- Novel multifunctional acyloxyalkyl ester prodrugs of 5-aminolevulinic acid display improved anticancer activity independent and dependent on photoactivation
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Multifunctional acyloxyalkyl ester prodrugs of 5-aminolevulinic acid in cancer cell lines inhibited the proteasome and induced apoptosis and heme synthesis. The most potent prodrug was butyryloxymethyl 5-amino-4-oxopentanoate (1a). The metabolically released formaldehyde from the prodrugs was the dominant factor affecting cell viability by a ROS-dependent mechanism and was responsible for rapid phosphorylation of H2AX, suppression of the cell survival protein c-myc, and transient elevation in the expression of p21. 1a, which differs from 2a by releasing butyric instead of pivalic acid, was a more potent inducer of heme and acetylated H4 expression and induced apoptosis through activation of caspase 9. 1a and 1b specifically increased the level of the photosensitizer protoporphyrin 9, leading to enhancement of cell death by photodynamic therapy (PDT). The advantage of these multifunctional prodrugs over 5-ALA is their greater potency in the non-PDT mechanism of cancer cell killing and their ability to also augment PDT.
- Berkovitch, Gili,Doron, Dvir,Nudelman, Abraham,Malik, Zvi,Rephaeli, Ada
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- Effects of vehicles and prodrug properties and their interactions on the delivery of 6-mercaptopurine through skin: Bisacyloxymethyl-6-mercaptopurine prodrugs
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A series of S6,9-bisacyloxymethyl-6-mercaptopurine (6,9-bis-6-MP) prodrug derivatives was synthesized and characterized. The solubilities of the derivatives in solvents (vehicles), which exhibited a wide range of polarities from water to oleic acid, were measured. The abilities of the prodrugs to deliver 6-mercaptopurine (6-MP) from the vehicles have also been determined, and experimental fluxes and permeability coefficients (K(p)) have been calculated for a large number of prodrug:vehicle combinations. Generally the best prodrugs of the series in terms of delivering 6-MP, regardless of the vehicle, were the first two members -the bisacetyl- and the bispropionyloxymethyl-6-mercaptopurine prodrugs. This result has been attributed mainly to the increased water solubility of these two prodrugs compared with that of 6-MP and the other prodrugs, since all of the prodrugs are much more lipid soluble than 6-MP. For three vehicles -isopropyl myristate, propylene glycol, and water- there was a good correlation between log experimental K(p) for the delivery of 6-MP by the prodrugs from those vehicles and the theoretical solubility parameters of the prodrugs. The stabilities of the bisacetyl-(2), bispropionyl-(3), and bisbutyryloxymethyl-6-mercaptopurine (4) derivatives were determined in buffer and in buffer containing enzymes leached from the dermis. Prodrug 2 was more stable than 3 or 4 in the buffer containing the enzymes, while 4 was more stable than 2 or 3 in the plain buffer.
- Waranis,Sloan
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- Atmospheric oxidation mechanism of methyl pivalate, (CH3)3CC(O)OCH3
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Smog chamber/FTIR techniques were used to study the Cl atom and OH radical initiated oxidation of methyl pivalate, (CH3)3CC(O)OCH3, in the presence of NOx in 700 torr of N2/O2 diluent at 296 K. The Cl atom initiated oxidation of methyl pivalate in the presence of 15-600 torr of O2 and 10-30 mtorr of NOx in 700 torr total pressure of N2 diluent at 296 K yielded HCHO, CO, acetone, CO2 and CH3OC(O)O2NO2. OH radical initiated oxidation of methyl pivalate in air produced acetone in a 51% yield. Flash photolysis-resonance fluorescence techniques were used to measure the rate constant for the reaction of OH radicals with methyl pivalate at 250-370 K. The rate constant showed a weak temperature dependence, increasing at both low and high temperature from a minimum value of about 1.2 × 10-12 cc/molecule-sec near room temperature. The data obtained were used to formulate a detailed mechanism describing the atmospheric oxidation of methyl pivalate. This mechanism gave predictions of the effects of methyl pivalate on O3 formation and other measures of reactivity that were in good agreement with results of environmental chamber experiments. It should be used in future airshed models to predict the effects of methyl pivalate emissions on air quality.
