Biomedical subjects

S Halleran

Publications and source records attributed to S Halleran.

6 recordsLinked to original sources

PubMed2001

Epidermal growth factor receptor transactivation by angiotensin II requires reactive oxygen species in vascular smooth muscle cells.

Angiotensin II (Ang II) is a vasoactive hormone with critical roles in vascular smooth muscle cell growth, an important feature of hypertension and atherosclerosis. Many of these effects are dependent on the production of reactive oxygen species (ROS). Ang II induces phosphorylation of the epidermal growth factor (EGF) receptor (EGF-R), which serves as a scaffold for various signaling molecules. Here, we provide novel evidence that ROS are critical mediators of EGF-R transactivation by Ang II. Pretreatment of vascular smooth muscle cells with the antioxidants diphenylene iodonium, Tiron, N-acetylcysteine, and ebselen significantly inhibited ( approximately 80% to 90%) tyrosine phosphorylation of the EGF-R by Ang II but not by EGF. Of the 5 autophosphorylation sites on the EGF-R, Ang II mainly phosphorylated Tyr1068 and Tyr1173 in a redox-sensitive manner. The Src family kinase inhibitor PP1, overexpression of kinase-inactive c-Src, or chelation of intracellular Ca(2+) attenuated EGF-R transactivation. Although antioxidants had no effects on the Ca(2+) mobilization or phosphorylation of Ca(2+)-dependent tyrosine kinase Pyk2, they inhibited c-Src activation by Ang II, suggesting that c-Src is 1 signaling molecule that links ROS and EGF-R phosphorylation. Furthermore, Ang II-induced tyrosine phosphorylation of the autophosphorylation site and the SH2 domain of c-Src was redox sensitive. These findings emphasize the importance of ROS in specific Ang II-stimulated growth-related signaling pathways and suggest that redox-sensitive EGF-R transactivation may be a potential target for antioxidant therapy in vascular disease.

1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium ↗

PubMed2001

Cytotoxic and anticancer properties of some 4-aryl-3-arylcarbonyl-1-ethyl-4-piperidinols and related compounds.

A previous investigation revealed that various 4-aryl-3-arylcarbonyl-1-ethyl-4-piperidinols and related vinylogs were cytotoxic to both murine and human tumour cell lines. In particular, 1a and 2a were identified as useful prototypic molecules. Structural modifications of 1a and 2a were accomplished leading to 1b-e and 2b-d which displayed cytotoxicity towards murine P388 and L1210 leukemic cells as well as human Molt 4/C8 and CEM T-lymphocytes. Among the new compounds, the greatest average potencies against these four cell lines were displayed by 1b and 2b, having approximately one quarter and one half of the potency of the reference drug melphalan, respectively. The synthesis and bioevaluation of three open chain analogues of 1b-d, namely 3a-c, did not reveal unequivocally whether this molecular modification led to increases in cytotoxicity or not. Compounds 2a-d were substantially more active than melphalan using a panel of human tumour cell lines. In addition, several compounds displayed selective toxicity to both colon and leukemic cancer cells. The 4-piperidinol 2d was active in the in vivo hollow fibre assay. This study revealed compounds with greater potency than 1a and 2a and it has confirmed that 1,3,4-trisubstituted-4-piperidinols and related compounds are novel groups of candidate antineoplastic and anticancer agents.

Animals↗

PubMed1998

Cytotoxic activities of Mannich bases of chalcones and related compounds.

