Enzymatic syntheses of 6-(4H-selenolo[3,2-b]pyrrolyl)-L-alanine, 4-(6H-selenolo[2,3-b]pyrrolyl)-L-alanine, and 6-(4H-furo[3,2-b]pyrrolyl-L-alanine

6-(4H-Selenolo[3,2-b]pyrrolyl)-L-alanine 1, 4-(6H-selenolo[2,3-b]pyrrolyl)-L-alanine 2, and 6-(4H-furo[3,2-b]pyrrolyl)-L-alanine 3 have been synthesized via reactions of selenolo[3,2-b]pyrrole, selenolo[2,3-b]pyrrole, and furo[3,2-b]pyrrole, respectively, with L-serine. The reactions are catalyzed by Salmonella typhimurium tryptophan synthase.     

SAR comparative studies on pyrimido[4,5-b][1,4] benzothiazine derivatives as 15-lipoxygenase inhibitors, using ab initio calculations

The enzyme inhibitory activity of a new group of 2-substituted pyrimido[4,5-b][1,4]benzothiazines on soybean 15-lipoxygenase (15-LO) was evaluated and compared with those of their 4-methyl analogs using ab initio calculations. The results of these studies showed that the lack of 4-methyl substituent in the pyrimido[4,5-b][1,4] benzothiazine molecules greatly reduces their 15-LO inhibitory activities.     

Synthesis and cytotoxic activity of pyrazino[1,2-b]-isoquinolines, 1-(3-isoquinolyl)isoquinolines, and 6,15-iminoisoquino[3,2-b]-3-benzazocines

A series of pyrazino[2,1-b]isoquinoline and 6,15-iminoisoquino[3,2-b]-3-benzazocine compounds related to renieramycins, cribrostatin 4, and phthalascidin was synthesized and their in vitro cytotoxic activities were evaluated against three human cancer cell lines. Pyrazino[2,1-b]isoquinolines, 6,15-iminoisoquino[3,2-b]-3-benzazocines, and other more complex octacyclic compounds have been obtained and derived to precursors of iminium ion species. Hydrogenolysis of the lactam function in pentacyclic compounds gave 1-(3-isoquinolyl)isoquinolines. The micromolar cytotoxic activity of representative structures was apparently uninfluenced by the ability to generate intermediates which would permit covalent bonding to DNA.     

Synthesis and biological evaluation of thiophene [3,2-b] pyrrole derivatives as potential anti-inflammatory agents

A series of thiophene [3,2-b] pyrrole derivatives were synthesized and evaluated their abilities to inhibit anti-inflammatory activity. In this series, substituent effects at the N-1, 2 and 5 positions of thiophene [3,2-b] pyrrole were examined. The results obtained are compared to those previously reported anti-inflammatory drugs like Tenidap sodium, Diclofenac sodium and Piroxicam. The results indicated the critical role of the group linked in the N-1 position and 2, 5 positions of thiophene [3,2-b] pyrrole with different functional groups.     

Synthesis, cytotoxic activity, NMR study and stereochemical effects of some new pyrano[3,2-b]thioxanthen-6-ones and pyrano[2,3-c]thioxanthen-7-ones

Some new substituted pyrano[3,2-b]thioxanthen-6-ones and pyrano[2,3-c]thioxanthen-7-ones were prepared and their cytotoxic activity was evaluated using acronycine as the reference compound. The conformation of the molecules was also investigated in an effort to correlate this parameter with the biological activity.     

Substituted furo[3,2-b]pyridines: novel bioisosteres of 5-HT 1F receptor agonists

Synthesis and evaluation of a series of 2,3,5- and 3,5-substituted furo[3,2-b]pyridines were undertaken in order to investigate their utility as bioisosteres of 5-HT(1F) receptor agonist indole analogues, 1-3. The replacement proved to be effective, providing compounds with similar 5-HT(1F) receptor affinity and improved selectivity when compared with the indole analogues. Through these studies we identified 4-fluoro-N-[3-(1-methyl-piperidin-4-yl)-furo[3,2-b]pyridin-5-yl]-benzamide (5), a potent and selective 5-HT(1F) receptor agonist with the potential to treat acute migraine.     

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 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.     

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.     

Synthesis and evaluation of isosteres of N-methyl indolo[3,2-b]-quinoline (cryptolepine) as new antiinfective agents

Isosteres of cryptolepine (1) were synthesized and evaluated for their antiinfective activities. Overall, the sulfur isostere, 5-methyl benzothieno[3,2-b]quinolinium salt (5b), was equipotent to 1 and has shown no cytotoxicity at 23.8 microg/mL. Compound 5b was also found to have a broad spectrum of activity. Both the carbon and oxygen isosteres were less potent than cryptolepine. A limited library of 2-substituted analogs of 5b has been synthesized and evaluated in antifungal screens but did not show increase in potency compared to the unsubstituted 5b. Similarly, evaluation of tricyclic benzothieno[3,2-b]pyridines while showing promise in individual screens did not produce an overall increase in potency. Overall, the evaluation of the activities of 5b compared with standard antifungal/anti-protozoal agents suggests that the benzothienoquinoline scaffold could serve as a lead for optimization.     

