- The in vitro metabolism of phospho-sulindac amide, a novel potential anticancer agent
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Phospho-sulindac amide (PSA) is a novel potential anti-cancer and anti-inflammatory agent. Here we report the metabolism of PSA in vitro. PSA was rapidly hydroxylated at its butane-phosphate moiety to form two di-hydroxyl-PSA and four mono-hydroxyl-PSA metabolites in mouse and human liver microsomes. PSA also can be oxidized or reduced at its sulindac moiety to form PSA sulfone and PSA sulfide, respectively. PSA was mono-hydroxylated and cleared more rapidly in mouse liver microsomes than in human liver microsomes. Of eight major human cytochrome P450s (CYPs), CYP3A4 and CYP2D6 exclusively catalyzed the hydroxylation and sulfoxidation reactions of PSA, respectively. We also examined the metabolism of PSA by three major human flavin monooxygenases (FMOs). FMO1, FMO3 and FMO5 were all capable of catalyzing the sulfoxidation (but not hydroxylation) of PSA, with FMO1 being by far the most active isoform. PSA was predominantly sulfoxidized in human kidney microsomes because FMO1 is the dominant isoform in human kidney. PSA (versus sulindac) is a preferred substrate of both CYPs and FMOs, likely because of its greater lipophilicity and masked-COOH group. Ketoconazole (a CYP3A4 inhibitor) and alkaline pH strongly inhibited the hydroxylation of PSA, but moderately suppressed its sulfoxidation in liver microsomes. Together, our results establish the metabolic pathways of PSA, identify the major enzymes mediating its biotransformations and reveal significant inter-species and inter-tissue differences in its metabolism.
- Xie, Gang,Cheng, Ka-Wing,Huang, Liqun,Rigas, Basil
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Read Online
- Enantioselective synthesis of Sulindac
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A highly enantioselective synthesis of Sulindac, a non-steroidal anti-inflammatory, is reported using the asymmetric Kagan sulfoxidation as key step.
- Maguire,Papot,Ford,Touhey,O'Connor,Clynes
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Read Online
- Catalyst-free visible light-mediated selective oxidation of sulfides into sulfoxides under clean conditions
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A facile and efficient visible-light-mediated method for directly converting sulfides into sulfoxides under clean conditions without using any photocatalysts is reported. This method exhibited favourable compatibility with functional groups and afforded a series of sulfoxides with high selectivity and yields. Moreover, in order to shed more light on such a transformation, detailed mechanism studies were carried out both experimentally and theoretically. The readily accessible, low-cost and eco-friendly nature of the developed method will endow it with attractive applications in chemical synthesis.
- Fan, Qiangwen,Zhu, Longwei,Li, Xuhuai,Ren, Huijun,Wu, Guorong,Zhu, Haibo,Sun, Wuji
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supporting information
p. 7945 - 7949
(2021/11/01)
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- Design, synthesis, and biological evaluation of novel sulindac derivatives as partial agonists of PPARγ with potential anti-diabetic efficacy
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Peroxisome proliferator-activated receptor gamma (PPARγ) is a valuable drug target for diabetic treatment and ligands of PPARγ have shown potent anti-diabetic efficacy. However, to overcome the severe side effects of current PPARγ-targeted drugs, novel PPARγ ligands need to be developed. Sulindac, an identified ligand of PPARγ, is widely used in clinic as a non-steroidal anti-inflammatory drug. To explore its potential application for diabetes, we designed and synthesized a series of sulindac derivatives to investigate their structure-activity relationship as PPARγ ligand and potential anti-diabetic effect. We found that meta-substitution in sulindac's benzylidene moiety was beneficial to PPARγ binding and transactivation. Z rather than E configuration of the benzylidene double bond endowed derivatives with the selectivity of PPARγ activation. The indene fluorine is essential for binding and regulating PPARγ. Compared with rosiglitazone, compound 6b with benzyloxyl meta-substitution and Z benzylidene double bond weakly induced adipogenesis and PPARγ-targeted gene expression. However, 6b potently improved glucose tolerance in a diabetic mice model. Unlike rosiglitazone, 6b was devoid of apparent toxicity to osteoblastic formation. Thus, we provided some useful guidelines for PPARγ-based optimization of sulindac and an anti-diabetic lead compound with less side effects.
