- Potent and selective aldo-keto reductase 1C3 (AKR1C3) inhibitors based on the benzoisoxazole moiety: application of a bioisosteric scaffold hopping approach to flufenamic acid
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The aldo-keto reductase 1C3 (AKR1C3) isoform plays a vital role in the biosynthesis of androgens and is considered an attractive target in prostate cancer (PCa). No AKR1C3-targeted agent has to date been approved for clinical use. Flufenamic acid and indomethacine are non-steroidal anti-inflammatory drugs known to inhibit AKR1C3 in a non-selective manner as COX off-target effects are also observed. Recently, we employed a scaffold hopping approach to design a new class of potent and selective AKR1C3 inhibitors based on a N-substituted hydroxylated triazole pharmacophore. Following a similar strategy, we designed a new series focused around an acidic hydroxybenzoisoxazole moiety, which was rationalised to mimic the benzoic acid role in the flufenamic scaffold. Through iterative rounds of drug design, synthesis and biological evaluation, several compounds were discovered to target AKR1C3 in a selective manner. The most promising compound of series (6) was found to be highly selective (up to 450-fold) for AKR1C3 over the 1C2 isoform with minimal COX1 and COX2 off-target effects. Other inhibitors were obtained modulating the best example of hydroxylated triazoles we previously presented. In cell-based assays, the most promising compounds of both series reduced the cell proliferation, prostate specific antigen (PSA) and testosterone production in AKR1C3-expressing 22RV1 prostate cancer cells and showed synergistic effect when assayed in combination with abiraterone and enzalutamide. Structure determination of AKR1C3 co-crystallized with one representative compound from each of the two series clearly identified both compounds in the androstenedione binding site, hence supporting the biochemical data.
- Pippione, Agnese Chiara,Carnovale, Irene Maria,Bonanni, Davide,Sini, Marcella,Goyal, Parveen,Marini, Elisabetta,Pors, Klaus,Adinolfi, Salvatore,Zonari, Daniele,Festuccia, Claudio,Wahlgren, Weixiao Yuan,Friemann, Rosmarie,Bagnati, Renzo,Boschi, Donatella,Oliaro-Bosso, Simonetta,Lolli, Marco Lucio
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Read Online
- Synthesis and evaluation of a ring-constrained Hsp90 C-terminal inhibitor that exhibits neuroprotective activity
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KU-596 is a second-generation C-terminal heat shock protein 90 KDa (Hsp90) modulator based on the natural product, novobiocin. KU-596 has been shown to induce Hsp70 levels and manifest neuroprotective activity through induction of the heat shock response. A ring-constrained analog of KU-596 was designed and synthesized to probe its binding orientation and ability to induce Hsp70 levels. Compound 2 was found to exhibit comparable or increased activity compared to KU-596, which is under clinical investigation for the treatment of neuropathy.
- Zhang, Zheng,You, Zhenyuan,Dobrowsky, Rick T.,Blagg, Brian S.J.
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Read Online
- Ni-Catalyzed Reductive Arylcyanation of Alkenes
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We disclose a Ni-catalyzed reductive arylcyanation of alkene using environmentally benign and nontoxic organo cyanating reagent N-cyano-N-phenyl-p-toluenesulfonamide. This reaction provides a new method for the rapid synthesis of cyano-substituted oxindoles and isoquinoline-1,3-diones and features high functional group tolerance. In addition, an enantioselective version was developed for the construction of enantiomerically enriched 3-cyanomethyl oxindole. This method has also been applied to the synthesis of natural alkaloids (+)-esermethole and (+)-physostigmine.
- Li, Hengxu,Chen, Jiachang,Dong, Jueqi,Kong, Wangqing
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supporting information
p. 6466 - 6470
(2021/08/23)
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- Palladium-Catalyzed Stereoselective Aza-Wacker-Heck Cyclization: One-Pot Stepwise Strategy toward Tetracyclic Fused Heterocycles
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Palladium-catalyzed intramolecular tandem cyclization reactions were conducted for the synthesis of densely cis/cis-fused aza-tetracyclic structures. The process involved a palladium(II)-catalyzed aerobic aza-Wacker reaction, followed by a palladium(0)-catalyzed Heck reaction. The effects of the solvent and benzene substitution pattern on the one-pot, two-step cascade reaction were studied systematically, and a probable mechanism was proposed. Strained pentahydrobenzo[f]cyclopenta[hi]indolizin-6-one and racemic γ-lycorane can also be synthesized rapidly using this palladium-catalyzed aza-Wacker-Heck cyclization reaction.