Mechanism of inhibition of human leukocyte elastase by two cephalosporin derivatives.

The cephalosporin derivatives L 658758 [1-[[3-(acetoxymethyl)-7 alpha-methoxy-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-en-2-yl]carbonyl]proline S,S-dioxide] and L 659286 [1-[[7 alpha-methoxy-8-oxo-3-[[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo- 1,2,4-triazin-3-yl)thio]methyl]-5-thia-1-aza-(6R)-bicyclo[4.2.0]-o ct-2-en-2-yl]carbonyl]pyrrolidine S,S-dioxide] are mechanism based inhibitors of human leukocyte elastase (HLE). The mechanism involves initial formation of a Michaelis complex followed by acylation of the active site serine. The group on the 3'-methylene is liberated during the course of these reactions, followed by partitioning of an intermediate between hydrolysis to regenerate active enzyme and further modification to produce a stable HLE-inhibitor complex. The partition ratio of 2.0 obtained for the reaction with L 658758 approaches that of an optimal inhibitor. These compounds are functionally irreversible inhibitors as the recovery of activity after inactivation is slow. The half-lives at 37 degrees C of the L 658758 and L 659286 derived HLE-I complexes were 9 and 6.5 h, respectively. The complexes produced by both inhibitors are similar chemically since the thermodynamic parameters for activation to regenerate active enzyme are essentially identical. The free energy of activation for this process is dominated primarily by the enthalpy term. The stability of the final complexes likely arises from Michael addition on the active site histidine to the 3'-methylene.     

New pyrimido[5,4-b]indoles and [1]benzothieno[3,2-d]pyrimidines: high affinity ligands for the alpha(1)-adrenoceptor subtypes

A number of new pyrimido[5,4-b]indole and [1]benzothieno[3,2-d]pyrimidine derivatives were synthesized and evaluated for their binding and functional properties at alpha(1)-adrenergic receptor (alpha(1)-AR) subtypes. They behaved as potent alpha(1)-AR antagonists. In binding experiments, some of them (RC24 and RC23) showed very high affinity for the alpha(1D)-AR subtype.     

Identification of a novel blue pigment as a melanoidin intermediate in the D-xylose-glycine reaction system

Some blue pigments were formed in the D-xylose (1 M)-glycine (0.1 M) reaction system. A novel blue pigment, designated as Blue-M2 (blue Maillard intermediate-2), was identified as 5-[1,4-dicarboxymethyl-5-(2,3-dihydroxypropyl)-1,4-dihydropyrrolo[3,2-b]pyrrole-2-ylmethylene]-1,4-dicarboxymethyl-2-{5-[N-carboxymethyl(2,3,4-trihydroxytetrahydrofuran-2-yl)methylamino]-2-hydroxymethyl-4-(1,2,3-trihydroxypropyl)tetrahydrofuran-3-yl}-4,5-dihydropyrrolo-[3,2-b]pyrrole-1-ium. Blue-M2 is presumed to have been generated by the reaction between Blue-M1, which was identified as the major blue pigment in a previous paper (Hayase et al., Biosci. Biotechnol. Biochem., 63, 1512-1514 (1999)), and di-D-xyluloseglycine. Blue pigments are important Maillard reaction intermediates through the formation of melanoidins.     

Synthesis of substituted indeno[1,2-b]quinoline-6-carboxamides, [1]benzothieno[3,2-b]quinoline-4-carboxamides and 10H-quindoline-4-carboxamides: evaluation of structure-activity relationships for cytotoxicity

New substituted indeno[1,2-b]quinoline-6-carboxamides, [1]benzothieno[3,2-b]quinoline-4-carboxamides and 10H-quindoline-4-carboxamides were prepared from methyl 2-amino-3-formylbenzoate by a new Friedlander synthesis. Evaluation of these carboxamides for cytotoxicity in a panel of cell lines showed that small lipophilic substituents in the non-carboxamide ring, in a pseudo-peri position to the side chain, significantly increased cytotoxic potency while retaining a pattern of cytotoxicity consistent with a non-topo II mode of action. The methyl-substituted indeno[1,2-b]quinoline-6-carboxamide demonstrated substantial effectiveness (20-day growth delays) in a sub-cutaneous colon 38 in vivo tumor model. This is comparable to that reported for the dual topo I/II inhibitor DACA that is in clinical trial.     

