- Novel hybrid conjugates with dual estrogen receptor α degradation and histone deacetylase inhibitory activities for breast cancer therapy
-
Hormone therapy targeting estrogen receptors is widely used clinically for the treatment of breast cancer, such as tamoxifen, but most of them are partial agonists, which can cause serious side effects after long-term use. The use of selective estrogen receptor down-regulators (SERDs) may be an effective alternative to breast cancer therapy by directly degrading ERα protein to shut down ERα signaling. However, the solely clinically used SERD fulvestrant, is low orally bioavailable and requires intravenous injection, which severely limits its clinical application. On the other hand, double- or multi-target conjugates, which are able to synergize antitumor activity by different pathways, thus may enhance therapeutic effect in comparison with single targeted therapy. In this study, we designed and synthesized a series of novel dual-functional conjugates targeting both ERα degradation and histone deacetylase inhibiton by combining a privileged SERD skeleton 7-oxabicyclo[2.2.1]heptane sulfonamide (OBHSA) with a histone deacetylase inhibitor side chain. We found that substituents on both the sulfonamide nitrogen and phenyl group of OBHSA unit had significant effect on biological activities. Among them, conjugate 16i with N-methyl and naphthyl groups exhibited potent antiproliferative activity against MCF-7 cells, and excellent ERα degradation activity and HDACs inhibitory ability. A further molecular docking study indicated the interaction patterns of these conjugates with ERα, which may provide guidance to design novel SERDs or PROTAC-like SERDs for breast cancer therapy.
- Zhao, Chenxi,Tang, Chu,Li, Changhao,Ning, Wentao,Hu, Zhiye,Xin, Lilan,Zhou, Hai-Bing,Huang, Jian
-
-
- Metal-free synthesis of biaryls from aryl sulfoxides and sulfonanilides via sigmatropic rearrangement
-
Treatment of aryl sulfoxides and sulfonanilides with trifluoroacetic anhydride resulted in the dehydrative metal-free construction of the corresponding unsymmetrical biaryls. The reaction would proceed via (1) the activation of aryl sulfoxide with the anhydride, (2) interrupted Pummerer reaction of the resulting arylsulfonium with sulfonanilide, (3) [3,3] sigmatropic rearrangement to cleave the transient S–N bond and to form the prospective biaryl C–C bond, and (4) global aromatization. The choice of the amino protecting group is crucial, and only N-sulfonylanilines, i.e., sulfonanilides, could participate in the formation of biaryls.
- Yoshida, Akira,Okamoto, Koichi,Yanagi, Tomoyuki,Nogi, Keisuke,Yorimitsu, Hideki
-
-
- Exploring the PROTAC degron candidates: OBHSA with different side chains as novel selective estrogen receptor degraders (SERDs)
-
As the mutant estrogen receptor (ER) continues to be characterized, breast cancer is becoming increasingly difficult to cure when treated with hormone therapy. In this regard, a strategy to selectively and effectively degrade the ER might be an effective alternative to endocrine therapy for breast cancer. In a previous study, we identified a novel series of 7-oxabicyclo[2.2.1]heptene sulfonamide (OBHSA) compounds as full ER antagonists while lacking the prototypical ligand side chain that has been widely used to induce antagonism of ERα. Further crystal structure studies and phenotypic assays revealed that these compounds are selective estrogen receptor degraders (SERDs) with a new mechanism of action. However, from a drug discovery point of view, there still is room to improve the potency of these OBHSA compounds. In this study, we have developed new classes of SERDs that contain the OBHSA core structure and different side chains, e.g., basic side chains, long alkyl acid side chains, and glycerol ether side chains, to simply mimic the degrons of proteolysis targeting chimera (PROTAC) and then investigated the structure-activity relationships of these PROTAC-like hybrid compounds. These novel SERDs could effectively inhibit MCF-7 cell proliferation and demonstrated good ERα degradation efficacy. Among the SERDs, compounds 17d, 17e and 17g containing a basic side chain with a N-trifluoroethyl substituent and a para methoxyl group at the phenyl group of the sulfonamide turned out to be the best candidates for ER degraders. A further docking study of these compounds with ERα elucidates their structure-activity relationships, which provides guidance to design new PROTAC degrons targeting ER for breast cancer therapy. Lastly, easy modification of these PROTAC-like SERDs enables further fine-tuning of their pharmacokinetic properties, including oral availability.
