- Hybrid inhibitors of DNA and HDACs remarkably enhance cytotoxicity in leukaemia cells
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Chlorambucil is a nitrogen mustard-based DNA alkylating drug, which is widely used as a front-line treatment of chronic lymphocytic leukaemia (CLL). Despite its widespread application and success for the initial treatment of leukaemia, a majority of patients eventually develop acquired resistance to chlorambucil. In this regard, we have designed and synthesised a novel hybrid molecule, chloram-HDi that simultaneously impairs DNA and HDAC enzymes. Chloram-HDi efficiently inhibits the proliferation of HL-60 and U937 leukaemia cells with GI50 values of 1.24 μM and 1.75 μM, whereas chlorambucil exhibits GI50 values of 21.1 μM and 37.7 μM against HL-60 and U937 leukaemia cells, respectively. The mechanism behind its remarkably enhanced cytotoxicity is that chloram-HDi not only causes a significant DNA damage of leukaemia cells but also downregulates DNA repair protein, Rad52, resulting in the escalation of its DNA-damaging effect. Furthermore, chloram-HDi inhibits HDAC enzymes to induce the acetylation of α-tubulin and histone H3.
- Liu, Kwang-Hyeon,Park, Sun You,Seo, Young Ho,Song, Yoojin,Wu, Zhexue
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Read Online
- A metal-free desulfurizing radical reductive C-C coupling of thiols and alkenes
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An intermolecular reductive C-C coupling of electrophilic alkyl radicals and alkenes has been developed. Thiols were used as both hydrogen-donating reagents and alkyl radical precursors in the presence of triethyl phosphite and radical initiator. A wide range of alkenes, including styrenes, and aliphatic olefins were well tolerated in this transformation. Mechanistic studies indicated that a phosphite promoted radical desulfurization of thiols to access electrophilic alkyl radicals and a radical chain propagation process may be involved in this transformation.
- Qin, Qixue,Wang, Weijing,Zhang, Cheng,Song, Song,Jiao, Ning
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supporting information
p. 10583 - 10586
(2019/09/06)
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- HETEROARYL INHIBITORS OF PDE4
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The present invention relates to compounds and methods useful as inhibitors of phosphodiesterase 4 (PDE4) for the treatment or prevention of disease.
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Paragraph 0722
(2014/05/24)
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- ANDROGEN RECEPTOR ANTAGONISTS AND USES THEREOF
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Disclosed are substituted thioimidazolidinone compounds and pharmaceutical compositions comprising such compounds. The compounds and compositions can be used for treatment of androgen receptor-associated diseases or disorders, such as prostate cancer, benign prostatic hypertrophy, male hair loss and hypertrichosis.
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Page/Page column 85
(2012/09/22)
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- Histone deacetylase inhibitors
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This invention relates to novel Histone deacetylases inhibitors. Also disclosed is a method for treating mucositis or cancer with these inhibitors.
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Page/Page column 8
(2011/12/03)
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- Synthesis, structural activity-relationships, and biological evaluation of novel amide-based allosteric binding site antagonists in NR1A/NR2B N-methyl-d-aspartate receptors
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The synthesis and structure-activity relationship analysis of a novel class of amide-based biaryl NR2B-selective NMDA receptor antagonists are presented. Some of the studied compounds are potent, selective, non-competitive, and voltage-independent antagonists of NR2B-containing NMDA receptors. Like the founding member of this class of antagonists (ifenprodil), several interesting compounds of the series bind to the amino terminal domain of the NR2B subunit to inhibit function. Analogue potency is modulated by linker length, flexibility, and hydrogen bonding opportunities. However, unlike previously described classes of NR2B-selective NMDA antagonists that exhibit off-target activity at a variety of monoamine receptors, the compounds described herein show much diminished effects against the hERG channel and α1-adrenergic receptors. Selections of the compounds discussed have acceptable half-lives in vivo and are predicted to permeate the blood-brain barrier. These data together suggest that masking charged atoms on the linker region of NR2B-selective antagonists can decrease undesirable side effects while still maintaining on-target potency.
- Mosley, Cara A.,Myers, Scott J.,Murray, Ernest E.,Santangelo, Rose,Tahirovic, Yesim A.,Kurtkaya, Natalie,Mullasseril, Praseeda,Yuan, Hongjie,Lyuboslavsky, Polina,Le, Phuong,Wilson, Lawrence J.,Yepes, Manuel,Dingledine, Ray,Traynelis, Stephen F.,Liotta, Dennis C.