- Wallington,Ninomiya,Orkin,Carter,Mashino,Huie,Luo,Kawasaki,Kurylo,Malkina
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- Substituted pyrazole compound, preparation method, pharmaceutical composition and applications thereof
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The invention discloses a substituted pyrazole compound represented by a formula I, and a preparation method, a pharmaceutical composition and applications thereof, wherein the compound has characteristics of good stability, excellent solubility, low cytotoxicity and remarkable neuroprotective effect, can effectively prevent and treat nerve cell injury, and is an ideal medicinal compound for preventing or treating cerebral stroke, cerebral embolism, cerebral stroke sequelae, cerebral stroke dyskinesia, mitochondrial encephalomyopathy and amyotrophic lateral sclerosis of spinal cord.
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Paragraph 0152-0155; 0158
(2020/03/12)
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- RODENTICIDAL NORBORMIDE ANALOGUES
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The present invention relates to norbormide analogues having rodenticidal activity; rodenticidal compositions comprising the analogues; uses of the analogues as rodenticides; uses of the analogues in the manufacture of rodenticidal compositions; and methods for controlling rodents using the compositions.
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Page/Page column 76
(2013/09/26)
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- Design and synthesis of prodrugs of the rat selective toxicant norbormide
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Norbormide [5-(α-hydroxy-α-2-pyridylbenzyl)-7-(α-2- pyridylbenzylidene)-5-norbornene-2,3-dicarboximide] (NRB), an existing but infrequently used rodenticide, is known to be uniquely toxic to rats but relatively harmless to other rodents and mammals. However, one major drawback of NRB as a viable rodenticide relates to an evolutionary aversion developed by the rat leading to sub-lethal dosing due to either its unpleasant 'taste' or rapid onset of effects. A series of NRB prodrugs were prepared in an effort to 'mask' this acute response. Their synthesis and biological evaluation (in vitro vasoconstrictory activity, in vitro hydrolytic and enzymatic stability and lethality/palatability in vivo) is described. Compound 19 displayed the most promising profile with respect to a delay in the onset of symptoms and was subsequently demonstrated to be significantly more palatable to rats.
- Rennison, David,Laita, Olivia,Bova, Sergio,Cavalli, Maurizio,Hopkins, Brian,Linthicum, Darwin S.,Brimble, Margaret A.
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supporting information; experimental part
p. 3997 - 4011
(2012/09/08)
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- PRODRUGS OF FUSED HETEROCYCLIC INHIBITORS OF D-AMINO ACID OXIDASE
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The invention relates to prodrugs of fused heterocyclic inhibitors of D-amino oxidase (DAAO) and methods of treating diseases and conditions, wherein modulation of D-amino acid oxidase activity, D-serine levels, D-serine oxidative products and NMDA receptor activity in the nervous system of a mammalian subject is effective.
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Page/Page column 98
(2011/02/26)
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- Design, synthesis, and cholesterol-lowering efficacy for prodrugs of berberrubine
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In order to enhance oral bioavailability of berberine (BBR) for its cholesterol-lowering efficacy in vivo, a series of ester or ether prodrugs of berberrubine (M1), which is an active metabolite of BBR after first-pass metabolism, were designed, semi-synthesized, and evaluated. Among these M1 prodrugs, compound 5g possessing palmitate at the 9-position showed a moderate Log P value and esterase hydrolysis rate for releasing M1 in blood. Its cholesterol-lowering efficacy in vivo was evaluated in hyperlipidemic SD rats. Compound 5g (100 mg/kg/d) reduced blood CHO and LDL-c by 35.8% and 45.5%, respectively, similar to that by BBR. It also exhibited a good safety in rats with no side-effect on liver and kidney function. Therefore, the design of M1 prodrug appears to be an effective strategy to improve pharmacokinetic feature of BBR for its lipid-lowering efficacy in vivo.
- Li, Ying-Hong,Li, Yi,Yang, Peng,Kong, Wei-Jia,You, Xue-Fu,Ren, Gang,Deng, Hong-Bin,Wang, Yue-Ming,Wang, Yan-Xiang,Jiang, Jian-Dong,Song, Dan-Qing
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experimental part
p. 6422 - 6428
(2010/10/04)
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- Prodrugs of protein tyrosine kinase inhibitors
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Novel compounds and salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds in the treatment of protein tyrosine kinase-associated disorders such as oncologic and immunologic disorders.