- Li, Yuanyuan,Zhang, Silong,Zhang, Jing,Hu, Zhiye,Xiao, Yuan,Huang, Jian,Dong, Chune,Huang, Shengtang,Zhou, Hai-Bing
-
-
- Carbon-Carbon Bond Formation of Trifluoroacetyl Amides with Grignard Reagents via C(O)-CF3 Bond Cleavage
-
The reaction of trifluoroacetyl amides with Grignard reagent for the substitution of CF3 group with various alkyl or aryl groups is described. A variety of aryl, quinolin-8-yl, and (hetero)alkyl functional groups as well as F, Cl, and Br atoms are well tolerated. These moisture-stable and easily available trifluoroacetyl amides can be conveniently obtained and used as new versatile precursors for isocyanates. The control experiments show that the reaction proceeds via an isocyanate intermediate and/or alkoxide/amide dual anionic intermediate.
- Zhu, Longzhi,Le, Liyuan,Yan, Mingpan,Au, Chak-Tong,Qiu, Renhua,Kambe, Nobuaki
-
p. 5635 - 5644
(2019/05/10)
-
- Synthetic method of trifluoroacetanilide derivative
-
The invention belongs to the technical field of organic synthetic intermediate, and more specifically relates to a method used for catalytic synthesis of a trifluoroacetanilide derivative under catalytic effect of copper. The method comprises following steps: 1, dimethyl sulfoxide, an aniline derivative, ethyl trifluoropyruvate, and cuprous chloride are delivered into a pressure-resistant reaction tube, the pressure-resistant reaction tube is sealed with a plug, and reaction is carried out for 12h in oil bath at 80 DEG C with magnetic stirring; 2, after reaction, extraction is carried out with ether, obtained organic phase substances are mixed, and reduced pressure distillation is carried out so as to remove most of the solvents, and an obtained mixed solution is subjected to column chromatography separation purification with an eluent composed of petroleum ether and ethyl acetate at a volume ratio of 2:1-10:1 so as to obtain a finished product. The trifluoroacetanilide derivative can be widely used in the fields such as organic synthesis, medicine industry, and pesticide industry; cost is low; operation is simple; the substances are widely available; yield is high; and application prospect is promising.
- -
-
Paragraph 0015-0017
(2017/09/01)
-
- A simple and efficient method for trifluoroacetylation of arylamines using trifluoroacetic acid and triphosgene
-
A simple and efficient one-pot procedure for trifluoroacetylation of arylamines using trifluoroacetic acid and triphosgene is reported. A mixed trifluoroacetic anhydride generated in situ reacts with a variety of arylamines to give the corresponding trifluroacetamides in high yields.
- Han, Ki-Jong,Kim, Misoo
-
experimental part
p. 559 - 561
(2012/06/04)
-
- Switching reaction pathways of trifluoromethylated thiobenzanilides by choice of different oxidative systems
-
Trifluoromethylated thiobenzanilides are efficiently converted to 2-trifluoromethylbenzothiazoles via intramolecular oxidative cyclization under CAN/NaHCO3 oxidation, while the dimerized products with "-S-S-" bond linkage are obtained when PIDA
- Zhu, Jiangtao,Xie, Haibo,Li, Shan,Chen, Zixian,Wu, Yongming
-
p. 306 - 309
(2011/06/20)
-
- A one-pot procedure for trifluoroacetylation of arylamines using trifluoroacetic acid as a trifluoroacetylating reagent
-
A convenient procedure for the preparation of aryl trifluoroacetamides from aryl amines is described that employs 2-4 M equiv of trifluoroacetic acid in refluxing xylene as a trifluoroacetylating agent. Addition of an amount of pyridine that is equimolar to the amount of trifluoroacetic acid present in the reaction mixture facilitates the trifluoroacetylation of rather basic arylamines.
- Ohtaka, Junpei,Sakamoto, Takeshi,Kikugawa, Yasuo
-
experimental part
p. 1681 - 1683
(2009/09/05)
-
- One-pot synthesis of highly functionalized stable ketenimines of 2,2,2-trifluoro-N-aryl-acetamides
-
Three-component reaction of alkyl isocyanides and dialkyl acetylenedicarboxylates in the presence of 2,2,2-trifluoro-N-aryl-acetamides in dichloromethane at ambient temperature afforded dialkyl 2-(N-(aryl)-2,2,2-trifluoroacetamido)-3-(alkylimino) methylene-succinate derivatives in excellent yields.