- Huang, Fengyu,Zeng, Zhiping,Zhang, Weidong,Yan, Zhiqiang,Chen, Jiayun,Yu, Liangfa,Yang, Qian,Li, Yihuan,Yu, Hongyu,Chen, Junjie,Wu, Caisheng,Zhang, Xiao-kun,Su, Ying,Zhou, Hu
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- Integrating hydrogen production with anodic selective oxidation of sulfides over a CoFe layered double hydroxide electrode
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Replacing the sluggish oxygen evolution reaction (OER) with oxidation reactions for the synthesis of complex pharmaceutical molecules coupled with enhanced hydrogen evolution reaction (HER) is highly attractive, but it is rarely explored. Here, we report an electrochemical protocol for selective oxidation of sulfides to sulfoxides over a CoFe layered double hydroxide (CoFe-LDH) anode in an aqueous-MeCN electrolyte, coupled with 2-fold promoted cathodic H2productivity. This protocol displays high activity (85-96% yields), catalyst stability (10 cycles), and generality (12 examples) in selective sulfide oxidation. We demonstrate its applicability in the synthesis of four important pharmaceutical related sulfoxide compounds with scalability (up to 1.79 g). X-ray spectroscopy investigations reveal that the CoFe-LDH material evolved into amorphous CoFe-oxyhydroxide under catalytic conditions. This work may pave the way towards sustainable organic synthesis of valuable pharmaceuticals coupled with H2production.
- Ma, Lina,Zhou, Hua,Xu, Ming,Hao, Peipei,Kong, Xianggui,Duan, Haohong
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p. 938 - 945
(2021/02/06)
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- Green synthesis method of sulindac
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The invention discloses a green synthesis method of sulindac and relates to the technical field of organic synthesis. The method comprises the following steps that: 6-fluoro-2-methyl indanone as a rawmaterial and cyanoacetic acid undergo a Knoevenagel reaction to obtain an intermediate 3, the intermediate 3 and p-methylthiobenzaldehyde undergo a Knoevenagel reaction to obtain an intermediate 4, the intermediate 4 undergoes a hydrolysis decarboxylation reaction to obtain an intermediate 5, and the intermediate 5 undergoes an oxidation reaction to obtain sulindac 1. Compared with an existing synthesis process, the process operation is greatly simplified, the raw material utilization rate and the process environmental protection property are improved, the total yield of sulindac reaches 80%or above, and the purity of sulindac reaches 99% or above.
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- Preparation method of 5-fluoro-2-methyl-1-(4-methylthiobenzene methylene)-3-indene acetonitrile and sulindac
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The invention provides a preparation method of 5-fluoro-2-methyl-1-(4-methylthiobenzene methylene)-3-indene acetonitrile and sulindac, and relates to the technical field of medicines. The preparationmethod provided by the invention comprises the following steps: mixing 6-fluoro-2-methyl-1-indanone, cyanoacetic acid, a first organic solvent and an acetate catalyst to carry out a first condensationreaction so as to obtain a first condensation reaction solution, the first condensation reaction solution comprising 5-fluoro-2-methyl-3-indene acetonitrile; and directly mixing the first condensation reaction solution with alkali, a second organic solvent and p-methylthiobenzaldehyde, and carrying out a second condensation reaction to obtain the 5-fluoro-2-methyl-1-(4-methylthiobenzene methylene)-3-indene acetonitrile. According to the method, a one-pot method is adopted to shorten a synthesis route, separation of the 5-fluoro-2-methyl-3-indene acetonitrile from a solvent is not needed, theprocess is simplified, and the yield of the 5-fluoro-2-methyl-1-(4-methylthiobenzene methylene)-3-indene acetonitrile is increased.
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- Sulfoxide and sulfone compounds, as well as selective synthesis method and application thereof
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The invention discloses a method for selectively synthesizing a sulfoxide compound shown as a formula (II) and a sulfone compound shown as a formula (III). In a reaction solvent, thioether (I) is usedas a reaction raw material and oxygen as an oxidation reagent, under the catalytic action of visible light and a photosensitive reagent; under the assistance of an additive, when a large-polarity proton-containing additive such as an acid and an alcohol or a solvent or an additive with excellent electron donating ability is used, a sulfoxide compound (II) is selectively generated; and when a small-polarity aprotic additive or a solvent is used, a sulfone compound (III) is selectively generated. The synthesis method has the advantages of easily available and cheap raw materials, simple reaction operation, mild reaction conditions, high yield and excellent functional group tolerance. According to the invention, synthesis and modification of some medicines are realized, and an efficient method for selectively constructing sulfoxide and sulfone compounds is provided for medicinal chemistry research.