Various Mannich bases of chalcones and related compounds displayed significant cytotoxicity toward murine P388 and L1210 leukemia cells as well as a number of human tumor cell lines. The most promising lead molecule was 21 that had the highest activity toward L1210 and human tumor cells. In addition, 21 exerted preferential toxicity to human tumor lines compared to transformed human T-lymphocytes. Other compounds of interest were 38, with a huge differential in cytotoxicity between P388 and L1210 cells, and 42, with a high therapeutic index when cytotoxicity to P388 cells and Molt 4/C8 T-lymphocytes were compared. In general, the Mannich bases were more cytotoxic than the corresponding chalcones toward L1210 but not P388 cells. A ClusCor analysis of the data obtained from the in vitro human tumor screen revealed that the mode of action of certain groups of compounds was similar. For some groups of compounds, cytotoxicity was correlated with the sigma, pi, or molar refractivity constants in the aryl ring attached to the olefinic group. In addition, the IC50 values in all three screens correlated with the redox potentials of a number of Mannich bases. X-ray crystallography and molecular modeling of representative compounds revealed various structural features which were considered to contribute to cytotoxicity. While a representative compound 15 was stable and unreactive toward glutathione (GSH) in buffer, the Mannich bases 15, 18, and 21 reacted with GSH in the presence of the pi isozyme of glutathione S-transferase, suggesting that thiol alkylation may be one mechanism by which cytotoxicity was exerted in vitro. Representative compounds were shown to be nonmutagenic in an intrachromosomal recombination assay in yeast, devoid of antimicrobial properties and possessing anticonvulsant and neurotoxic properties. Thus Mannich bases of chalcones represent a new group of cytotoxic agents of which 21 in particular serves as an useful prototypic molecule.

Animals↗

PubMed1997

Synthesis and cytotoxic evaluation of some carbohydrazones and thiocarbohydrazones of various unsaturated ketones and related Mannich bases.

A number of 1-aryl-1-penten-3-ones 1 and related Mannich bases 2 were synthesized and converted either directly or indirectly to the corresponding biscarbohydrazones 3 and 4. Reaction of representative unsaturated ketones with thiocarbohydrazide led to the formation of only the monothiocarbohydrazones 5. The cytotoxicity of these compounds against murine P388 and L1210 cells, human T-lymphocytes and human tumour cell lines was undertaken in order to ascertain their bioactivity and review these data in the light of the theory of sequently cytotoxicity whereby the carbohydrazones would be predicted to be more than twice as cytotoxic as the ketones and Mannich bases from which they were derived. In general, conversion of 1 into 3 was accompanied by a lowering of cytotoxicity. On the other hand, in general the compounds in series 4 were significantly more potent cytotoxic agents than the analogues 2; in fact, some compounds displayed activity comparable with or exceeding that of melphalan. Thus the biscarbohydrazones 4 represent a novel group of cytotoxic agents serving as lead molecules for subsequent development.

Animals↗

PubMed1995

Synthesis and cytotoxic evaluation of some Mannich bases of alicyclic ketones.

A number of Mannich bases of alicyclic ketones containing one and two basic centres were prepared in order to evaluate the theory of sequential cytotoxicity and develop structure-activity relationships in these series of compounds. The compounds were evaluated in vitro against murine P388 D1 lymphocytic leukemia cells. The data generated supported the theory of sequential cytotoxicity and in general, compounds containing alicyclic rings of five and six carbon atoms possessed greater activity than the corresponding dodecyl analogues. Those Mannich bases containing dialkylamino groups were associated with greater cytotoxicity than related compounds possessing a basic heterocycle. Calculations of the atomic charges of the enone groups from selected compounds afforded some rationalization for the cytotoxic screening results.

Animals↗

PubMed1990

Differences between multisite postmortem ethanol concentrations as related to agonal events.

In a study of postmortem ethanol concentrations, blood was withdrawn from the right atrium, ascending aorta, and inferior vena cava. These samples, vitreous humor, and gastric fluid were analyzed in 307 autopsies, where a minimum blood ethanol concentration of 0.05% weight/volume (w/v) was present. Premortem, agonal, and postmortem events were reviewed in an attempt to account for differences in blood ethanol concentrations between sites. The agonal aspiration of vomitus having at least 0.80% w/v ethanol appears to be associated with an increase in aortic ethanol concentrations. We conclude that valid interpretation of postmortem ethanol concentrations must take into consideration the possible entry of ethanol into the pulmonary venous circulation via the respiratory system.

Adult↗