- Chen, Li-Yuan,Chuang, Ta-Hsien,Lai, Chin-Hung,Tang, Rong-Shiow
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supporting information
p. 9337 - 9341
(2020/12/21)
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- Design, synthesis and biological evaluation of novel 1-phenyl phenanthridin-6(5H)-one derivatives as anti-tumor agents targeting TOPK
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T–lymphokine-activated killer cell–originated protein kinase (TOPK) is a serine-threonine mitogen-activated protein kinase that is highly expressed in many types of human cancer. Due to its important role in cancer progression, TOPK is becoming an attractive target in chemotherapeutic drug design. In this study, a series of 1-phenyl phenanthridin-6(5H)-one derivatives have been identified as a novel chemical class of TOPK inhibitors. Some of them displayed very potent anti-cancer activity with IC50s less than 100 nM, superior than reference compound OTS964. The most potent compound, 9g suppressed the growth of cancer cells by apoptosis and specifically inhibited the activities of TOPK. Oral administration of 9g effectively suppressed tumor growth with TGI >79.7% in colorectal cancer xenograft models, demonstrating superior efficacy compared to OTS964. Pharmacokinetic studies reveal its good oral bioavailability. Our findings therefore show that 9g is a specific inhibitor of TOPK both in vitro and in vivo that may be further developed as a potential therapeutic agent against colorectal cancer.
- Hu, Quan-Fang,Gao, Tian-Tao,Shi, Yao-Jie,Lei, Qian,Liu, Zhi-Hao,Feng, Qiang,Chen, Zhen-Jia,Yu, Luo-Ting
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p. 407 - 422
(2018/11/24)
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- Utilization of BozPhos as an Effective Ligand in Enantioselective C-H Functionalization of Cyclopropanes: Synthesis of Dihydroisoquinolones and Dihydroquinolones
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The bisphosphine monoxide (R,R)-BozPhos enables enantioselective C-H functionalization of cyclopropanes in a palladium-catalyzed cyclization. The synthesis of a broad spectrum of dihydroisoquinolones and dihydroquinolones in good yields and high enantiomeric excess was achieved through the use of this hemilabile ligand. Furthermore, the isolation of an intermediary palladium(II)-BozPhos complex after oxidative addition was successful and a second complex provided further insight into bond length and angles through a crystal structure.
- Mayer, Camilla,Ladd, Carolyn L.,Charette, André B.
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supporting information
p. 2639 - 2644
(2019/04/17)
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- Palladium-catalyzed intramolecular C-H arylation of 2-halo-: N -Boc- N -arylbenzamides for the synthesis of N-H phenanthridinones
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A palladium catalyzed synthesis of N-H phenanthridinones was developed via C-H arylation. The protocol gives phenanthridinones regioselectively by one-pot reaction without deprotection. It exhibits broad substrate scope and affords targets in up to 95% yields. Importantly, it could be applied for the less reactive o-chlorobenzamides.
- Hu, Quan-Fang,Gao, Tian-Tao,Shi, Yao-Jie,Lei, Qian,Yu, Luo-Ting
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p. 13879 - 13890
(2018/04/25)
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- Ni-Catalyzed Alkene Carboacylation via Amide C-N Bond Activation
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We report Ni-catalyzed formal carboacylation of o-allylbenzamides with arylboronic acid pinacol esters. The reaction is triggered by oxidative addition of an activated amide C-N bond to a Ni(0) catalyst and proceeds via alkene insertion into a Ni(II)-acyl bond. The exo-selective carboacylation reaction generates 2-benzyl-2,3-dihydro-1H-inden-1-ones in moderate to high yields (46-99%) from a variety of arylboronic acid pinacol esters and substituted o-allylbenzamides. These results show that amides are practical substrates for alkene carboacylation via amide C-N bond activation, and this approach bypasses challenges associated with alkene carboacylation triggered by C-C bond activation.
- Walker, James A.,Vickerman, Kevin L.,Humke, Jenna N.,Stanley, Levi M.