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Paragraph 0045-0048; 0186-0189
(2019/12/02)
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- Selective Late-Stage Oxygenation of Sulfides with Ground-State Oxygen by Uranyl Photocatalysis
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Oxygenation is a fundamental transformation in synthesis. Herein, we describe the selective late-stage oxygenation of sulfur-containing complex molecules with ground-state oxygen under ambient conditions. The high oxidation potential of the active uranyl cation (UO22+) enabled the efficient synthesis of sulfones. The ligand-to-metal charge transfer process (LMCT) from O 2p to U 5f within the O=U=O group, which generates a UV center and an oxygen radical, is assumed to be affected by the solvent and additives, and can be tuned to promote selective sulfoxidation. This tunable strategy enabled the batch synthesis of 32 pharmaceuticals and analogues by late-stage oxygenation in an atom- and step-efficient manner.
- Li, Yiming,Rizvi, S. Aal-e-Ali,Hu, Deqing,Sun, Danwen,Gao, Anhui,Zhou, Yubo,Li, Jia,Jiang, Xuefeng
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supporting information
p. 13499 - 13506
(2019/08/21)
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- Method for preparing sulindac
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The invention relates to the technical field of medicine composition and in particular relates to a method for preparing sulindac. The method comprises the following steps: mixing 5-fluorine-2-methyl-1-(4-methyl thiobenzene methylene)-3-indene acetic acid, a photosensitizer, an oxidant and a reaction solvent, and carrying out an oxidation reaction under an ultraviolet radiation condition, therebyobtaining sulindac, wherein the 5-fluorine-2-methyl-1-(4-methyl thiobenzene methylene)-3-indene acetic acid comprises an E-shaped isomer and a Z-shaped isomer. By adopting the method provided by the invention, the sulindac is prepared from the 5-fluorine-2-methyl-1-(4-methyl thiobenzene methylene)-3-indene acetic acid of the E-shaped isomer and the Z-shaped isomer as raw materials through the oxidation reaction directly, separation purification is avoided, and the operation is simple. Experiment results of the embodiment show that when the sulindac is prepared by using the method provided by the invention, the yield is up to 98.9%, the purity is greater than 99.5%, and the method has the advantages of being high in yield and good in purity.
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Paragraph 0040-0054
(2019/08/01)
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- Treatment of genitourinary tract disorders
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Genitourinary system disorders are treated with therapeutic agents, and optionally further with radiation treatments.
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- Process for the preparation of organic compounds containing a sulfinyl or sulfonyl group
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A process for the oxidation of thioethers to sulfoxides or sulfones or for the oxidation of sulfoxides to sulfones by treatment of thioethers or sulfoxides with an oxidizing amount of ε-phthalimidoperhexanoic acid is particularly useful for the preparation of compounds of industrial interest, in particular pharmaceuticals for human or veterinary use.
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- Process for the preparation of organic compounds containing a sulfinyl or sulfonyl group in the presence of epsilon-phthalimidoperhexanoic acid
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A process for the oxidation of thioethers to sulfoxides or sulfones or for the oxidation of sulfoxides to sulfones by treatment of thioethers or sulfoxides with an oxidizing amount of ε-phthalimidoperhexanoic acid is particularly useful for the preparation of compounds of industrial interest, in particular pharmaceuticals for human or veterinary use.
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- Treatment of genitourinary tract disorders
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Genitourinary system disorders are treated with therapeutic agents, and optionally further with radiation treatments.
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- Esters and amides of substituted indenyl acetic acids
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Esters and amides of substituted indenyl acetic acids of the formula: n is an integer of at least 2;, Q is a deprotonated residue of polymer or macromolecular structure having a molecular weight of at least about 1000 containing at least two primary and/or secondary amino groups and/or hydroxy groups;, R1 is selected from hydrogen, lower alkyl, or haloalkyl;, R2 is selected from hydrogen or alkyl;, R3 and R4 are one or more members each independently chosen from hydrogen, alkyl, acyloxy, alkoxy, nitro, amino, acylamino, alkylamino, diakylamino, dialkylaminoalkyl, sulfamyl, alkythio, mercapto, hydroxy, hydroxyalkyl, alkylsulfonyl, halogen, cyano, carboxyl, carbalkoxy, carbamido, haloalkyl or cycloalkoxy; and, R5 is selected from alkylsulfenyl, alkylsulfinyl or alkylsulfonyl. are useful in the treatment of colonic polyps.
