- Synthesis, chiral high performance liquid chromatographic resolution and enantiospecific activity of a potent new geranylgeranyl transferase inhibitor, 2-hydroxy-3-imidazo[1,2-a]pyridin-3-yl-2-phosphonopropionic Acid
-
3-(3-Pyridyl)-2-hydroxy-2-phosphonopropanoic acid (3-PEHPC, 1) is a phosphonocarboxylate (PC) analogue of 2-(3-pyridyl)-1- hydroxyethylidenebis(phosphonic acid) (risedronic acid, 2), an osteoporosis drug that decreases bone resorption by inhibiting farnesyl pyrophosphate synthase (FPPS) in osteoclasts, preventing protein prenylation. 1 has lower bone affinity than 2 and weakly inhibits Rab geranylgeranyl transferase (RGGT), selectively preventing prenylation of Rab GTPases. We report here the synthesis and biological studies of 2-hydroxy-3-imidazo[1,2-a]pyridin-3-yl-2- phosphonopropionic acid (3-IPEHPC, 3), the PC analogue of minodronic acid 4. Like 1, 3 selectively inhibited Rab11 vs. Rap 1A prenylation in J774 cells, and decreased cell viability, but was 33-60 × more active in these assays. After resolving 3 by chiral HPLC (>98% ee), we found that (+)-3-E1 was much more potent than (-)-3-E2 in an isolated RGGT inhibition assay, ～17 × more potent (LED 3 μM) than (-)-3-E2 in inhibiting Rab prenylation in J774 cells and >26× more active in the cell viability assay. The enantiomers of 1 exhibited a 4-fold or smaller potency difference in the RGGT and prenylation inhibition assays.
- McKenna, Charles E.,Kashemirov, Boris A.,B?azewska, Katarzyna M.,Mallard-Favier, Isabelle,Stewart, Charlotte A.,Rojas, Javier,Lundy, Mark W.,Ebetino, Frank H.,Baron, Rudi A.,Dunford, James E.,Kirsten, Marie L.,Seabra, Miguel C.,Bala, Joy L.,Marma, Mong S.,Rogers, Michael J.,Coxon, Fraser P.
-
-
Read Online
- Iodine-mediated aminohalogenation-oxidation to synthesize 2-fluoroalkyl imidazole derivatives
-
A simple and efficient method of iodine-mediated aminohalogenation-oxidation of fluorinated N’-propargyl amidines to synthesize 2-fluoroalkyl imidazole-5-carbaldehydes was developed. This method showed good functional group compatibility and wide substrat
- Li, Shan,Liang, Jian,Liu, Xiaofeng,Xian, Liqing,Du, Mingxu
-
p. 1041 - 1053
(2020/10/02)
-
- Copper- A nd DMF-mediated switchable oxidative C-H cyanation and formylation of imidazo[1,2-: A] pyridines using ammonium iodide
-
The cyanation and formylation of imidazo[1,2-a]pyridines were developed under copper-mediated oxidative conditions using ammonium iodide and DMF as a nontoxic combined cyano-group source and DMF as a formylation reagent. Mechanistic studies indicate that the cyanation of imidazo[1,2-a]pyridines proceeds through a two-step sequence: Initial iodination and then cyanation. The cyanation has a broad substrate scope and high functional group tolerance, and can be safely conducted on a gram scale. A novel copper-mediated formylation using the widely available DMF as the formylation reagent and environmentally friendly molecular oxygen as the oxidant has also been developed. This protocol also provided a convenient approach for the synthesis of clinically used saripidem. This journal is
- Ji, Fanghua,Jiang, Guangbin,Li, Xuan,Liu, Meichen,Wang, Shoucai,Zang, Jiawang
-
p. 9100 - 9108
(2020/11/27)
-
- Method for synthesizing formyl-substituted imidazo[1,2a]pyridine compounds
-
The invention discloses a method for synthesizing formyl-substituted imidazo[1,2a]pyridine compounds. The method is carried out according to the following steps: taking a substituted pyridine allyl amine compound represented by the formula I as an initiat
- -
-
Paragraph 0028-0031
(2019/12/29)
-
- Novel method for constructing imidazolyl[1,2-a]pyridyl-3-aldehyde by taking DMF as formylation reagent
-
The invention discloses a novel method for constructing imidazolyl[1,2-a]pyridyl-3-aldehyde in one step by taking DMF (N,N-dimethylformamide) as a formylation reagent. According to the method, imidazolyl[1,2-a]pyridine serves as a reactant, and the imidazolyl[1,2-a]pyridyl-3-aldehyde is constructed in one step by taking the DMF (N,N-dimethylformamide) as the formylation reagent. According to the method disclosed by the invention, the means of synthesis is novel, the reaction conditions are mild, the reaction reagent is cheap and readily available, the N,N-dimethylformamide can serve as a reaction solvent and also can serve as a formylation reagent, and thus, the method is in line with development requirements of green chemistry.