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Page/Page column 21
(2010/10/20)
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- Bioreversible quaternary N-acyloxymethyl derivatives of the tertiary amines bupivacaine and lidocaine - Synthesis, aqueous solubility and stability in buffer, human plasma and simulated intestinal fluid
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Design of water-soluble prodrugs may constitute a means to improve the oral bioavailability of drugs suffering from dissolution rate-limited absorption. The model drug bupivacaine containing a tertiary amine function has been converted into bioreversible quaternary N-acyloxymethyl derivatives. The pH-independent solubility of the N-butanoyloxymethyl derivate exceeded 1000 mg ml-1 corresponding approximately to a 10,000-fold increase in water solubility compared to that of bupivacaine base. The kinetics of hydrolysis of the prodrugs was studied in the pH range 0.1-9.8 (37°C). Decomposition was found to follow first-order kinetics and U-shaped pH-rate profiles were constructed. The observed differences between the hydrolytic lability of the derivatives might most likely be ascribed to steric effects. In most cases, the prodrugs were quantitatively converted into bupivacaine. However, for the hydrolysis of the N-butanoyloxymethyl derivative at neutral to slightly alkaline pH parallel formation of bupivacaine (～80%) and an unknown compound X (～20%) was observed. LC-MS analysis of the latter compound suggests that an aromatic imide structure has been formed from an intramolecular acyl transfer reaction involving a nucleophilic attack of the amide nitrogen atom on the ester carbonyl carbon atom. Whereas the derivatives were poor substrates for plasma enzymes; they were hydrolyzed rapidly to parent bupivacaine in the presence of pancreatic enzymes (simulated intestinal fluid) at 37°C. The data indicate that such prodrugs possess sufficient stability in the acidic environment of the stomach to reach the small intestine in intact form where they can be cleaved efficiently by action of pancreatic enzymes prior to drug absorption. Thus, the N-acyloxymethyl approach might be of potential utility to enhance oral bioavailability of tertiary amines exhibiting pKa values below approximately 6 and intrinsic solubilities in the low μM range.
- Nielsen, Anders Bach,Buur, Anders,Larsen, Claus
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p. 433 - 440
(2007/10/03)
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- Prodrugs of CL316243: A selective β3-adrenergic receptor agonist for treating obesity and diabetes
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CL316243 is a highly selective and potent β3-adrenergic receptor agonist, and has been shown in rodent models to be an effective agent for treating obesity and Type II diabetes. To improve the oral absorption and pharmacokinetic profiles of CL316243, a number of prodrugs have been synthesized and evaluated. Several ester-type prodrugs show significant improvements in oral bioavailability in both rodent and primate models.
- Sum,Gilbert,Venkatesan,Lim,Wong,O'Dell,Francisco,Chen,Grosu,Baker,Ellingboe,Malamas,Gunawan,Primeau,Largis,Steiner
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p. 1921 - 1926
(2007/10/03)
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- Synthesis of iodoalkylacylates and their use in the preparation of S-alkyl phosphorothiolates
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Synthesis of iodoalkylacylates 3a-f and use of 3c in the preparation of an oligonucleoside phosphorothiate prodrug analog 5 is described.
- Iyer,Yu,Ho,Agrawal
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p. 2739 - 2749
(2007/10/02)
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- Process for producing halomethyl ester of aliphatic carboxylic acid
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The present invention provides a process for producing a halomethyl ester of an aliphatic carboxylic acid in which a metal salt of an aliphatic carboxylic acid is reacted with a dihalomethane in the presence of a phase transfer catalyst, whereby the efficient production of a halomethyl ester of an aliphatic carboxylic acid has been made possible without the formation of a halomethyl ether as a by-product. The bis compound bis[aliphatic carbonyloxy)methane], which is obtained as a by-product, is hydrolyzed to enable the quantitative recovery of an aliphatic carboxylic acid and its reuse. Thus, the present process is preferable as a process for industrial production of a halomethyl ester of an aliphatic carboxylic acid.
