53531-68-3Relevant academic research and scientific papers
Design, synthesis and biological evaluation of novel N-sulfonylamidine-based derivatives as c-Met inhibitors via Cu-catalyzed three-component reaction
Fang, Sen-Biao,Li, Hui-Jing,Nan, Xiang,Wu, Rui,Wu, Yan-Chao,Zhang, Jing,Zhang, Zhi-Zhou
, (2020/06/04)
In our continuing efforts to develop novel c-Met inhibitors as potential anticancer candidates, a series of new N-sulfonylamidine derivatives were designed, synthesized via Cu-catalyzed multicomponent reaction (MCR) as the key step, and evaluated for their in vitro biological activities against c-Met kinase and four cancer cell lines (A549, HT-29, MKN-45 and MDA-MB-231). Most of the target compounds showed moderate to significant potency at both the enzyme-based and cell-based assay and possessed selectivity for A549 and HT-29 cancer cell lines. The preliminary SAR studies demonstrated that compound 26af (c-Met IC50 = 2.89 nM) was the most promising compound compared with the positive foretinib, which exhibited the remarkable antiproliferative activities, with IC50 values ranging from 0.28 to 0.72 μM. Mechanistic studies of 26af showed the anticancer activity was closely related to the blocking phosphorylation of c-Met, leading to cell cycle arresting at G2/M phase and apoptosis of A549 cells by a concentration-dependent manner. The promising compound 26af was further identified as a relatively selective inhibitor of c-Met kinase, which also possessed an acceptable safety profile and favorable pharmacokinetic properties in BALB/c mouse. The favorable drug-likeness of 26af suggested that N-sulfonylamidines may be used as a promising scaffold for antitumor drug development. Additionally, the docking study and molecular dynamics simulations of 26af revealed a common mode of interaction with the binding site of c-Met. These positive results indicated that compound 26af is a potential anti-cancer candidate for clinical trials, and deserves further development as a selective c-Met inhibitor.
Alkyne Linchpin Strategy for Drug:Pharmacophore Conjugation: Experimental and Computational Realization of a Meta-Selective Inverse Sonogashira Coupling
Bhowmick, Suman,Guin, Srimanta,Kumar Singh, Vikas,Maiti, Debabrata,Paton, Robert S.,Porey, Sandip,Zhang, Xinglong
supporting information, p. 3762 - 3774 (2020/03/10)
The late-stage functionalization (LSF) of pharmaceutical and agrochemical compounds by the site-selective activation of C-H bonds provides access to diverse structural analogs and expands synthetically-accessible chemical space. We report a C-H functionalization LSF strategy that hinges on the use of an alkyne linchpin to assemble conjugates of sp2-rich marketed pharmaceuticals and agrochemicals with sp3-rich 3D fragments and natural products. This is accomplished through a template-assisted inverse Sonogashira reaction that displays high levels of selectivity for the meta position. This protocol is also amenable to distal structural modifications of α-amino acids. The transformation of alkyne functionality to other functional groups further highlights the applicative potential. Computational and experimental mechanistic studies shed light on the detailed mechanism. Turnover-limiting 1,2-migratory insertion of the bromoalkyne coupling partner occurs after relatively fast C-H activation. While this insertion occurs unselectively, regioconvergence results from one of the adducts undergoing a 1,2-trialkylsilyl migration to form the alkynylated product. A heterobimetallic Pd-Ag transition structure is essential for product formation in the β-bromide elimination step.
Design, synthesis and evaluation of sulfonylurea-containing 4-phenoxyquinolines as highly selective c-Met kinase inhibitors
Nan, Xiang,Jiang, Yi-Fan,Li, Hui-Jing,Wang, Jun-Hu,Wu, Yan-Chao
supporting information, p. 2801 - 2812 (2019/05/15)
Deregulation of receptor tyrosine kinase c-Met has been reported in human cancers and is considered as an attractive target for small molecule drug discovery. In this study, a series of 4-phenoxyquinoline derivatives bearing sulfonylurea moiety were designed, synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against tested four cell lines in vitro. The pharmacological data indicated that most of the tested compounds showed moderate to significant potency as compared with foretinib, with the most promising compound 13x (c-Met kinase IC50 = 1.98 nM) demonstrated relatively good selectivity versus 10 other tyrosine kinases and remarkable cytotoxicities against HT460, MKN-45, HT-29 and MDA-MB-231 with IC50 values of 0.055 μM, 0.064 μM, 0.16 μM and 0.49 μM, respectively. The preliminary structure activity relationships indicated that a sulfonylurea moiety as linker as well as mono-EGWs (such as R1 = 4-F) on the terminal phenyl rings contributed to the antitumor activity.