- -
-
Paragraph 0020-0029
(2019/11/12)
-
- Microwave-assisted synthesis of 3-formyl substituted imidazo[1,2-a]pyridines
-
An efficient, metal-free method for the synthesis of 3-formyl imidazo[1,2-a]pyridines is reported. The method utilises commercially available substrates and features a broad substrate scope. The intermediate enamine was isolated and a plausible reaction mechanism proposed.
- Kusy, Damian,Maniukiewicz, Waldemar,B?a?ewska, Katarzyna M.
-
supporting information
(2019/10/16)
-
- Visible light induced tetramethylethylenediamine assisted formylation of imidazopyridines
-
A metal-free visible light induced C-3 formylation of imidazo[1,2-a]pyridine has been developed using tetramethylethylenediamine (TMEDA) as a one carbon source. An array of 3-formyl imidazo[1,2-a]pyridines with wide functionality are synthesized using rose bengal as a photosensitizer under ambient air.
- Kibriya, Golam,Bagdi, Avik K.,Hajra, Alakananda
-
p. 3473 - 3478
(2018/05/23)
-
- Aerobic iron(III)-catalyzed direct formylation of imidazo[1,2-a]pyridine using DMSO as carbon source
-
A novel and efficient iron(III)-catalyzed C3-formylation reaction of imidazo[1,2-a]pyridine in an oxygen atmosphere has been developed. The method is conducted in dimethyl sulfoxide (DMSO), which serves as both the carbonyl carbon source and solvent, in the presence of acetic acid to directly generate structurally diverse 3-formylimidazo[1,2-a]pyridine derivatives in moderate to good yields.
- Xiang, Shijian,Chen, Huoji,Liu, Qiang
-
supporting information
p. 3870 - 3872
(2016/08/02)
-
- Cu-Catalyzed selective C3-formylation of imidazo[1,2-a]pyridine C-H bonds with DMSO using molecular oxygen
-
Using the widely available DMSO as the formylation reagent under oxidative conditions, an efficient Cu-catalyzed C3-formylation reaction of imidazo[1,2-a]pyridine C-H bonds to directly generate structurally sophisticated 3-formyl imidazo[1,2-a]pyridine derivatives has been developed. The reaction proceeded to generate products in good yields, and used the environmentally friendly molecular oxygen as the oxidant.
- Cao, Hua,Lei, Sai,Li, Naiying,Chen, Longbin,Liu, Jingyun,Cai, Huiyin,Qiu, Shuxian,Tan, Jingwen
-
supporting information
p. 1823 - 1825
(2015/01/30)
-
- Gold-catalyzed synthesis of 3-acylimidazo[1,2-a]pyridines via carbene oxidation
-
A convenient gold-catalyzed strategy for the synthesis of imidazo[1,2-a]pyridine derivatives has been developed via gold carbene complexes. This transformation opens a new synthetic route to a variety of 3-carbonyl-substituted imidazo[1,2-a]pyridines using air as oxidant affording the products in good yields.
- Zhan, Haiying,Zhao, Limin,Liao, Jinqiang,Li, Naiying,Chen, Qinlin,Qiu, Shuxian,Cao, Hua
-
supporting information
p. 46 - 50
(2015/02/19)
-
- Design, synthesis and biological evaluation of acylhydrazone derivatives as PI3K inhibitors
-
Since the PI3K signaling pathway is the most commonly activated in human cancers, inhibition of PI3K is a promising approach to cancer therapy. In this study, a series of 2-methyl-5-nitrobenzeneacylhydrazones were designed and synthesized. All the new der
- Gao, Guo-Rui,Liu, Jia-Li,Mei, De-Sheng,Ding, Jian,Meng, Ling-Hua,Duan, Wen-Hu
-
p. 118 - 120
(2015/01/30)
-
- Transition metal-mediated C=O and C=C bond-forming reactions: A regioselective strategy for the synthesis of imidazo[1,2- A ]pyridines and imidazo[1,2- A ]pyrazines
-
A novel and convenient transformation for the regiospecific synthesis of functionalized imidazo[1,2-a]pyridine aldehydes/ketones and 3-vinyl imidazo[1,2-a]pyridines has been developed via copper(I)- and palladium(II)-catalyzed cyclization. The one-pot reaction proceeds smoothly with commercially available catalysts and affords the products in moderate to good yields. It represents an efficient approach for the formation of C-N, C=O, and C=C bonds under mild conditions.