- Anary-Abbasinejad, Mohammad,Moslemine, Mohammad H.,Anaraki-Ardakani, Hossein
-
experimental part
p. 368 - 371
(2009/12/01)
-
- Copper-catalyzed synthesis of primary arylamines from aryl halides and 2,2,2-trifluoroacetamide
-
A catalytic method was developed to synthesize primary arylamines from the corresponding aryl bromides and iodides under mild conditions (yields = 80-99%). Crystalline 2,2,2-trifluoroacetamide was used as ammonia surrogate and CuI/N,N′-dimethyl ethylenediamine was used as catalyst to achieve the C-N cross-coupling.
- Tao, Chuan-Zhou,Li, Juan,Fu, Yao,Liu, Lei,Guo, Qing-Xiang
-
-
- Trifluoroacetylation of arylamines using poly-phosphoric acid trimethylsilylester (PPSE)
-
A new, simple and useful procedure is described for the trifluoroacetylation of arylamines using trifluoroacetic acid and poly-phosphoric acid trimethylsilylester (PPSE) as the condensation agent.
- López, Simón E.,Pérez, Yelsi,Restrepo, Jelem,Salazar, José,Charris, Jaime
-
p. 566 - 569
(2007/12/27)
-
- Pd-catalyzed amidations of aryl chlorides using monodentate biaryl phosphine ligands: A kinetic, computational, and synthetic investigation
-
We present results on the amidation of aryl halides and sulfonates utilizing a monodentate biaryl phosphine-Pd catalyst. Our results are in accord with a previous report that suggests that the formation of κ2- amidate complexes is deleterious to the effectiveness of a catalyst for this transformation and that their formation can be prevented by the use of appropriate bidentate ligands. We now provide data that suggest that the use of certain monodentate ligands can also prevent the formation of the κ2-amidate complexes and thereby generate more stable catalysts for the amination of aryl chlorides. Furthermore, computational studies shed light on the importance of the key feature(s) of the biaryl phosphines (a methyl group ortho to the phosphorus center) that enable the coupling to occur. The use of ligands that possess a methyl group ortho to the phosphorus center allows a variety of aryl and heteroaryl chlorides with various amides to be coupled in high yield.
- Ikawa, Takashi,Barder, Timothy E.,Biscoe, Mark R.,Buchwald, Stephen L.
-
p. 13001 - 13007
(2008/09/17)
-
- Direct microwave promoted trifluoroacetylation of aromatic amines with trifluoroacetic acid
-
A simple microwave-promoted procedure has been developed for the direct preparation of trifluoroacetanilides. An equimolar mixture of substituted anilines and trifluoroacetic acid was microwave irradiated at short reaction times, giving the corresponding anilides in high yields and purity.
- Salazar, José,López, Simón E.,Rebollo, Oscar
-
p. 111 - 113
(2007/10/03)
-
- Nickel catalyzed addition of -NH- containing compounds to vinyl and aryl halides
-
A process for producing unsaturated nitrogen containing compounds such as enamides, enamines and aryl amines/amides is disclosed. A vinyl halide or aryl halide is reacted with an -NH- containing compound in the presence of a catalytic amount of a catalyst precursor composition comprising zero-valent nickel and an organophosphine ligand. One step coupling of vinyl halides and aryl halides with -NH- containing compounds is made possible by practice of this invention.
- -
-
-
- A new, convenient and selective 4-dimethylaminopyridine-catalyzed trifluoroacetylation of anilines with ethyl trifluoroacetate
-
A new, convenient, and selective 4-dimethylaminopyridine-catalyzed trifluoroacetylation of anilines with ethyl trifluoroacetate is described. Anilines, containing other functional groups, e.g. alcohols, phenols, hindered secondary amines, and secondary anilines, are also selectively trifluoroacetylated in high yields under these newly developed conditions. (C) 2000 Elsevier Science Ltd.
- Prashad,Hu,Har,Repic,Blacklock
-
p. 9957 - 9961
(2007/10/03)
-
- A convenient synthesis of Trifluoroacetamides from sodium trifluoroacetate and amines
-
Trifluoroacetamides were prepared readily by reaction of sodium trifluoroacetate with triphenylphosphine di-iodide and amines consecutively under mild conditions with good yields.
