivatives (quinolones) were synthesized. 'Cyclic' compounds displayed a rather strong and differential antiproliferative effect on various cell lines, while the 'acyclic' amidino-substituted compounds were much more active, but showing mostly non-differential cytotoxicity, whereas cyano-substituted compounds (2a,b) produced a strikingly strong effect selectively on HeLa and Hep-2 cell lines. Antiproliferative activity of 'cyclic' derivatives is very likely caused by intercalation into DNA, while their 'acyclic' analogues use other target(s) and/or mechanisms of action.     

Nucleosides 137. Synthetic Modifications at the 2′Position of Pyrrolo[3,2-D]Pyrimidine and Thieno[3,2-D]Pyrimidine C-Nucleosides,Synthesis of “2′-Deoxy-9-Deazzadenosine” and of “9-Deaza ARA-A”

Abstract

The syntheses and preliminary biological evaluation of several novel pyrrolo[3,2-d]pyrimidine and thieno[3,2-d]pyrimidine C-nucleosides incorporating the arabinofuranosyl or 2′-deoxyribofuranosyl sugar moiety are described. The 2′-deoxy thieno[3,2-d]pyrimidine C-nucleosides (15 and 16) were obtained from 7-(β-D-ribofuranosyl)-4-oxo-3H-thieno[3,2-d]pyrimidine (3) and its 4-SMe derivative 8. “2”-Deoxy-9-deazaadenosine (31), “9-Deaza ara-A” (38) and the 2′-substituted arabinosyl pyrrolo[3,2-d]pyrimidine C-nucleosides (42 - 44) were synthesized from 4-amino-7-(2,3-O-isopropylidene-5-O-trityl-β-D-ribofuranosyl)-5H-pyrrolo[3,2-d]pyrimidine (21)     

Novel thieno[2,3-b]- and [3,4-b]pyrans as potassium channel openers. Thiophene systems—XVII

The syntheses and antihypertensive activity of the thieno[3,4-b]pyran and thieno[2,3-b]pyran isosteres of the potassium channel opener (PCO) RWJ 26629 (± 2a) are reported. While the unsubstituted thiophene derivatives were active at 20 mg/kg, introduction of a strong electron withdrawing group in the 2-position of the thieno[3,2-b] series increased potency. Similar substitution on the thieno[3,4-b] series significantly lowered potency. Compounds 26 and 30 are approximately 5-fold more potent than the prototypic PCO cromakalim (± 1).     

Synthesis of thiophenes and thieno[3,2-c]pyran-4-ones as antileishmanial and antifungal agents

A series of highly functionalized thiophene (2) and thieno[3,2-c]pyran-4-one(4) derivatives have been synthesized and evaluated for their antileishmanial and antifungal activities.     

Synthesis and antiproliferative evaluation of certain pyrido[3,2-g]quinoline derivatives

The present report describes the synthesis and evaluation of tricyclic pyrido[3,2-g]quinoline derivatives in which an additional pyridine ring is linearly fused on the antibacterial quinoline-3-carboxylic acid. Among them, only diethyl 4,6-diamino-10-methylpyrido[3,2-g]quinoline-3,7-dicarboxylate (9a) and diethyl 4,6-bis-(3-dimethylaminopropylamino)-10-methylpyrido[3,2-g]quinoline-3,7-dicarboxylate (9d) were able to completely inhibit cell proliferation of MCF7 (Breast), NCI-H460 (Lung), and SF-268 (CNS) implying either amino or dimethylaminopropyl moiety at C-4 and C-6 positions is crucial for the antiproliferative activity of pyrido[3,2-g]quinoline derivatives. Compounds 9a-9d were further evaluated for their activity against the growth of MCF-7 and two prostate cancer cell lines, LNCaP and PC-3. Results indicated the antiproliferative activity decreased in an order 9d>9a>9b and 9c. Compound 9d was the most cytotoxic with an IC50 value of 5.63 and 3.96 microM, respectively, against LNCaP and MCF-7. Flow cytometric analyses revealed that growth inhibition of LNCaP by 9d was due to cell cycle arrest in G1 phase, and followed by apoptosis.     

Novel agents combining platelet activating factor (PAF) receptor antagonist with thromboxane synthase inhibitor (TxSI)

Compounds 1 or 2 which possess dual-acting PAF antagonist/TxSI in a previous paper were modified and evaluated for the dual-acting activity. It was found that several compounds were potent dual-acting PAF antagonist/TxSI in and ex vivo. 6-(2-Chlorophenyl)-3-[4-[(E/Z)-6-ethoxycarbonyl-1-(3-pyridyl)-1-hexenyl]phenylmethyl]-8,11-dimethyl-2,3,4,5-tetrahydro-8H-pyrido[4',3': 4,5]thieno[3,2-f]triazolo[4,3-a]diazepine (12) is excellent orally dual-acting PAF antagonist/TxSI.