- Cao, Hua,Liu, Xiaohang,Liao, Jinqiang,Huang, Jianping,Qiu, Huifang,Chen, Qinlin,Chen, Yaoyi
-
p. 11209 - 11214
(2015/01/08)
-
- Silver-catalyzed cyclization of N-(prop-2-yn-1-yl)pyridin-2-amines
-
We report herein the silver-catalyzed cycloisomerization of readily available N-(prop-2-yn-1-yl)pyridine-2-amines as a new and practical method for the synthesis of differently substituted 3-methylimidazo[1,2-a]pyridines. The isomerization reactions proce
- Chioua, Mourad,Soriano, Elena,Infantes, Lourdes,Jimeno, M. Luisa,Marco-Contelles, Jose,Samadi, Abdelouahid
-
-
- Synthesis of imidazo[1,2-a]pyridines: "Water-mediated" hydroamination and silver-catalyzed aminooxygenation
-
Aqueous syntheses of methylimidazo[1,2-a]pyridines without any deliberate addition of catalyst are reported. Imidazo[1,2-a]pyrazine and imidazo[2,1-a]isoquinoline were also obtained in good yields under similar conditions. With acetonitrile as solvent, Ag
- Chandra Mohan, Darapaneni,Nageswara Rao, Sadu,Adimurthy, Subbarayappa
-
supporting information
p. 1266 - 1272
(2013/08/24)
-
- Copper-catalyzed intramolecular dehydrogenative aminooxygenation: Direct access to formyl-substituted aromatic N-heterocycles
-
A direct synthesis of carbaldehydes through intramolecular dehydrogenative aminooxygenation has been developed. The process uses a catalytic amount of copper(II) in DMF or DMA under oxygen and does not require additional oxidants (see scheme). Mechanistic studies suggest that the carbonyl oxygen atom of the aldehyde is derived from oxygen through a copper-mediated oxygen activation process via a peroxy-copper(III) intermediate. Copyright
- Wang, Honggen,Wang, Yong,Liang, Dongdong,Liu, Lanying,Zhang, Jiancun,Zhu, Qiang
-
supporting information; experimental part
p. 5678 - 5681
(2011/08/02)
-
- Synthesis, stereochemistry and SAR of a series of minodronate analogues as RGGT inhibitors
-
Phosphonocarboxylate (PC) analogues of bisphosphonates are of interest due to their selective inhibition of a key enzyme in the mevalonate pathway, Rab geranylgeranyl transferase (RGGT). The dextrarotatory enantiomer of 2-hydroxy-3-(imidazo[1,2-a]pyridin-3-yl)-2-phosphonopropanoic acid (3-IPEHPC, 1) is the most potent PC-type RGGT inhibitor thus far identified. The absolute configuration of (+)-1 in the active site complex has remained unknown due to difficulties in obtaining RGGT inhibitor complex crystals suitable for X-ray diffraction analysis. However, we have now succeeded in crystallizing (-)-1 and here report its absolute configuration (AC) obtained by X-ray crystallography, thus also defining the AC of (+)-1. An Autodock Vina 1.1 computer modeling study of (+)-1 in the active site of modified RGGT binding GGPP (3DSV) identifies stereochemistry-dependent interactions that could account for the potency of (+)-1 and supports the hypothesis that this type of inhibitor binds at the TAG tunnel, inhibiting the second geranylgeranylation step. We also report a convenient 31P NMR method to determine enantiomeric excess of 1 and its pyridyl analogue 2, using α- and β-cyclodextrins as chiral solvating agents, and describe the synthesis of a small series of 1 α-X (X = H, F, Cl, Br; 7a-d) analogues to assess the contribution of the α-OH group to activity at enzyme and cellular levels. The IC50 of 1 was 5-10× lower than 7a-d, and the LED for inhibition of Rab11 prenylation in vitro was 2-8× lower than for 7a-d. However, in a viability reduction assay with J774 cells, 1 and 7b had similar IC50 values, ～10× lower than those of 7a and 7c-d.
