Synthesis and hypoglycemic activity of phenacyltriphenylphosphoranes and phosphonium salts

Blank, Benjamin; DiTullio, Nicholas W.; Deviney, L.; Roberts, John; Saunders, Harry L.

doi:10.1021/jm00243a021

Cited by 11 publications

(8 citation statements)

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“…As pharmacological agents, certain phosphonium salts have demonstrated anti-microbial activity against gram negative and positive bacteria and the parasite T. cruzi. , antiglycemic properties in animal models and anti-proliferative activity in cell- and animal-based systems [4], [5], [6], [7]. As anti-cancer agents, phosphonium salts show great promise for the diagnosis and treatment of neoplasms.…”

Section: Introductionmentioning

confidence: 99%

Preclinical Evaluation of Novel Triphenylphosphonium Salts with Broad-Spectrum Activity

et al. 2010

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BackgroundRecently, there has been a surge of interest in developing compounds selectively targeting mitochondria for the treatment of neoplasms. The critical role of mitochondria in cellular metabolism and respiration supports this therapeutic rationale. Dysfunction in the processes of energy production and metabolism contributes to attenuation of response to pro-apoptotic stimuli and increased ROS production both of which are implicated in the initiation and progression of most human cancers.Methodology/Principal FindingsA high-throughput MTT-based screen of over 10,000 drug-like small molecules for anti-proliferative activity identified the phosphonium salts TP187, 197 and 421 as having IC50 concentrations in the submicromolar range. TP treatment induced cell cycle arrest independent of p53 status, as determined by analysis of DNA content in propidium iodide stained cells. In a mouse model of human breast cancer, TP-treated mice showed significantly decreased tumor growth compared to vehicle or paclitaxel treated mice. No toxicities or organ damage were observed following TP treatment. Immunohistochemical staining of tissue sections from TP187-treated tumors demonstrated a decrease in cellular proliferation and increased caspase-3 cleavage. The fluorescent properties of analog TP421 were exploited to assess subcellular uptake of TP compounds, demonstrating mitochondrial localization. Following mitochondrial uptake cells exhibited decreased oxygen consumption and concomittant increase in mitochondrial superoxide production. Proteomics analysis of results from a 600 target antibody microarray demonstrated that TP compounds significantly affected signaling pathways relevant to growth and proliferation.Conclusions/SignificanceThrough our continued interest in designing compounds targeting cancer-cell metabolism, the Warburg effect, and mitochondria we recently discovered a series of novel, small-molecule compounds containing a triphenylphosphine moiety that show remarkable activity in a panel of cancer cell lines as well as in a mouse model of human breast cancer. The mechanism of action includes mitochondrial localization causing decreased oxygen consumption, increased superoxide production and attenuated growth factor signaling.

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Section: Introductionmentioning

confidence: 99%

Preclinical Evaluation of Novel Triphenylphosphonium Salts with Broad-Spectrum Activity

et al. 2010

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“…Two classes of derivatives of angiotensin have been prepared for the study of its vascular receptor sites: fluorescent derivatives for light microscopic visualization of receptors (6)(7)(8) and reactive derivatives for the covalent labeling of receptors (5 and 9).…”

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confidence: 99%

2,5,5-Trimethylthiazolidine-4-carboxylic acid, a D(-)-penicillamine-directed pseudometabolite of ethanol. Detoxication mechanism for acetaldehyde

Nagasawa¹,

Goon²,

DeMaster³

1978

J. Med. Chem.

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“…p-Bromobenzyl bromide (7.1 g, 0.0284 mol) was added and the mixture was refluxed for a few minutes under N2. After allowing the mixture to stand overnight at room temperature, methanol was concentrated and cooled, and crystals of methyl 5-[(p-bromobenzyl)thio]-2-pyridinecarboxylate (7) (R = CH2C6H4-4-Br) [2.6 g, 31% based on methyl 5-(thiocyanate)-2-pyridinecarboxylate (6); mp 108-111 °C] were collected.…”

Section: -[(P-bromobenzylmentioning

confidence: 99%

“…6 Extensive work has been carried out on the isomeric 3-thio-2-pyridinecarboxylic acids because of their hypoglycemic activity. 7 The paucity of work on 5-substituted 2-pyridinecarboxylic acids reflects the synthetic difficulties inherent in the 2,5 orientation of substituents in the pyridine ring. We have recently de-scribed a new route to such compounds.8 Butyl 6methyl-3-pyridyl sulfoxide8 (2) prepared by this route could be nitrosated to the oxime of 5-(butylsulfinyl)-2pyridinecarboxaldehyde (3).…”

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confidence: 99%

Synthesis and antihypertensive activity of 5-thio-2-pyridinecarboxylic acid derivatives

Finch¹,

Campbell²,

Gemenden³

et al. 1978

J. Med. Chem.

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Synthesis of various substituted 5-thio-2-pyridinecarboxylic acids and their derivatives is described by three methods, i.e., displacement of nitrite from methyl 5-nitro-2-pyridinecarboxylate (10) by a thiol anion, alkylation of methyl 5-thio-2-pyridinecarboxylate derived from reaction of the diazotized methyl-5-amino-2-pyridinecarboxylate (5) with thiocyanate followed by borohydride reduction of the product, and alkylation of 5-thio-2-pyridinecarbonitrile followed by hydrolysis. 5-Thio-2-pyridinecarbonitrile was obtained from butyl 6-methyl-3-pyridyl sulfoxide (2) by nitrosation and dehydration of the oxime. Many of these 5-thio-2-pyridinecarboxylic acid derivatives were orally active antihypertensive agents in the spontaneously hypertensive rat. Optimization of the structural parameters for this activity yiedled 5-[m-trifluorobenzyl) thio]-2-pyridinecarboxylic acid (41) and its sulfoxide, 42. Further biological studies with these compounds are described.

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Synthesis and hypoglycemic activity of phenacyltriphenylphosphoranes and phosphonium salts

Cited by 11 publications

References 0 publications

Preclinical Evaluation of Novel Triphenylphosphonium Salts with Broad-Spectrum Activity

Preclinical Evaluation of Novel Triphenylphosphonium Salts with Broad-Spectrum Activity

2,5,5-Trimethylthiazolidine-4-carboxylic acid, a D(-)-penicillamine-directed pseudometabolite of ethanol. Detoxication mechanism for acetaldehyde

Synthesis and antihypertensive activity of 5-thio-2-pyridinecarboxylic acid derivatives

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