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p. 6463 - 6480
(2011/03/17)
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- Salicylate-urea-based soluble epoxide hydrolase inhibitors with high metabolic and chemical stabilities
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We investigated N-adamantyl-N′-phenyl urea derivatives as simple sEH inhibitors. Salicylate ester derivatives have high inhibitory activities against human sEH, while the free benzoic acids are less active. The methyl salicylate derivative is a potent sEH inhibitor, which also has high metabolic and chemical stabilities; suggesting that such inhibitors are potential lead molecule for bioactive compounds acting in vivo.
- Kasagami, Takeo,Kim, In-Hae,Tsai, Hsing-Ju,Nishi, Kosuke,Hammock, Bruce D.,Morisseau, Christophe
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supporting information; experimental part
p. 1784 - 1789
(2009/12/03)
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- CARBOXYLIC DERIVATIVES FOR USE IN THE TREATMENT OF CANCER
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The invention provides novel compounds of formula (I), wherein: R1 is a radical derived from one of the known ring systems; R2 is a phenyl radical optionally substituted; Xn represents a birradical selected from the group consisting of: -(CH2)1-4-, (C2-C4)-alkenyl, (C2-C4)alkynyl, -S-(CH2)1-3-#, and -(CH2)1-3-O-#; wherein the symbol # indicates the position at which Xn is attached to R1; Yn is a birradical selected from the group consisting of: -(CH2)2-4-, -S-(CH2)1-3#, and -O-(CH2)1-3-#,; where in the symbol # indicates the position at which Yn is attached to R2; and R3 is a radical selected from the group consisting of: -OR4. The compounds of formula (I) are useful in the treatment of cancer
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Page/Page column 52
(2009/07/25)
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- Inhibitors of histone deacetylase
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The invention relates to the inhibition of histone deacetylase. The invention provides compounds and methods for inhibiting histone deacetylase enzymatic activity. The invention also provides compositions and methods for treating cell proliferative diseases and conditions.
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- NAPHTHALENE AMIDES HAVING LEUKOTRIENE-ANTAGONISTIC ACTION
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Naphthalene amides of formula (I) wherein the substituent containing A is bound to the 6- or 7- position of the 2-naphthol system; the substituent containing B is bound to the benzene ring at any free position; R is hydrogen or methyl; R is hydrogen, fluorine, chlorine or -OCH3, which is bound to the naphthalene system at any positions except the 2- and the one occupied by the other substituent; R is hydrogen, fluorine, chlorine or bromine; A- is -CO-NR- or -NR-CO- group, wherein R is hydrogen or methyl; B is a 5-tetrazolyl or -COOR group, wherein R is hydrogen, a (C1-C4)-alkyl or a phenylalkyl group of less than 10 carbon atoms; m is 0 or 1; n and p are integers from 0 to 6, with the proviso that n + p is less or equal to 6; as well as the solvates and pharmaceutically acceptable salts thereof, have leukotriene antagonistic action.
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- Design and synthesis of a novel class of histone deacetylase inhibitors.
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Histone deacetylase inhibitors (HDACs) have emerged as a novel class of antiproliferative agents. Utilizing structure-based design, the synthesis of a series of sulfonamide hydroxamic acids is described. Further optimization of this series by substitution of the terminal aromatic ring yielded HDAC inhibitors with good in vitro and in vivo activities.
- Lavoie,Bouchain,Frechette,Woo,Abou-Khalil,Leit,Fournel,Yan,Trachy-Bourget,Beaulieu,Li,Besterman,Delorme
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p. 2847 - 2850
(2007/10/03)
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- Synthesis of 4-[3′-bis(2″-chloroethyl) aminophenyl] -4,4-difluorobutanoic acid [4,4-difluoro-meta-chlorambucil]
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The synthetic sequence to make 4-[4′-bis(2″-chloroethyl)aminophenyl]-4,4-difluorobutanoic acid {4,4-difluorochlorambucil} was not taken beyond the intermediate stage involving methyl 4,4-difluoro-4-(4′-aminophenyl) butanoate, since this amine was hydrolytically unstable. Reaction of methyl 4-(3′-nitrophenyl)-4-oxobutanoate with sulfur tetrafluoride, followed by hydrogenation, afforded the stable isomer, methyl 4,4-difluoro-4-(3′-aminophenyl)butanoate. Bis(hydroxyethylation) by treatment with oxirane, conversion of OH to Cl by Ph3P/ CCl4, and then hydrolysis of the ester group, gave 4-[3′-bis(2″-chloroethyl)aminophenyl]-4,4-difluorobutanoic acid {4,4-difluoro-meta-chlorambucil}.
