1,721,001 research outputs found
Thioanalogues of Antitumor Antibiotics. 1. Synthesis of 7,8-disubstituted 5,11-Dioxo-1,2,3,11a-tetrahydro-5H,11H- and 5-Oxo-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c][1,4]benzothiazepine
No full textPolycondensed heterocycles. X. A new method for the preparation of pyrrolo[2,1-c][1,4]benzothiazepines by intramolecular mitsunobu cyclisation
No full textA modified Mitsunobu reaction of 2-hydroxymethylpyrrole and suitable thiophenol derivatives lead to intermediates which can be easily elaborated and eventually cyclised to the title compounds. The cyclisation step consists of another Mitsunobu reaction variation by which an 'activated' pyrrole is N- alkylated intramolecularly, under very mild conditions
Polycondensed heterocycles. V. Synthesis of 5H,11H-Pyrrolo[2,1-c][1,4]benzothiazepine
No full textThe 5H,11H-pyrrolo [2, 1-c][1,4] benzothiazepine ring system has been prepared by two synthetic pathways, involving the intramolecular nucleophilic displacement on 1-(2-fluorobenzyl)-2-mercaptomethylpyrrole or the Pummerer rearrangement of 1-(2-ethoxycarbonylmethylsulfinyl-benzyl)pyrrole followed by in situ cyclization, respectively. © 1990
Polycondensed heterocycles. VIII. Synthesis of 11-aryl-5H,11H-Pyrrolo[2,1-c][1,4]benzothiazepines by Pummerer rearrangement-cyclization reaction
No full text11-Phenyl-5Hl1H-pyrrolo[2,1-c][1,4]benzothiazepine has been prepared by an intramolecular nucleophilic displacement reaction. The same compound, as well as some analogues thereof, were more conveniently obtained by Pummerer rearrangement-cyclization of sulfinyl precursors. The latter method was also effective for the synthesis of 4-phenyl-4H-pyrrolo[2,1-c][1,4]benzothiazine. © 1992
Pyrrolo-1,5-benzoxazepines Induce Apoptosis in HL-60, Jurkart, and Hut-78 Cells: A New Class of Apoptotic Agents
No full textSome, but not all, of a series of novel pyrrolo-1,5-benzoxazepines (PBOXs) induce apoptosis as shown by cell shrinkage, chromatin condensation, and DNA fragmentation in three human cell lines, HL-60 promyelocytic, Jurkat T lymphoma, and Hut-78 s.c. lymphoma cells. This chemical selectivity, together with the lack of apoptotic activity against rat Leydig cells, argues against a general cell poisoning effect. PBOX-6, a potent member of the series, caused activation of a member of the caspase-3 family of proteases. In addition, the caspase-3-like inhibitor z-DEVD-fmk, but not the caspase-1- like inhibitor zYVAD-fmk prevented PBOX-6-induced apoptosis, suggesting that caspase 3-like proteases are involved in the mechanism by which PBOX compounds induce apoptosis. The release of cytochrome c into the cytosol in HL-60 cells in response to PBOX-6 suggests that this cellular response may be important in the mechanism by which PBOX-6 induces apoptosis. However, reactive oxygen intermediates do not play a key role in PBOX-6-induced apoptosis because neither the free radical scavenger TEMPO nor the antioxidant N-acetylcysteine had any effect on PBOX-6-induced apoptosis. The apoptotic induction seems independent of the mitochondrial peripheral-type benzodiazepine receptor (PBR) that binds these pyrrolobenzoxazepines with high affinity, due to the lack of correlation between their affinities for the receptor and their apoptotic potencies, their high apoptotic activity in PBR-deficient cells such as Jurkats, and their lack of apoptotic induction in PBR-rich rat Leydig cells. These PBOXs also can overcome nuclear factor-κB- mediated resistance to apoptosis. This suggests an important potential use of these compounds in drug-resistant cancers
Polycondensed Heterocycles. Part 11: Preparation and Regioselective Reductions of 5-Phenyl-4H-pyrrolo[1,2-a][1]benzazepin-4-one
No full textThe Wadsworth-Emmons olefination between 2-(1H-pyrrol-1-yl)benzaldehyde and methyl α-(diethylphosphonyl)phenyl-acetate leads exclusively to the cis-isomer of methyl 2-(1H-pyrrol-1-yl)-α-phenylcinnamate, which, after transformation into the corresponding acid chloride, was easily cyclised to the title enone. This latter was regioselectively reduced to the corresponding saturated ketone or unsaturated alcohol, under different experimental conditions. An improved preparation of starting 2-(1H-pyrrol-1-yl)benzaldehyde is also reported. (C) 2000 Elsevier Science Ltd
Polycondensed heterocycles. IX. Pyrrolo[2,1-c][1,4]benzothiazepines. Synthesis of 3-(dimethylamino)methyl derivatives
