81926-24-1Relevant articles and documents
Synthesis and cytotoxic activity of novel tetrahydrobenzodifuran–imidazolium salt derivatives
Zhang, Chao-Bo,Liu, Yang,Liu, Zheng-Fen,Duan, Sheng-Zu,Li, Min-Yan,Chen, Wen,Li, Yan,Zhang, Hong-Bin,Yang, Xiao-Dong
supporting information, p. 1808 - 1814 (2017/04/04)
The synthesis of a series of novel 4-substituted 2,3,6,7-tetrahydrobenzo [1,2-b;4,5-b′]difuran–1H-imidazolium salts is presented. The biological properties of the compounds were evaluated in vitro against a panel of human tumor cell lines. Results suggest that the 5,6-dimethyl-benzimidazole or 2-methyl-benzimidazole ring, and substitution of the imidazolyl-3-position with a 2-naphthylmethyl substituent or 2-naphthylacyl substituent, were important to the cytotoxic activity. Notably, 3-(2-Naphthylmethyl)-1-((2,3,6,7-tetrahydrobenzo[1,2-b;4,5-b′]difuran-4-yl)methyl)-1H-5,6-dimethyl-benzimidazol-3-ium bromide (42) was found to be the most potent derivative against five human tumor cell lines with IC50 values of 1.06–4.34?μM and more selective towards SMMC-7721, A549 and SW480 cell lines. 3-(2-Naphthylacyl)-1-((2,3,6,7-tetrahydrobenzo[1,2-b;4,5-b′]difuran-4-yl)methyl)-1H-2-methyl-benzimidazol-3-ium bromide (37) showed higher selectivity to SMMC-7721 and MCF-7 cell lines with IC50 values 2.7-fold and 8.4-fold lower than DDP. Study regarding to the antitumor mechanism of action showed that compound 37 could induce cell cycle G1 phase arrest and apoptosis in SMMC-7721 cells.
Enantiospecific synthesis and pharmacological evaluation of a series of super-potent, conformationally restricted 5-HT2A/2C receptor agonists
Chambers,Kurrasch-Orbaugh,Parker,Nichols
, p. 1003 - 1010 (2007/10/03)
The affinity of ligands for either the 5-HT2A or 5-HT2C agonist binding site was enhanced by modification of the 2,5-oxygen substituents that are found in typical hallucinogenic amphetamines such as 4b (DOB). Restriction of the conformationally flexible 2,5-dimethoxy substituents into fused dihydrofuran rings generally resulted in increased potency relative to the parent 2,5-dimethoxy compounds. The pure enantiomers of these arylalkylamines were obtained by enantiospecific synthesis that involved acylation of the heterocyclic nucleus 7 with N-trifluoroacetyl-protected D- or L-alanyl chloride, followed by ketone reduction and N-deprotection. The enantiomers demonstrated modest stereoselectivity at the two receptors. Several general trends within these classes of new compounds were observed during their pharmacological investigation. For most pairs of optical isomers tested, the R-enantiomers of the compounds containing heterocycle 7 bound with only slightly higher affinity than their S-antipodes at the 5-HT2A and 5-HT2C receptors. Likewise, functional studies indicated that the R-enantiomers generally displayed increased potency compared to the S-enantiomers. Aromatization of the dihydrofuran rings of these arylalkylamines further increased affinity and potency. Only a few compounds were full agonists with most of them possessing intrinsic activities in the range of 60-80%. These compounds with a fully aromatic linear tricyclic nucleus are some of the highest-affinity ligands for the 5-HT2A receptor reported to date.
Dihydrobenzofuran analogues of hallucinogens. 3. Models of 4-substituted (2,5-dimethoxyphenyl)alkylamine derivatives with rigidified methoxy groups
Monte, Aaron P.,Marona-Lewicka, Danuta,Parker, Matthew A.,Wainscott, David B.,Nelson, David L.,Nichols, David E.
, p. 2953 - 2961 (2007/10/03)
Tetrahydrobenzodifuran functionalities were employed as conformationally restricted bioisosteres of the aromatic methoxy groups in prototypical hallucinogenic phenylalkylamines 1 and 2. Thus, a series of 8-substituted 1- (2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran-4-yl)-2-aminoalkanes (7a-e) were prepared and evaluated for activity in the two-lever drug discrimination paradigm in rats trained to discriminate saline from LSD tartrate (0.08 mg/kg) and for the ability to displace [3H]ketanserin from rat cortical homogenate 5-HT(2A) receptors and [3H]-8-OH-DPAT from rat hippocampal homogenate 5-HT(1A) receptors. In addition, 1-(8-bromo-2,3,6,7- tetrahydrobenzo[1,2-b:4,5-b']difuran-4-yl)-2-aminopropane (7b), which was found to be extremely potent in the rat in vivo assays, was evaluated for its ability to compete with [125I]DOI and [3H]ketanserin binding to cells expressing cloned human 5-HT(2A), 5-HT(2B), and 5-HT(2C) receptors. All of the dihydrofuranyl compounds having a hydrophobic substituent para to the alkylamine side chain had activities in both the in vitro and in vivo assays that equaled or surpassed the activity of the analogous conformationally flexible parent compounds. For example, 7b substituted for LSD in the drug discrimination assay with an ED50 of 61 nmol/kg and had K(i) values in the nanomolar to subnanomolar range for the displacement of radioligand from rat and human 5-HT2 receptors, making it one of the most potent hallucinogen- like phenylalkylamine derivatives reported to date. The results suggest that the dihydrofuran rings in these new analogues effectively model the active binding conformations of the methoxy groups of the parent compounds 1 and 2. In addition, the results provide information about the topography and relative orientation of residues involved in agonist binding in the serotonin 5-HT2 receptors.
Synthesis of Dihydrobenzofurans from Phenolic Mannich Bases and their Quaternized Derivatives
Blade-Font, Artur,Rocabayera, Teodoro de Mas
, p. 841 - 848 (2007/10/02)
Reaction of dimethylsulphoxonium methylide with quaternized derivatives of phenolic Mannich bases, and in certain cases with the bases themselves, constitutes a useful synthesis of dihydrobenzofurans.On the other hand treatment of those same quaternized derivatives with diazomethane may be a useful alternative procedure for the preparation of coumarans with base-sensitive groups.
