Anti-apoptotic effects of Z alpha-1 antitrypsin in human bronchial epithelial cells.

α1-antitrypsin (α1-AT) deficiency is a genetic disease which manifests as early-onset emphysema or liver disease. Although the majority of α1-AT is produced by the liver, it is also produced by bronchial epithelial cells, amongst others, in the lung. Herein, we investigate the effects of mutant Z α1-AT (ZAAT) expression on apoptosis in a human bronchial epithelial cell line (16HBE14o-) and delineate the mechanisms involved.

Control, M variant α1-AT (MAAT)- or ZAAT-expressing cells were assessed for apoptosis, caspase-3 activity, cell viability, phosphorylation of Bad, nuclear factor (NF)-κB activation and induced expression of a selection of pro- and anti-apoptotic genes.

Expression of ZAAT in 16HBE14o- cells, like MAAT, inhibited basal and agonist-induced apoptosis. ZAAT expression also inhibited caspase-3 activity by 57% compared with control cells (p = 0.05) and was a more potent inhibitor than MAAT. Whilst ZAAT had no effect on the activity of Bad, its expression activated NF-κB-dependent gene expression above control or MAAT-expressing cells. In 16HBE14o- cells but not HEK293 cells, ZAAT upregulated expression of cIAP-1, an upstream regulator of NF-κB. cIAP1 expression was increased in ZAAT versus MAAT bronchial biopsies.

The data suggest a novel mechanism by which ZAAT may promote human bronchial epithelial cell survival.

Differential modulation of a radiation-induced bystander effect in glioblastoma cells by pifithrin-alpha and wortmannin

The implication of radiation-induced bystander effect (RIBE) for both radiation protection and radiotherapy has attracted significant attention, but a key question is how to modulate the RIBE. The present study found that, when a fraction of glioblastoma cells in T98G population were individually targeted with precise helium particles through their nucleus, micronucleus (MN) were induced and its yield increased non-linearly with radiation dose. After co-culturing with irradiated cells, additional MN could be induced in the non-irradiated bystander cells and its yield was independent of irradiation dose, giving direct evidence of a RIBE. Further results showed that the RIBE could be eliminated by pifithrin-alpha (p53 inhibitor) but enhanced by wortmannin (PI3K inhibitor). Moreover, it was found that nitric oxide (NO) contributed to this RIBE, and the levels of NO of both irradiated cells and bystander cells could be extensively diminished by pifithrin-alpha but insignificantly reduced by wortmannin. Our results indicate that RIBE can be modulated by p53 and PI3K through a NO-dependent and NO-independent pathway, respectively. (C) 2009 Elsevier B.V. All rights reserved.

Non-thiazolidinedione antihyperglycaemic agents. Part 3: The effects of stereochemistry on the potency of alpha-methoxy-beta-phenylpropanoic acids.

Rhizopus delemar lipase catalyzed ester hydrolysis of the alpha-methoxy-beta-phenylpropanoate (I) affords the (R)-(+) and (S)-(-) isomers in > 84% enantiomeric excess. Abs. stereochem. was detd. by a single crystal X-ray anal. of a related synthetic analog. The activity of these two enantiomers on glucose transport in vitro and as anti-diabetic agents in vivo is reported and their unexpected equivalence attributed to an enzyme-mediated stereospecific isomerization of the (R)-(+) isomer. Binding studies using recombinant human PPAR-gamma (peroxisomal proliferator activated receptor gamma), now established as a mol. target for this compd. class, indicate a 20-fold higher binding affinity for the (S) antipode relative to the (R) antipode.

New members of the chiral pool:  -hydroxypiperidine carboxylates from bakers' yeast reductions of the corresponding keto-esters.

. Knight, David W.; Lewis, Neil; Share, Andrew C.; Haigh, David. Chem. Dept., Univ. of Nottingham, Nottingham, UK. Tetrahedron: Asymmetry (1993), 4(4), 625-8. CODEN: TASYE3 ISSN: 0957-4166. Journal written in English. CAN 120:54423 AN 1994:54423 CAPLUS (Copyright (C) 2009 ACS on SciFinder (R)) Abstract Redn. of the keto-piperidinecarboxylates I and II with fermenting bakers' yeast produced the corresponding hydroxy-esters III and IV in good yields with >99% diastereomeric excess and >93% enantiomeric excess in both cases.