- Zhou, Qi-Zhong,Chen, Zhen-Chu
-
p. 3189 - 3194
(2007/10/03)
-
- A novel synthesis of isocyanates and ureas via β-elimination of haloform
-
A novel synthesis of isocyanates via base-induced β-elimination of haloform from N-monosubstituted trihaloacetamides is described. The rate of reaction exhibits a strong dependence on the nature of the trihalomethyl group. Thus, while the reaction of tribromoacetamides proceeds at room temperature and the reaction of trichloroacetamides requires heating in polar solvents, no reaction could be observed for any of the corresponding trifluoro derivatives. This novel β-elimination of haloform from stable and readily available trihaloacetamides was applied to a 'one-pot' synthesis of ureas which avoids the use of phosgene and isolation of isocyanates.
- Braverman,Cherkinsky,Kedrova,Reiselman
-
p. 3235 - 3238
(2007/10/03)
-
- Microwave-promoted trifluoroacetylation of amines with TiO(CF3CO2)2
-
Conversion of amines to their corresponding trifluoroacetamides was performed with TiO(CF3CO2)2 in a conventional microwave oven under solvent-free conditions in excellent yields.
- Iranpoor, Nasser,Zeynizadeh, Behzad
-
p. 124 - 125
(2007/10/03)
-
- Novel generation of phenylnitrenium ions from S,S-dialkylanilinosulfonium salts in trifluoroacetic acid and formation of anilines by a new intramolecular hydride-shift to the phenylnitrenium ions
-
Reactions of S,S-dialkylanilinosulfonium salts in trifluoroacetic acid give anilines, trifluoroacetanilides and dialkyl sulfoxides via novel intramolecular hydride-shift from the α-C-H of sulfide to phenylnitrenium ions (not completely free from the sulfide) interacting with both the unshared electron pair of the sulfide and the counter ion.
- Takeuchi, Hiroshi,Taniguchi, Tomohito,Masuzawa, Mamoru,Isoda, Kazuya
-
p. 1743 - 1746
(2007/10/03)
-
- Generation and Reaction of (N-Aryltrifluoroacetimidoyl)zinc Halide
-
(N-Aryltrifluoroacetimidoyl)zinc halides were easily generated at room temparature by the oxidative addition of imidoyl halides to activated zinc powder. zinc halides react with aldehydes to give the corresponding alcohols smoothly to excellent yields.These adducts could be readily transformed to the α-amino ketones.
- Tamura, Kenji,Yan, Fengyang,Sakai, Takashi,Uneyama, Kenji
-
p. 300 - 303
(2007/10/02)
-
- 2-(Trifluoroacetyloxy)pyridine as a Mild Trifluoroacetylating Reagent of Amines and Alcohols
-
A new trifluoroacetylating reagent, 2-(trifluoroacetyloxy)pyridine (TFAP), was prepared by the reaction of 2-pyridinol and trifluoroacetic anhydride.TFAP has been found to be effective in the trifluoroacetylation of aliphatic and aromatic amines and alcohols including phenol under mild conditions.The reaction of p-nitrophenol with TFAP in ether gave the hydrogen-bonded complex between the phenol and 2-pyridone.This reagent has also been shown to be useful for the intramolecular dehydration of aldehyde oximes and amides to give nitriles in high yields.
- Keumi, Takashi,Shimada, Masakazu,Morita, Toshio,Kitajima, Hidehiko
-
p. 2252 - 2256
(2007/10/02)
-
- Synthesis of 1-Trifluoroacetyl-3-dialkylaminomethyl-5-monosubstituted Benzimidazoline-2-thiones using Trifluoroacetic Acid as an Acylating Agent
-
1-Trifluoroacetyl-3-dialkylaminomethyl-5-monosubstituted benzimidazoline-2-thiones have been synthesized from p-substituted anilines which were acetylated with trifluoroacetic acid.The trifluoroacetanilides were nitrated, reduced and cyclised with carbon
- Joshi, Krishna C.,Misra, Ram A.,Jain, Renuka,Sharma, Kanti
-
p. 409 - 412
(2007/10/02)
-
- Process for preparing 6H-pyrido[1,2-c][1,3,5]benzothiadiazepines and benzooxadiazepines and derivatives
-
Compounds of the formula SPC1 Exhibit central nervous system stimulating properties and act as muscle relaxants.
- -
-
-
- Pyridine containing compounds
-
Compounds of the formula SPC1 And tautomers thereof, wherein R, R', R", Z, m and n are as defined hereinafter, exhibit central nervous system stimulating properties and act as muscle relaxants.
- -
-
-