Rhodium-Catalyzed meta-C?H Functionalization of Arenes
Bera, Milan,Agasti, Soumitra,Chowdhury, Rajdip,Mondal, Rahul,Pal, Debasis,Maiti, Debabrata
supporting information, p. 5272 - 5276 (2017/04/27)
Rhodium-catalyzed ortho-C?H functionalization is well known in the literature. Described herein is the Xphos-supported rhodium catalysis of meta-C?H olefination of benzylsulfonic acid and phenyl acetic acid frameworks with the assistance of a para-methoxy-substituted cyano phenol as the directing group. Complete mono-selectivity is observed for both scaffolds. A wide range of olefins and functional groups attached to arene are tolerated in this protocol.
Palladium-Catalyzed Remote meta-Selective C-H Bond Silylation and Germanylation
Modak, Atanu,Patra, Tuhin,Chowdhury, Rajdip,Raul, Suman,Maiti, Debabrata
supporting information, p. 2418 - 2423 (2017/07/17)
Selective meta-C-H activation of arenes to date has met with a limited number of functionalizations. Expanding the horizon of meta-C-H functionalization, herein we disclose an unprecedented meta-silylation and -germanylation protocol by employing a simple nitrile-based directing template. Longer linkers between the target site and the directing template were successfully explored for meta-silylation (sp2-? and sp2-ζ). Additionally, synthetic utility was demonstrated with several postsynthetic elaborations and with a formal synthesis of TAC101, a promising drug for the treatment of lung cancer.
Synthesis and receptor binding studies of novel 4,4-disubstituted arylalkyl/arylalkylsulfonyl piperazine and piperidine-based derivatives as a new class of σ1 ligands
Sadeghzadeh, Masoud,Sheibani, Shahab,Ghandi, Mehdi,Daha, Fariba Johari,Amanlou, Massoud,Arjmand, Mohammad,Hasani Bozcheloie, Abolfazl
, p. 488 - 497 (2013/07/27)
This study presents the synthesis and biological evaluation of a new series of arylalkyl/arylalkylsulfonyl piperazine and piperidine-based derivatives as sigma receptor ligands. It was found that a number of halogen substituted sulfonamides display relatively high and low affinities to σ1 and σ2 receptors, respectively. The σ1 affinities and subtype selectivities of four piperidine derivatives were also found to be generally comparable to those of piperazine analogues. Compared to σ1-Rs compounds with n = 0 and 2, those with n = 1 proved to have optimal length of carbon chain by exhibiting higher affinities. Within this series, the 4-benzyl-1-(3-iodobenzylsulfonyl)piperidine sigma ligand was identified with 96-fold σ1/σ2 selectivity ratio (Kiσ1 = 0.96 ± 0.05 nM and K iσ2 = 91.8 ± 8.1 nM).
REACTION OF ARYLMETHANESULFONYL AND STYRYLMETHANESULFONYL CHLORIDES WITH TRIETHYLAMINE
Nakayama, Juzo,Tanuma, Mitsuru,Honda, Yoshiko,Hoshino, Masamatsu
, p. 4553 - 4556 (2007/10/02)
A series of arylmethanesulfonyl chlorides were treated with triethylamine in THF to give stilbenes in excellent yields.Workup of the mixtures below 10 deg C permits isolation of stilbene episulfones which on warming decompose to yield the corresponding stilbenes stereospecifically.Application of the reaction to 9-fluorenylsulfonyl chloride affords bifluorenylidene, while trans-styrylmethanesulfonyl chloride gives 4,5-dihydro-4,5-diphenylthiepin 1,1-dioxide and 1,6-diphenylhexatriene.
