ABSTRACT
Triple negative breast cancer (TNBC) is one of the breast cancers with poorer prognosis and survival rates. TNBC has a disproportionally high incidence and mortality in women of African descent. We report on the evaluation of Ru-IM (1), a water-soluble organometallic ruthenium compound, in TNBC cell lines derived from patients of European (MDA-MB-231) and African (HCC-1806) ancestry (including IC50 values, cellular and organelle uptake, cell death pathways, cell cycle, effects on migration, invasion, and angiogenesis, a preliminary proteomic analysis, and an NCI 60â cell-line panel screen). 1 was previously found highly efficacious in MDA-MB-231 cells and xenografts, with little systemic toxicity and preferential accumulation in the tumor. We observe a similar profile for this compound in the two cell lines studied, which includes high cytotoxicity, apoptotic behavior and potential antimetastatic and antiangiogenic properties. Cytokine M-CSF, involved in the PI3/AKT pathway, shows protein expression inhibition with exposure to 1. We also demonstrate a p53 independent mechanism of action.
Subject(s)
Antineoplastic Agents/pharmacology , Coordination Complexes/pharmacology , Imines/pharmacology , Phosphoranes/pharmacology , Rubidium/pharmacology , Triple Negative Breast Neoplasms/drug therapy , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Cycle/drug effects , Cell Death/drug effects , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Imines/chemistry , Molecular Structure , Phosphoranes/chemistry , Rubidium/chemistry , Structure-Activity Relationship , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/pathologyABSTRACT
Cancer, as one of the leading causes of death in the world, is caused by malignant cell division and growth that depends on rapid DNA replication. To develop anti-cancer drugs this feature of cancer could be exploited by utilizing DNA-damaging molecules. To achieve this, the paraben substituted cyclotetraphosphazene compounds have been synthesized for the first time and their effect on DNA (genotoxicity) has been investigated. The conventional genotoxicity testing methods are laborious, take time and are expensive. Biosensor based assays provide an alternative to investigate this drug/compound DNA interactions. Here for the first time, a new, easy and rapid screening method has been used to investigate the DNA damage, which is based on an automated biosensor device that relies on the real-time electrochemical profiling (REP™) technology. Using both the biosensor based screening method and the in vitro biological assay, the compounds 9 and 11 (propyl and benzyl substituted cyclotetraphosphazene compounds, respectively), have resulted in higher DNA damage than the others with 65% and 80% activity reduction, respectively.
Subject(s)
Biosensing Techniques/instrumentation , DNA Damage/drug effects , Parabens/chemistry , Parabens/pharmacology , Phosphoranes/chemistry , Phosphoranes/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , DNA/genetics , Equipment Design , Humans , Models, Molecular , Mutagenicity Tests , Neoplasms/drug therapy , Neoplasms/genetics , Parabens/chemical synthesis , Phosphoranes/chemical synthesisABSTRACT
Hexachlorocyclotriphosphazene is an old compound which affords very new properties in the field of dendrimers. Indeed, it can be used as a branching point for the rapid synthesis of highly dense dendrimers, but also for the synthesis of dendrimers having precisely one function different from all the others. These types of dendrimers are useful in the field of materials, affording highly reusable catalysts, chemical sensors, or supports for cell cultures. However, the most developed uses concern fluorescence. These dendrimers have been used for in vivo imaging, and for trying to elucidate biological mechanisms, in particular for anti-inflammatory dendrimers. This review will display important examples in the field.
Subject(s)
Dendrimers/chemistry , Phosphoranes/chemistry , Dendrimers/pharmacology , Humans , Nanostructures/chemistry , Phosphoranes/pharmacologyABSTRACT
Unprotected peptidyl phosphoranes 1 with sequence Ac-L-aspartyl-L-glutamyl-L-valinyl-L-aspartyl are released from polymer support and react with aliphatic and aromatic aldehydes in aqueous medium in a Wittig ligation. Obtained vinyl ketones 6-12 are potent inhibitors of caspase-3. Vinyl ketone 6, derived from formaldehyde, undergoes Michael ligations with thiol nucleophiles furnishing products 14-16, also in aqueous medium. The demonstrated ligation reactions enable the modification of complex functionalized peptides in water providing bioactive protein ligands without side-chain protection.
Subject(s)
Caspase 3/drug effects , Caspase Inhibitors/chemistry , Caspase Inhibitors/pharmacology , Oligopeptides/chemistry , Oligopeptides/pharmacology , Phosphoranes/chemistry , Phosphoranes/pharmacology , Caspase Inhibitors/chemical synthesis , Molecular Structure , Oligopeptides/chemical synthesis , Phosphoranes/chemical synthesis , Water/chemistryABSTRACT
The major plant growth regulator ethephon degrades to ethylene and phosphate in aqueous solutions and plants and is spontaneously activated to a butyrylcholinesterase (BChE) inhibitor in alkaline solutions and animal tissues. In the present (31)P NMR kinetic study of the reactions of ethephon in pH 7.4 carbonate buffer, we observed a transient peak at 28.11 ppm. The time course for the appearance and disappearance of this peak matches the activation/degradation kinetic profile of the BChE inhibitor, and the chemical shift supports the proposed 2-oxo-2-hydroxy-1,2-oxaphosphetane structure.