Biodesulfurization of naphthothiophene and benzothiophene through selective cleavage of carbon-sulfur bonds by Rhodococcus sp. strain WU-K2R

Naphtho[2,1-b]thiophene (NTH) is an asymmetric structural isomer of dibenzothiophene (DBT), and in addition to DBT derivatives, NTH derivatives can also be detected in diesel oil following hydrodesulfurization treatment. Rhodococcus sp. strain WU-K2R was newly isolated from soil for its ability to grow in a medium with NTH as the sole source of sulfur, and growing cells of WU-K2R degraded 0.27 mM NTH within 7 days. WU-K2R could also grow in the medium with NTH sulfone, benzothiophene (BTH), 3-methyl-BTH, or 5-methyl-BTH as the sole source of sulfur but could not utilize DBT, DBT sulfone, or 4,6-dimethyl-DBT. On the other hand, WU-K2R did not utilize NTH or BTH as the sole source of carbon. By gas chromatography-mass spectrometry analysis, desulfurized NTH metabolites were identified as NTH sulfone, 2'-hydroxynaphthylethene, and naphtho[2,1-b]furan. Moreover, since desulfurized BTH metabolites were identified as BTH sulfone, benzo[c][1,2]oxathiin S-oxide, benzo[c][1,2]oxathiin S,S-dioxide, o-hydroxystyrene, 2-(2'-hydroxyphenyl)ethan-1-al, and benzofuran, it was concluded that WU-K2R desulfurized NTH and BTH through the sulfur-specific degradation pathways with the selective cleavage of carbon-sulfur bonds. Therefore, Rhodococcus sp. strain WU-K2R, which could preferentially desulfurize asymmetric heterocyclic sulfur compounds such as NTH and BTH through the sulfur-specific degradation pathways, is a unique desulfurizing biocatalyst showing properties different from those of DBT-desulfurizing bacteria.     

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.     

New pyrrolo[3,2-b]pyrroles with AIE characteristics for detection of dichloromethane and chloroform

Three new pyrrolo[3,2-b]pyrrole derivatives containing methoxyphenyl, pyrene or tetraphenylethylene (TPE) units (compounds 1 – 3) have been designed, synthesized and fully characterized. The aggregation-induced emission (AIE) properties of compounds 1 – 3 were tested in different water fraction (f_w) of tetrahydrofuran (THF). The pyrrolo[3,2-b]pyrrole derivative 3 containing TPE units exhibited typical AIE features with an enhanced emission (∼32-fold) in the solid state versus in solution; compounds 1 and 2 exhibited an aggregation-caused quenching effect. In addition, the steric and electronic effects of the peripheral moieties on the emission behavior, both in solution and in the solid state, have been investigated. Moreover, pyrrolo[3,2-b]pyrrole 1 exhibits high sensitivity and selectivity for dichloromethane and chloroform solvents, with the system displaying a new emission peak and fast response time under ultraviolet irradiation.     

Identification of the blue pigment formed in a D-glucose-glycine reaction system

D-Glucose (0.7 M), glycine (0.3 M), and sodium hydrogencarbonate (0.1 M) were dissolved in aqueous 30% ethanol at pH 8.0 and left at 50 °C for 4 d in a dark room under nitrogen displacement. The resulting blue pigment was isolated and purified from the blue solution by anionic exchange and gel filtration chromatography. This blue pigment, which is designated Blue-G1, was identified as 5-[1,4-bis-carboxymethyl-5-(2,3,4-trihydroxybutyl)-1,4-dihydropyrrolo[3,2-b]pyrrol-2-ylmethylene]-1,4-bis-carboxymethyl-2-(2,3,4-trihydroxybutyl)-4,5-dihydropyrrolo[3,2-b]pyrrol-1-ium. Blue-G1 had two symmetrical pyrrolopyrrole structures with a trihydroxybutyl group. Blue-G1 had a polymerizing activity, suggesting it to be an important Maillard reaction intermediate through the formation of melanoidins.     

Discovery and in vitro evaluation of potent TrkA kinase inhibitors: oxindole and aza-oxindoles

The discovery, synthesis, potential binding mode, and in vitro kinase profile of 3-(3-bromo-4-hydroxy-5-(2'-methoxyphenyl)-benzylidene)-5-bromo-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one, 3-[(1-methyl-1H-indol-3-yl)methylene]-1,3-dihydro-2H-pyrrolo[3,2-b]-pyridin-2-one as potent TrkA inhibitors are discussed.     

Benzothieno[3,2-b]indole derivatives as potent selective estrogen receptor modulators

A series of estrogen receptor ligands based on benzothieno[3,2-b]indole were synthesized and their binding affinity for estrogen receptor subtypes (ERalpha and ERbeta) and effects on mouse uterus and bone were evaluated. Some of these compounds showed strong binding affinity to ER and significantly increased the bone mineral density of ovariectomized mice.