No full textThe synthesis of 3-(dimethylamino)methyl-5H,11H-pyrrolo[2,1- c][1,4]benzothiazepine derivatives 2a-c which might show significant central nervous system (CNS) activity, is described. The basic side chain was introduced by a Mannich condensation with the preformed heterocyclic systems 1a-c. Synthesis of novel 5-phenyl-5H,11H-pyrrolo[2,1-c][1,4]benzothiazepine le by a nucleophilic aromatic fluoride displacement-cyclization and an attempted alternative route to le via a Pummerer rearrangement-cyclization are also reported. A mechanism for an unexpected formation of a pyrrole-2- carbaldehyde is proposed, as well
An approach to modified heterocyclic analogues of huperzine A and isohuperzine A. Synthesis of the pyrimidone and pyrazole analogues, and their anticholinesterase activity
No full textSynthetic approaches to the pyrimidone and the pyrazole analogues of the naturally occurring acetylcholinesterase (AChE) inhibitor huperzine A and its unnatural regioisomer, isohuperzine, are described. The pyrimidone analogues of huperzine A were obtained starting from cyclohexane-1,4-dione monoethylene ketal by first annealing to this monocycle a pyrimidine ring and then constructing the unsaturated three-carbon bridge using the previously described palladium-catalysed bicycloannulation methodology. A major problem in this synthetic undertaking proved to be introduction of the ethylidene appendage onto tricycle 10. While both Wittig and Takai olefination protocols proved unsuccessful, the ethylidene moiety was eventually introduced using the Danheiser methodology which involves a two step reaction sequence consisting of the intermediate construction of a β-lactone, which in turn undergoes a [2 + 2] cycloreversion leading to the desired olefin. This β-lactone synthesis, which has not previously been applied to β-keto esters, was found to proceed with excellent diastereoselectivity. In turn, the β-lactone underwent a stereospecific decarboxylation reaction to provide the E-olefin product as the sole isomer. Additionally, starting from the bicyclo[3.3.1]nonene intermediate 2 we describe a synthetic strategy for procuring modified heterocyclic analogues of isohuperzine A. This chemistry provides an attractive approach to the synthesis of heterocyclic analogues with unsaturation in the 6,7 position. While none of these new analogues was found to rival huperzine A in its ability to act as a reversible inhibitor of AChE, the data reported herein should prove useful to modeling efforts aimed at acquiring a better understanding of huperzine A's binding topography within AChE
Synthesis and biological evaluation of conformationally restricted analogs of tolmetin and ketorolac
No full textInhibition of G1 cyclin-dependent kinase activity during growth arrest of human astrocytoma cells by the pyrrolo-1,5-benzoxazepine, PBOX-21
No full textThe present study examines the molecular mechanisms by which a member of a novel series of pyrrolo-1,5-benzoxazepines, PBOX-21, induces G1 arrest in 1321N1 cells. PBOX-21-induced G1 arrest is preceded by both a decrease in CDK2 kinase activity, which is critical for the G1/S transition, and a downregulation in cyclin D3 protein expression levels, suggesting that these two events may be crucially involved in the mediation of the cell cycle arrest. The decrease in CDK2 activity may be due to an observed decrease in CDK2 protein levels following PBOX-21 treatment. Coinciding with the arrest is a reduction in the activity of CDK4, due to either the observed PBOX-21 induced downregulation in CDK4 expression, or a reduction in complex formation between cyclin D3-CDK4 leading to a decrease in the levels of active cyclin D3-CDK4 complexes with kinase activity. The level of CDK6 activity was also seen to be reduced following PBOX-21 treatment, also possibly due to a reduction in complex formation with cyclin D3. However, this reduction in CDK6 kinase activity was not seen until after PBOX-21-induced G1 arrest has reached its maximum, and therefore may be viewed as a consequence of, and a method of maintaining the PBOX-21-induced arrest, rather than a cause. Also in parallel with the G1 arrest elicited by PBOX-21 is an upregulation in the universal CDK inhibitor, p21. Furthermore, the retinoblastoma protein (Rb), a substrate of CDK2 and CDK6, whose phosphorylation is necessary for cell cycle progression, becomes hypophosphorylated. These results indicate that PBOX-21 exerts its growth inhibitory effects through the modulation of the expression and activity of several key G1 regulatory proteins
- …