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supporting information
p. 10228 - 10231
(2017/08/10)
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- Design, synthesis and insecticidal activity of novel anthranilic diamides with benzyl sulfide scaffold
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A series of novel anthranilic diamides with benzyl sulfide scaffold were synthesized, in which N-pyridylpyrazole moiety generally regarded as key pharmacophore was abandoned. The target compounds were characterized by 1H NMR, 13C NMR, 19F NMR and HRMS. The preliminary bioassays indicated that half of the title compounds were endowed with good insecticidal activities against armyworm (Mythimna sepatara) at the concentration of 500 mg/L. Exhilaratingly, the synthesized compound 3a was also active against Tetranychus cinnabarinus at 100 mg/L. The difference in activities between the target compounds was influenced by the substituents, which provided some hints for further investigation on structure modifications.
- Chen, Yin-Bo,Li, Ji-Ling,Shao, Xu-Sheng,Xu, Xiao-Yong,Li, Zhong
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p. 673 - 676
(2013/07/26)
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- Novel one-pot synthesis of xanthones via sequential fluoride ion-promoted fries-type rearrangement and nucleophilic aromatic substitution
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A novel and efficient synthesis of xanthones is described. 2-(Trimethylsilyl)phenyl 2-fluorobenzoate derivatives undergo Fries-type rearrangement and intramolecular SNAr reaction in a one-pot sequential manner under fluoride ion-promoted mild conditions. The method provides efficient access to xanthones that have significant steric congestion around the C9 carbonyl, which are not readily available by conventional methods. Georg Thieme Verlag Stuttgart · New York.
- Fujimoto, Yuuki,Itakura, Ryohei,Hoshi, Hiroki,Yanai, Hikaru,Ando, Yoshio,Suzuki, Keisuke,Matsumoto, Takashi
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supporting information
p. 2575 - 2580
(2013/12/04)
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- Enantioselective synthesis of axially chiral biaryls by the pd-catalyzed suzuki-miyaura reaction: Substrate scope and quantum mechanical investigations
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We report efficient syntheses of axially chiral biaryl amides in yields ranging from 80-92%, and with enantioselectivity in the range 88-94% ee employing an asymmetric Suzuki-Miyaura process with Pd(OAc)2 and KenPhos as ligand. These studies demonstrate that electron-rich and electron-deficient o-halobenzamides can be efficiently coupled with 2-methyl-1-naphthylboronic acid and 2-ethoxy-1-naphthylboronic acid. The yields and selectivities of the reactions are independent of the nature of halogen substituent on the benzamide coupling partner. Our investigations demonstrate that axially chiral heterocyclic and biphenyl compounds can also be synthesized with this methodology. We also report computational studies used to determine the origin of stereoselectivity during the selectivity-determining reductive elimination step of the related coupling of tolyl boronic acid with naphthylphosphonate bromide that was reported in a previous publication (J. Am. Chem. Soc. 2000, 122, 12051-12052). These studies indicate that the stereoselectivity arises from a combination of weak -(C)H??O interactions as well as steric interactions between the tolyl and naphthylphosphonate addends in the transition state for C-C coupling.
- Shen, Xiaoqiang,Jones, Gavin O.,Watson, Donald A.,Bhayana, Brijesh,Buchwald, Stephen L.
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supporting information; experimental part
p. 11278 - 11287
(2010/10/04)
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- BENZOXAZEPINE DERIVATIVES AND USE THEREOF
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Compounds represented by the general formula (I): wherein each symbol is as defined in the description [with the proviso that 9-chloro-7-(1,1-dimethylethyl)-2,3,4,5-tetrahydro-1,4-benz-oxazepine and N-[[(5S)-2-oxo-3-(2,3,4,5-tetrahydro-1,4-benz-oxazepin-7-yl)-5-oxazolidinyl]methyl]acetamide are excluded], salts of the same, and prodrugs thereof have selective activation effect on serotonin 5-HT2C receptor and are useful as preventive and therapeutic agents for lower urinary tract diseases, obesity, and/or pelvic organ prolapse.
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Page/Page column 59
(2009/12/07)
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- NOVEL COMPOUNDS
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The present invention provides compounds of formula (I): a process for their preparation, to pharmaceutical compositions comprising the compounds and the preparation of said compositions, to intermediates and to use of the compounds for the manufacture of a medicament for therapeutic treatment, particularly for the treatment of inflammation, allergy and/or auto-immune conditions.
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Page/Page column 112-113
(2008/06/13)
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