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- Prodrug derivatives of carboxylic acid drugs
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Novel ester derivatives of carboxylic acid medicaments of formula (I), wherein R--COO--represents the acyloxy residue of a carboxylic acid drug or medicament, n is an integrer from 1 to 3, and R1 and R2 are the same or different and are selected from a group consisting of an alkyl, an alkenyl, an aryl, an aralkyl, a cycloalkyl and which group may be unsubstituted or substituted, or R1 and R2 together with the N forms a 4-, 5-, 6- or 7-membered heterocyclic ring, which in addition to the nitrogen atom may contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and which heterocyclic group may be substituted. These compounds are highly biolabile prodrug forms of the corresponding carboxylic acid compounds and are highly susceptible to undergoing enzymatic hydrolysis in vivo whereas they are highly stable in aqueous solution. The novel derivatives are less irritating to mucosa than the parent carboxylic acids and may provide an improved bio-availability of the drugs.
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- High molecular weight prodrug derivatives of antiinflammatory drugs
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Compounds of the formula 1, PS - O - A - (CH2)n- B - D (1), wherein PS-O represents an alkoxide residue of any of the free hydroxy groups of a polysaccharide (PS-OH) compound with molecular weight (Mw) of from 40,000 to 5,000,000 selected from dextran, carboxymethyl dextran, diethylaminoethyl dextran, starch, hydroxyet-hyl starch, alginates, glycogen, pullullan, agarose, cellulose, chitosan, chitin and carrageenan,A is a carbonyl group or absent,n is zero or a positive integer from 1 to 14,B is oxygen, a carbonyl group, NR wherein R is hydrogen or lower alkyl, or B is absent, and, D is (i) a group of the formula:, R1 - CO - (11), wherein R1-CO- represents the acyl residue of a carboxylic acid drug (R1-COOH) used in the treatment of inflammatory disorders; or (ii) a group of the formula:, R2 - O - (12), wherein R2-O- refers to the C-21 alkoxide residue of a known antiinflammatory steroid (R2-OH) or an alkoxide residue of any other drug or medicament containing a hydroxy functional group used in the treatment of inflammatory disorders; with the proviso that when A is absent, n is 0, and B is absent, then R1-CO- is different from the acyl residue of acetylsalicylic acid;, and non-toxic pharmaceutically acceptable acid addition salts thereof;, and non-toxic pharmaceutically acceptable cation salts thereof. Such compounds are biolabile prodrugs providing controlled release and prolonged duration of action of the parent active antiinflamma-tory agents locally at the administration site after intra-articular, intra-muscular, subcutaneous or extra-dural application while at the same time being highly stable in aqueous solution in the pH range 3--5. After oral administration of such prodrugs the parent drug is liberated selectively in the terminal ileum and the colon over an extended period of time.
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- Esters and amides containing the 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetyl moiety
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Compounds of the formula STR1 wherein each X, which may be identical or different from the other X, is oxygen or imino; R1 is hydrogen, fluorine, chlorine or bromine; R2 and R3, which may be identical or different from each other, are each hydrogen; unsubstituted or mono-substituted alkyl of 1 to 6 carbon atoms, where the substituent is phenyl or dialkylamino with 1 to 3 carbon atoms in each alkyl moiety; pyridyl; or cycloalkyl of 5 to 7 carbon atoms; R2 and R3, together with each other and the nitrogen atoms to which they are attached, are pyrrolidino, piperidino, hexamethyleneimino, morpholino, N-aryl-piperazino or N-(alkyl of 1 to 3 carbon atoms)-piperazino; A is cycloalkylene of 5 to 7 carbon atoms; unsubstituted or substituted alkylene of 2 to 10 carbon atoms, where the substituents are one to two alkyls of 1 to 3 carbon atoms each, one to two carbalkoxys of 2 to 4 carbon atoms each, one to two phenyls, one to four hydroxyls, one halomethyl, one hydroxymethyl, one alkanoyloxy of 1 to 18 carbon atoms, one alkanoyloxymethyl of 1 to 18 carbon atoms in the alkanoyl moiety or one STR2 where R1, R2 and R3 have the meanings previously defined; or alkylene of 2 to 10 carbon atoms interrupted by oxygen, sulfur, sulfoxide, sulfonyl, phenyl, cyclohexyl, pyridyl, piperazino or unsubstituted or substituted imino, where the substituent on the imino group is alkyl of 1 to 6 carbon atoms, phenyl or phenylalkyl of 1 to 3 carbon atoms in the alkyl moiety; B is the acyl residue of an antiphlogistic carboxylic acid; and their non-toxic, pharmacologically acceptable acid addition salts. The compounds as well as their salts are useful as anti-inflammatories.
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