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- Synthesis, hydrolytic behavior, and anti-HIV activity of selected acyloxyalkyl esters of trisodium phosphonoformate (foscarnet sodium)
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The synthesis and anti-HIV activity of selected (acyloxy)-alkyl esters of trisodium phosphonoformate (foscarnet sodium) are described. The conversion of bis(trimethylsilyl) (alkoxycarbonyl)phosphonates 11a-d to the corresponding disilver salts 12a-d and their subsequent reaction with iodoalkyl acrylates 4a-c gave the desired bis(acyloxyalkyl) phosphonates 6- 9(a-c). Of the analogs tested, only the dichlorophenyl analog 9a showed a dose-dependent inhibition of HIV activity in H9 cells. Using 31P-NMR, bioreversibility has been investigated in an attempt to rationalize these results.
- Iyer,Boal,Phillips,Thakker,Egan
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p. 1269 - 1273
(2007/10/02)
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- Process for producing a halomethyl pivalate
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A process for producing a halomethyl pivalate which comprises reacting an aqueous solution of a metal salt of pivalic acid with a dihalomethane selected from the group consisting of bromochloromethane, chloroiodomethane and bromoiodomethane in the presence of a phase transfer catalyst.
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- A process for producing haloalkyl alkanoates
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A haloalkyl alkanoate (III) is useful as a reagent for preparing some oral antibacterials. The compound is now found to be preparable economically and safely by treating alkanoic acid salt (I) with 10 equivalents or more of dihaloalkane (II) in 2 to 5 parts by weight of alkanoic acid dialkylamide. (wherein R and R1 each is hydrogen or optionally substituted alkyl, M is a salt forming atom or group, and X and Hal each is halogen)
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- Synthesis of acyloxyalkyl acylphosphonates as potential prodrugs of the antiviral, trisodium phosphonoformate (foscarnet sodium)
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Bis(trimethylsilyl) acylphosphonates via their silver salts couple with iodoalkyl esters to provided an efficient synthesis of the corresponding acyloxyalkyl esters as potential prodrugs of the antiviral agent, trisodium phophonoformate. These compounds were tested as inhibitors of HIV-1 in chronically infected H9 cells.
- Iyer,Phillips,Biddle,Thakker,Egan
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p. 7141 - 7144
(2007/10/02)
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- 2β-Chloromethyl-2α-methylpenam-3α-carboxylic acid sulfone and salts and esters thereof
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2β-Chloromethyl-2α-methylpenam-3α-carboxylic acid sulfone and salts and esters thereof were synthesized and found to be potent inhibitors of β-lactamases.
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- Chlorination of Carboxylic Acid Derivatives. VIII. Liquid Phase Chlorination of the Aliphatic C5-Carboxylic Acids and Their Chlorides, Methyl Esters and Chloromethyl Esters with Chlorine
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The chlorination of pentanoic, 3-methylbutanoic, 2-methylbutanoic and 2,2-dimethylpropanoic acids and their derivatives with chlorine in the liquid phase have been investigated.The monochloro products formed were determined by gas-liquid chromatography (GLC) and gas-liquid chromatography-mass spectrometry (GLC-MS) as their esters through the comparison with authentic samples.The deactivation of position 2 decreases in the order COCl > CO2H > CO2CH2Cl > CO2CH3, the effect of the COCl-group in pentanoic acid derivatives being 4.3 times stronger than that of the CO2CH3-group.The deactivation is smallest in 2-methylbutanoic acid derivatives owing to the electron-donating methyl group.The EI mass spectra of the methyl and chloromethyl esters have been studied in detail.
- Kornonen, Ilpo O. O.
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p. 467 - 474
(2007/10/02)
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- Derivatives of 6-bromo penicillanic acid
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2β-Chloromethyl-2α-methylpenam-3α-carboxylic acid sulfone and salts and esters thereof were synthesized and found to be potent inhibitors of β-lactamases.
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- Sodium β-[2,6-dimethyl-3,5-bis(ethoxycarbonyl)-4-(3-nitrophenyl)-1,4-dihydropyridine-1-yl]ethyl sulfate
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Novel 1-substituted-1, 4-dihydropyridine derivatives, particularly diethyl 1-ethoxymethyl-4-(3-nitrophenyl)-2, 6-dimethyl-1, 4-dihydropyridine-3,5-dicarboxylate are provided. The novel derivatives have cerebral vascular dilator activity with low toxicity.
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