22470-99-1Relevant academic research and scientific papers
Nucleotide Delivery from cycloSaligenyl-3′-azido-3′-deoxythymidine Monophosphates (cycloSal-AZTMP)
Meier, Chris,De Clercq, Eric,Balzarini, Jan
, p. 837 - 846 (1998)
The application of our cycloSaligenyl- (cycloSal) pronucleotide concept to the approved anti-HIV dideoxynucleoside 3′-azido-3′-deoxythymidine AZT (1) is reported. This pronucleotide concept has been designed to deliver the corresponding 3′-azido-3′-deoxythymidine monophosphate AZTMP (2) by selective chemical hydrolysis from the lipophilic precursors cycloSal-AZTMP 4a-h. All derivatives 4a-h were synthesized using differently substituted salicyl alcohols 7a-h as starting materials. In hydrolysis studies, compounds 4 decomposed selectively releasing AZTMP (2) and the salicyl alcohols 7 following the designed tandem reaction. Furthermore, due to the electronic properties introduced by substituents, the half-lives of the triesters 4 could be ajusted over a wide range. Phosphotriesters 4 exhibited considerable biological activity in HIV-1 and HIV-2 infected wild-type human T-lymphocyte (CEM/O) cells, whereas, contrary to our expectations, nearly all activity was lost in HIV-2 infected thymidine-kinase-deficient CEM cells.
Efficient Procedure for Preparing Salicyl Alcohols
Belyanin,Filimonov,Krasnov
, p. 103 - 105 (2001)
A new convenient procedure was developed for selective ortho-hydroxymethylation of phenols by reaction of paraformaldehyde with a mixture of phenol and orthoboric acid. The method is general for phenols containing no strong electron-withdrawing substituents; it allows preparation of o-hydroxybenzyl alcohols of high purity in a high yield.
Cyclo-saligenyl-5-fluoro-2′-deoxyuridinemonophosphate (cycloSal-FdUMP), A new prodrug approach for fdump
Lorey, Martina,Meier, Chris,De Clercq, Eric,Balzarini, Jan
, p. 1307 - 1310 (1997)
The synthesis of cycloSal-FdUMP 3a-d as a new prodrug approach for FdU 1 is described. Phosphotriesters 3 release the FdUMP 2 selectively by a controlled, chemically induced tandem reaction in hydrolysis studies. The biological activity (IC50) of cycloSal-phosphotriesters 3 was evaluated in FM3A/O cells and FM3A/TK- cells. Copyright
MAO inhibitory activity of bromo-2-phenylbenzofurans: Synthesis,: in vitro study, and docking calculations
Delogu,Pintus,Mayán,Matos,Vilar,Munín,Fontenla,Hripcsak,Borges,Vi?a
, p. 1788 - 1796 (2017/09/29)
Monoamine oxidase (MAO) is an enzyme responsible for metabolism of monoamine neurotransmitters which play an important role in brain development and function. This enzyme exists in two isoforms, and it has been demonstrated that MAO-B activity, but not MAO-A activity, increases with aging. MAO inhibitors show clinical value because besides the monoamine level regulation they reduce the formation of by-products of the MAO catalytic cycle, which are toxic to the brain. A series of 2-phenylbenzofuran derivatives was designed, synthesized and evaluated against hMAO-A and hMAO-B enzymes. A bromine substituent was introduced in the 2-phenyl ring, whereas position 5 or 7 of the benzofuran moiety was substituted with a methyl group. Most of the tested compounds inhibited preferentially MAO-B in a reversible manner, with IC50 values in the low micro or nanomolar range. The 2-(2′-bromophenyl)-5-methylbenzofuran (5) was the most active compound identified (IC50 = 0.20 μM). In addition, none of the studied compounds showed cytotoxic activity against the human neuroblastoma cell line SH-SY5Y. Molecular docking simulations were used to explain the observed hMAO-B structure-activity relationship for this type of compounds.
2-Phenylbenzofuran derivatives as butyrylcholinesterase inhibitors: Synthesis, biological activity and molecular modeling
Delogu, Giovanna L.,Matos, Maria J.,Fanti, Maura,Era, Benedetta,Medda, Rosaria,Pieroni, Enrico,Fais, Antonella,Kumar, Amit,Pintus, Francesca
, p. 2308 - 2313 (2016/04/20)
A series of 2-phenylbenzofurans compounds was designed, synthesized and evaluated as cholinesterase inhibitors. The biological assay experiments showed that most of the compounds displayed a clearly selective inhibition for butyrylcholinesterase (BChE), while a weak or no effect towards acetylcholinesterase (AChE) was detected. Among these benzofuran derivatives, compound 16 exhibited the highest BChE inhibition with an IC50 value of 30.3 μM. This compound was found to be a mixed-type inhibitor as determined by kinetic analysis. Moreover, molecular dynamics simulations revealed that compound 16 binds to both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of BChE and it displayed the best interaction energy value, in agreement with our experimental data.