Anomalous fluorinations of 3-aryl-2-hydroxypropanoic esters by diethylaminosulfur trifluoride (DAST).

Anomalous fluorinations of 3-aryl-2-hydroxypropanoic esters by diethylaminosulfur trifluoride (DAST). Haigh, David; Jefcott, Lee J.; Magee, Katherkine; McNab, Hamish. Dep. Med. chem., SmithKline Beecham Pharmaceuticals, Epsom, UK. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1996), (24), 2895-2900. Publisher: Royal Society of Chemistry, CODEN: JCPRB4 ISSN: 0300-922X. Journal written in English. CAN 126:143928 AN 1997:56534 CAPLUS (Copyright (C) 2009 ACS on SciFinder (R)) Abstract Treatment of 3-aryl-2-hydroxypropanoic esters with diethylaminosulfur trifluoride (DAST) gives considerable amts. of rearranged 2-aryl-3-fluoropropanoic esters, together with the expected products. The extent of rearrangement is dependent on solvent and on the substitution pattern of the aryl ring; the mechanism of rearrangement probably involves anchimeric assistance by the aryl group in the SN1 component of the reaction pathway. Reaction of the isomeric 3-hydroxy-2-phenylpropanoic ester shows much less rearrangement under similar conditions, and an elimination product is also obtained.

N-H insertion reactions of rhodium carbenoids. Part 2. Preparation of N-substituted amino(phosphoryl)acetates (N-substituted phosphorylglycine esters).

Rhodium(II) acetate-catalyzed reaction of Et 2-diazo-2-diethoxyphosphorylate, EtO2CC(:N2)PO(OEt)2, with carbamates, amides, ureas or anilines gives a range of N-substituted 2-amino-2-diethoxyphosphorylacetates, EtO2CCH(NHR1)PO(OEt)2 (where R1 = Boc, Cbz, acetyl, propionyl, pivaloyl, n-Pr, Ph and substituted Ph groups), by N-H insertion reaction of the intermediate rhodium carbenoid.

Non-thiazolidinedione antihyperglycemic agents. 2: alpha-Carbon substituted-beta-phenylpropanoic acids.

Buckle, D. R.; Cantello, B. C. C.; Cawthorne, M. A.; Coyle, P. J.; Dean, D. K.; Faller, A.; Haigh, D.; Hindley, R. M.; Lefcott, L. J.; et al. Dep. Medicinal Chem., Smithkline Beecham Pharmaceuticals, Surrey, UK. Bioorganic & Medicinal Chemistry Letters (1996), 6(17), 2127-2130. Publisher: Elsevier, CODEN: BMCLE8 ISSN: 0960-894X. Journal written in English. CAN 125:238227 AN 1996:573179 CAPLUS (Copyright (C) 2009 ACS on SciFinder (R)) Abstract The thiazolidine-2,4-dione ring of insulin-sensitizing antidiabetic agents can be replaced by ?-acyl-, ?-alkyl- and ?-(aralkyl)-carboxylic acids. The inclusion of an addnl. lipophilic moiety affords compds., equipotent to BRL 48482.

Non-thiazolidinedione antihyperglycemic agents. 1: Alpha-Heteroatom substituted-beta-phenylpropanoic acids.

A review with 22 refs. The 5-benzylthiazolidine-2,4-dione moiety of insulin sensitizing antidiabetic agents can be replaced by a range of ?-heteroatom functionalized ?-phenylpropanoic acids. ?-Oxy-carboxylic acids show potent antidiabetic activity and one compd., the ?-ethoxyacid (SB 213068), is one of the most potent antihyperglycemic agents yet reported.

A simple route to N-acylaminophosphonoacetates (N-protected phosphonylglycine esters).

Rhodium(II) acetate catalyzed reaction of tri-Et diazophosphonoacetate with amides, carbamates or ureas gives a range of N-acyl phosphonylglycine derivs. by N-H insertion reaction of the intermediate rhodium carbenoid.