Subject(s)
Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/pharmacology , Organophosphorus Compounds/chemistry , Phosphoranes/pharmacology , Cholinesterase Inhibitors/chemistry , Kinetics , Phosphoranes/chemical synthesis , Phosphoranes/chemistry , Structure-Activity RelationshipABSTRACT
The t-Bu-P4 base was found to be an excellent catalyst for the condensation of trimethylsilylacetate or trimethylacetonitrile with carbonyl compounds to form functionalized alkenes and beta-enaminoesters were also synthesized by the condensation with formanilides.
Subject(s)
Alkenes/chemical synthesis , Carbon/chemistry , Esters/chemical synthesis , Organosilicon Compounds/chemistry , Phosphoranes/pharmacology , Acetonitriles/chemistry , Alkenes/chemistry , Catalysis , Esters/chemistry , Formamides/chemistryABSTRACT
Alkylation of adenine in solution and on solid phase was accelerated by phosphazene base P1-tBu compared to mineral bases. The reactions in solution afforded regioselectively the appropriate N9-alkylated adenines with high preparative yields while the reaction with polystyrene resin-bound N-bromoacetylated peptides gave three regioisomers (alkylated at the N9, N7, and N3 position of adenine) in a 4:2:1 molar ratio. Ten novel nonphosphate nucleotide analogues were tested in an ADP-induced platelet aggregation assay.
Subject(s)
Adenine/chemistry , Adenine/pharmacology , Aziridines/chemistry , Phosphoranes/chemistry , Polystyrenes/chemistry , Purinergic Antagonists , Solutions/chemistry , Adenine/analogs & derivatives , Alkylation , Humans , Phosphoranes/pharmacology , Platelet Aggregation Inhibitors/pharmacology , Stereoisomerism , Time FactorsABSTRACT
The reactions of phosphorus trichloride with various amino acids afford the pentacoordinated spirophosphoranes. The reaction procedures were traced by (31)P NMR spectra techniques. A new crystal structure of alanine derivative was characterized, which is a slightly distorted TBP structure. Besides, this kind of spirophosphoranes are potent inhibitors to tyrosinase.
Subject(s)
Amino Acids/chemistry , Chlorides/chemistry , Enzyme Inhibitors/chemical synthesis , Phosphoranes/chemical synthesis , Phosphorus Compounds/chemistry , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Magnetic Resonance Spectroscopy , Molecular Structure , Monophenol Monooxygenase/antagonists & inhibitors , Phosphoranes/chemistry , Phosphoranes/pharmacologyABSTRACT
In this study we investigated the effects of a series of phosphonium salts and phosphoranes on the catalytic activity of acetylcholinesterase and on the viability of the various life stages of Schistosoma mansoni worms. All the tested compounds showed an inhibitory effect towards the S. mansoni acetylcholinesterase (AChE) activity. The most effective compound, p-xylylene bis(triphenylphosphonium) dibromide (No. 16) displayed approximately 100% inhibition at concentration of 10(-5)-10(-6)M. No significant difference was found in the sensitivity of the enzyme obtained from the various stages of the parasite life cycle to the effect of the drugs. Each compound was also tested for its toxicity towards 3 h old schistosomula and 7-9 week adult worms under in vitro culture conditions. In the case of the larvae, after 2 days in culture, only three compounds (Nos. 4, 11 and 12) out of sixteen tested exhibited efficient killing of the schistosomula while the others had a very slight toxic activity or no toxicity at all. On the other hand, all the compounds showed a significant toxicity towards the adult worms and the most effective one, allytriphenylphosphonium bromide (No. 11), retained its toxic effect even at an extremely high dilution (10(-8)M). However, the cumulative results in this paper do not demonstrate a significant correlation between the inhibitory effect of the phosphonium salts and phosphoranes on the AChE activity of the schistosomes and their toxicity towards the worms. The LD50 value (i.v.) of the compound which showed the highest toxic effect in vitro (No. 11) was found to be 30 +/- 1.7 mg/kg in mice.(ABSTRACT TRUNCATED AT 250 WORDS)
Subject(s)
Acetylcholinesterase/metabolism , Phosphoranes/pharmacology , Schistosoma mansoni/drug effects , Schistosomicides/pharmacology , Trityl Compounds/pharmacology , Animals , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , Phosphoranes/toxicity , Schistosoma mansoni/enzymology , Schistosoma mansoni/growth & development , Schistosomiasis/drug therapy , Schistosomicides/toxicity , Snails , Trityl Compounds/therapeutic use , Trityl Compounds/toxicityABSTRACT
The kinetics of interaction of eel acetylcholinesterase (EC 3.1.1.7) with 1,3,2-dioxaphosphorinane 2-oxides were investigated. It was demonstrated that the rate of spontaneous re-activation as well as the re-activation profile in the presence of 2-pyridine aldoxime methiodide of the inhibited enzyme are irrespective of the leaving group of three inhibitors and exhibit the same values. The dissociation constant of the corresponding Michaelis complex was evaluated by two independent methods and the results were found to be in close agreement. It was shown that the active site is essential for interaction between the enzyme and the various dioxaphosphorinanes. The mixed anhydride of diethyl phosphoric acid and 2-hydroxy-1,3,2-dioxaphosphorinane 2-oxide behaves exactly as would be predicted from a typical diethyl phosphate inhibitor. Enxyme that was incubated with the cyclic acid or the corresponding methyl ester recovered immediately upon extensive dilution. Inhibition of enzyme in the presence of high concentratasions of the corresponding 2-chloro and 2-fluoro derivatives decreased the regeneration rates as well as the maximal amount of the re-activated enzyme. This observation could not be explained in terms of a classical aging process. On the basis of the kinetics observations it is suggested that an unstable covalent phospho-enzyme intermediate is formed during the reaction between acetylcholinesterase and 1,3,2-dioxaphosphorinane 2-oxides.