Palladium-catalyzed three-component coupling reactions of 2-(cyanomethyl)phenol, aryl halides, and carbon monoxide
Murai, Masahito,Okamoto, Kazuhiro,Miki, Koji,Ohe, Kouichi
supporting information, p. 4432 - 4437 (2015/06/08)
Three-component coupling reactions of 2-(cyanomethyl)phenol, aryl halides, and carbon monoxide (CO) in orthogonal-tandem catalysis were investigated. In the reactions, 2-(cyanomethyl)phenyl esters, which are produced through Pd(PPh3)4-catalyzed alkoxycarbonylation of aryl halides with 2-(cyanomethyl)phenol, undergo cycloisomerization in situ catalyzed by Pd(PCy3)2 as a co-catalyst to give 3-acyl-2-aminobenzofurans. Palladium species with homoleptic tertiary phosphines, such as Pd(PPh3)4 and Pd(PCy3)2, can catalyze the mechanistically distinct reactions in an orthogonal-tandem manner without interference. By switching the base used in this reaction, 3-acyl-2-(N-acylamino)benzofurans were obtained as major products instead of 3-acyl-2-aminobenzofurans. Given that 2-(cyanomethyl)phenols can be synthesized from commercially available salicylic acid derivatives in two steps, the present method thus provides facile access to synthetically useful 3-acyl-2-aminobenzofurans.
Water-promoted ortho-selective monohydroxymethylation of phenols in the NaBO2 system
Li, Hui-Jing,Wu, Ying-Ying,Wu, Qin-Xi,Wang, Rui,Dai, Chun-Yang,Shen, Zhi-Lun,Xie, Cheng-Long,Wu, Yan-Chao
, p. 3100 - 3107 (2014/05/06)
Water-promoted ortho-selective monohydroxymethylation of phenols in the NaBO2 system generates salicyl alcohols in 65-97% yields. A remarkable rate-enhancement by water was observed, and NaBO2 appeared to serve the dual role of a suitable base and an efficient chelating reagent. This protocol possesses many advantages such as short reaction times, expanded substrate scope, and high mono- and regio-selectivities. The experimental results were explained by the calculations based on local ionisation energy minima, leading to a possible reaction mechanism.
Asymmetric induction via short-lived chiral enolates with a chiral C-O axis
Yoshimura, Tomoyuki,Tomohara, Keisuke,Kawabata, Takeo
, p. 7102 - 7105 (2013/06/27)
A novel method has been developed for the asymmetric cyclization of alkyl aryl ethers. The reactions were assumed to proceed via short-lived chiral enolate intermediates with a chiral C-O axis to give cyclic ethers with tetrasubstituted carbon in up to 99% ee. The half-life of racemization of the chiral enolate intermediate was roughly estimated to be ～1 s at -78 C.
Radiolabeled cyclosaligenyl monophosphates of 5-iodo-2′-deoxyuridine, 5-iodo-3′-fluoro-2′,3′-dideoxyuridine, and 3′-fluorothymidine for molecular radiotherapy of cancer: Synthesis and biological evaluation
Kortylewicz, Zbigniew P.,Kimura, Yu,Inoue, Kotaro,MacK, Elizabeth,Baranowska-Kortylewicz, Janina
supporting information; experimental part, p. 2649 - 2671 (2012/06/16)
Targeted molecular radiotherapy opens unprecedented opportunities to eradicate cancer cells with minimal irradiation of normal tissues. Described in this study are radioactive cyclosaligenyl monophosphates designed to deliver lethal doses of radiation to cancer cells. These compounds can be radiolabeled with SPECT- and PET-compatible radionuclides as well as radionuclides suitable for Auger electron therapies. This characteristic provides an avenue for the personalized and comprehensive treatment strategy that comprises diagnostic imaging to identify sites of disease, followed by the targeted molecular radiotherapy based on the imaging results. The developed radiosynthetic methods produce no-carrier-added products with high radiochemical yield and purity. The interaction of these compounds with their target, butyrylcholinesterase, depends on the stereochemistry around the P atom. IC50 values are in the nanomolar range. In vitro studies indicate that radiation doses delivered to the cell nucleus are sufficient to kill cells of several difficult to treat malignancies including glioblastoma and ovarian and colorectal cancers.
Diastereoselective synthesis of cyclosaligenyl-nucleosyl-phosphotriesters
Riosa Morales, Edwuin H.,Balzarini, Jan,Meier, Chris
body text, p. 1649 - 1659 (2011/04/15)
A diastereoselective synthesis of cycloSal-phosphotriesters (cycloSal=cycloSaligenyl) based on chiral auxiliaries has been developed that allows the synthesis of single diastereomers of the cycloSal-pronucleotides. In previously described synthesis routes, the cycloSal-compounds were always obtained as 1:1 diastereomeric mixtures that could be separated in only rare cases. However, it was shown that the diastereomers have different antiviral activity, toxicity, and hydrolysis stabilities. Here, first a chiral thiazoline derivative was used to prepare nonsubstituted and 5-methyl-cycloSal- phosphotriesters in 48 and ≥95%a de (de=diastereomeric excess). However, this approach failed to give the important group of 3-substituted cycloSal-nucleotides. Therefore, two other chiral groups were discovered that allowed the synthesis of (RP)- and (SP)-3-methyl-cycloSal- phosphotriesters as well. The antiviral activity was found to be five- to 20-fold different between the two individual diastereomers, which proved the importance of this approach. Chiral chemical Trojan horses: cycloSal-nucleotides (cycloSal=cycloSaligenyl) of thymidine and cycloSal-pronucleotides of 3′-azido-3′-deoxythymidine (AZT) and 3′-deoxy-2′, 3′-didehydrothymidine (d4T) were prepared by a diastereoselective route for the first time by using a chiral auxiliary approach with up to ≥95%a de (see scheme). The procedure is suitable to synthesize cycloSal-phosphotriesters with different substitution patterns in the aromatic residue.