- Buss, Christopher W.,Coe, Paul L.,Tatlow, John Colin
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p. 119 - 126
(2007/10/03)
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- Quinazoline derivatives possessing anti-tumor activity
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The invention relates to quinazoline derivatives, or pharmaceutically-acceptable salts thereof, which possess anti-tumor activity; to processes for their manufacture; and to pharmaceutical compositions containing them. The invention provides a quinazoline of the formula: STR1 wherein R1 is hydrogen or amino, or alkyl or alkoxy each of up to 6 carbon atoms; or R1 is substituted alkyl or alkoxy each of up to 3 carbon atoms; R2 is hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, halogenoalkyl or cyanoalkyl each of up to 6 carbon atoms; Ar is phenylene or heterocyclene; L is a group of the formula --CO.NH--, --NH.CO--, --CO.NR3 --, --NR3. CO--, --CH=CH--, --CH2 O--, --OCH2, --CH2 S--, --SCH2 --, --CO.CH2 --, --CH2.CO-- or --CO.O--, wherein R3 is alkyl of up to 6 carbon atoms; and Y is aryl or heteroaryl or a hydrogenated derivative thereof: or Y is a group of the formula --A--Y1 in which A is alkylene, cycloalkylene, alkenylene or alkynylene each of up to 6 carbon atoms and Y1 is aryl or heteroaryl or a hydrogenated derivative thereof; or a pharmaceutically-acceptable salt thereof.
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- DNA-Directed Alkylating Agents. 3. Structure-Activity Relationships for Acridine-Linked Aniline Mustards: Consequences of Varying the Length of the Linker Chain
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Four series of acridine-linked aniline mustards have been prepared and evaluated for in vitro cytotoxicity, in vivo antitumor activity, and DNA cross-linking ability.The anilines were attached to the DNA-intercalating acridine chromophores by link groups (-O-, -CH2-, -S-, and -SO2-) of widely varying electronic properties, providing four series of widely differing mustard reactivity where the alkyl chain linking the acridine and mustard moieties was varied from two to five carbons.Relationships were sought between chain length and biological properties.Within eachseries, increasing the chain length did not alter the reactivity of the alkylating moiety but did appear to position it differently on the DNA, since cross-linking ability (measured by agarose gel assay) altered with chain length, being maximal with the C4 analogue.The in vivo antitumor activities of the compounds dependend to some extent on the reactivity of the mustard, with the least reactive SO2 compounds being inactive.However, DNA-targeting did appear to allow the use of less reactive mustards, since the S-linked acridine mustards showed significant activity whereas the parent S-mustard did not.Within each active series, the most active compound was the C4 homologue, suggesting some relationship between activity and extent of DNA alkylation.
- Valu, Kisione K.,Gourdie, Trudi A.,Boritzki, Theodore J.,Gravatt, G. Lance,Baguley, Bruce C.,et al.
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p. 3014 - 3019
(2007/10/02)
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- 1-Aryl-3-(2-chloroethyl) ureas: Synthesis and in vitro assay as potential anticancer agents
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1-Aryl-3-(2-chlorethyl) ureas and 1-aryl-3-nitrose-3-(2-chloroethyl) ureas, derived from 4-phenylbutyric acid and alkylanillines, were synthesized and their cytotoxicity was evaluated on human adenocarcinoma cells in vitro. Methyl 4-[p-[3-(2-chloroethyl)ureido]-phenyl]butyrate, 4-methyl [3-(2-chloroethyl)ureido]benzene, and 4-butyl[3-(2-chloroethyl)ureido]benzene were found to be at least as cytotoxic as 4-[p-[bis-(2-chloroethyl)amino]phenyl]butyric acid (chlorambucil), while their N-nitrose derivatives were inactive.
- Gaudreault,lacroix,Page,Joly
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p. 185 - 187
(2007/10/02)
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- Mass spectrometry of chlorambucil, its degradation products, and its metabolite in biological samples
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A sensitive and specific method for the determination of chlorambucil and its metabolite in biological fluids is reported. The method is based on selected-ion monitoring detection following simple extraction of the parent compound, its metabolite, and an internal standard (chlorambucil-d8) from plasma and urine samples. The precision (reproducibility) of the method was 94.3 ± 1.3% with 200 ng of chlorambucil added to 1 ml of plasma. Chlorambucil degradation or alkylation of plasma proteins was minimal with plasma incubated at 24° for 4 hr. However, chlorambucil recovery decreased to 56% after plasma incubation at 37° for 4 hr. Three chlorambucil degradation products in ethyl acetate solution were found, and their structures were studied by mass spectrometry.
- Chang,Larcom,Alberts,Larsen,Walson,Sipes
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