- B?aewska, Katarzyna M.,Ni, Feng,Haiges, Ralf,Kashemirov, Boris A.,Coxon, Fraser P.,Stewart, Charlotte A.,Baron, Rudi,Rogers, Michael J.,Seabra, Miguel C.,Ebetino, Frank H.,McKenna, Charles E.
-
experimental part
p. 4820 - 4826
(2011/11/13)
-
- A practical two-step synthesis of imidazo[1,2-a]pyridines from N-(prop-2-yn-1-yl)pyridin-2-amines
-
The Sandmeyer reaction of differently C-2 substituted N-(prop-2-yn-1- ylamino)pyridines is an efficient, mild, new and practical method for the stereospecific synthesis of (E)-exo-halomethylene bicyclic pyridones bearing the imidazo[1,2-a]pyridine heteroc
- Sucunza, David,Samadi, Abdelouahid,Chioua, Mourad,Silva, Daniel B.,Yunta, Cristina,Infantes, Lourdes,Carmo Carreiras,Soriano, Elena,Marco-Contelles, Jose
-
supporting information; experimental part
p. 5043 - 5045
(2011/06/10)
-
- 2-OXO-1-PYRROLIDINE DERIVATIVES
-
The present invention concerns 2-oxo-1 -pyrrolidine derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals.
- -
-
Page/Page column 64; 65
(2008/06/13)
-
- THERAPEUTIC AGENTS I
-
Compounds of formula(I), processes for preparing such compounds, their use in the treatment of obesity, psychiatric disorders, cognitive disorders, memory disorders, schizophrenia, epilepsy, and related conditions, and neurological disorders such as dementia, multiple sclerosis, Parkinson's disease, Huntington's chorea and Alzheimer's disease and pain related disorders, and pharmaceutical compositions containing them.
- -
-
Page/Page column 89-90
(2010/02/12)
-
- Synthesis and electron-transfer reactions of some 3-difluoroacetylated imidazo[1,2-a]pyridine derivatives
-
The synthesis of new 3-chlorodifluoroacetylated imidazo[1,2-a]pyridines 1-6 and their difluoroacetyl derivatives is presented. The reductive cleavage of the halogenated ketones was investigated by cyclic voltammetry, and tetrakis(dimethylamino)ethylene (T
- Burkholder, Conrad,Dolbier Jr., William R.,Médebielle, Maurice,Ait-Mohand, Samia
-
p. 3077 - 3080
(2007/10/03)
-
- Phosphonocarboxylate compounds pharmaceutical compositions, and methods for treating abnormal calcium and phosphate metabolism
-
The present invention relates to compositions comprising pharnaceutically-acceptable carriers and a phosphonocarboxylate, or a pharmaceutically-acceptable salt thereof, having a structure according to formula (I): STR1
- -
-
-
- Synthesis of acyclo-C-nucleosides in the imidazo[1,2-a]pyridine and pyrimidine series as antiviral agents
-
The synthesis and the antiviral activities of C-3 acyclic nucleoside analogues of imidazo[1,2-a]pyridine and pyrimidine are reported. From these compounds, 20, 21, 22, 23, 28, and 34 showed a specific activity against cytomegalovirus and/or varicella-zoster virus.
- Gueiffier, Alain,Lhassani, Mohammed,Elhakmaoui, Ahmed,Snoeck, Robert,Andrei, Graciela,Chavignon, Olivier,Teulade, Jean-Claude,Kerbal, Abdelali,Essassi, El Mokhtar,Debouzy, Jean-Claude,Witvrouw, Myriam,Blache, Yves,Balzarini, Jan,De Clercq, Erik,Chapat, Jean-Pierre
-
p. 2856 - 2859
(2007/10/03)
-
- CHLORAL AS A FORMYLATING AGENT FOR SOME BRIDGE HETEROCYCLES
-
The interaction of condensed nitrogen-containing bridge systems with chloral has been studied and the high sensitivity of the reaction to the ?-excess of the initial heteroaromatic system has been established.It has been shown that chloral is a convenient
- Anisimova, V. A.,Avdyunina, N. I.,Pozharskii, A. F.,Simonov, A. N.,Talanova, L. N.
-
p. 409 - 417
(2007/10/02)
-