Subject(s)
Cholinesterase Inhibitors , Cyclic P-Oxides/pharmacology , Electrophorus/metabolism , Phosphoranes/pharmacology , Acetylthiocholine , Animals , Chemical Phenomena , Chemistry , Cholinesterase Reactivators , KineticsABSTRACT
A procedure is described in which an initial small group of compounds is selected, tested, and ordered according to potency. The potency order in the group is then compared to the tabulated potency order calculated for various parameter dependencies relating to hydrophobic, electronic, and steric effects. From this activity pattern analysis the probable operative parameters can be deduced and a new substituent selection made for the synthesis of potentially more potent analogues. Application of the method is illustrated with a series of examples. It differs from a previously described decision tree, single compound stepwise approach in that it involves the batchwise analysis of small groups of compounds, usually the preferred procedure for logistical reasons if the compounds are relatively easy to synthesize.
Subject(s)
Chemistry, Pharmaceutical/methods , Structure-Activity Relationship , Alcohol Oxidoreductases/antagonists & inhibitors , Amphetamines/pharmacology , Anti-Inflammatory Agents/chemical synthesis , Benzamides/pharmacology , Benzene Derivatives/chemical synthesis , Benzene Derivatives/pharmacology , Carbonic Anhydrase Inhibitors/chemical synthesis , Cyclopropanes/pharmacology , Escherichia coli/drug effects , Fibrinolysis/drug effects , Guanine/analogs & derivatives , Guanine/pharmacology , Guanine Deaminase/antagonists & inhibitors , Hypoglycemic Agents/chemical synthesis , Indans/pharmacology , Mitochondria, Liver/drug effects , Passive Cutaneous Anaphylaxis/drug effects , Phenylethanolamine N-Methyltransferase/antagonists & inhibitors , Phenylurea Compounds/pharmacology , Phosphoranes/chemical synthesis , Phosphoranes/pharmacology , Photosynthesis/drug effects , Propionates/pharmacology , Purinones/pharmacology , Sulfonamides/pharmacology , Xanthine Oxidase/antagonists & inhibitorsABSTRACT
A new series of cyclic organophosphorus esters, 2-S-[2'-N,N-dialkylamino)ethyl]thio-1,3,2-dioxaphosphorinane 2-oxide and their quaternary derivatives, was synthesized and studied as potential antiglaucoma agents. Thes compounds inhibit acetylcholinesterase (E.C.3.1.1.7)at a bimoecular rate constant (ki) in the range of 10(3)-10(4) M-1 min-1. Values of the affinity (K) and phosphorylation (k') rate constants for this enzyme indicate that k' is responsible for the relatively low values of ki as compared with similar data for the open-chain analogues, O,O-diethyl phosphorothiolates (10(6) M-1 min-1). The mammalian toxicity of the new compounds in terms of acute LD50 values in mice is 1-3 x 10(3) less than that of phospholine, an open-chain analogue. In an initial clinical trial, one member of the new series (alkyl = C2H5) caused a significant decrease of intraocular pressure in aphakic glaucoma, while phospholine proved to be ineffective.
Subject(s)
Glaucoma/drug therapy , Phosphoranes/chemical synthesis , Animals , Cholinesterase Inhibitors , Eels , Electric Organ/enzymology , Female , Kinetics , Lethal Dose 50 , Mice , Onium Compounds/chemical synthesis , Onium Compounds/pharmacology , Onium Compounds/toxicity , Phosphoranes/pharmacology , Phosphoranes/toxicityABSTRACT
Phenacyl-riphenylphosphorane (1a) and several analogs substituted in the meta position of the phenacyl group lowered blood glucose levels in 48-hr fasted rats. The corresponding phosphonium salts had comparable hypoglycemic activity. Two compounds (1a and 1b) were also hypoglycemic in fed rats, but hypoglycemia could not be elicited in another species.
