946-39-4Relevant academic research and scientific papers
New tranylcypromine derivatives containing sulfonamide motif as potent LSD1 inhibitors to target acute myeloid leukemia: Design, synthesis and biological evaluation
Cen, Meifeng,Du, Yongliang,Ganesan, A.,Huang, Peng,Liang, Liyun,Luo, Bingling,Meng, Ning,Wang, Haiwen,Wen, Shijun
, (2020)
Lysine-specific demethylase 1 (LSD1) is frequently elevated in acute myeloid leukemia (AML) and often leads to tumorigenesis. In recent years, numerous LSD1 inhibitors based on tranylcypromine (TCP) scaffolding have reached clinical trials. Most TCP derivatives were modified at the amino site of cyclopropane motif. Herein, we for the first time introduced a sulfonamide group in TCP benzene ring of series a compounds and performed a systematical study on structure and activity relationships by varying sulfonamide groups. The introduction of sulfonamide significantly increased the targeting capacity of TCP against LSD1. Moreover, we discovered that the Boc attached LSD1 inhibitors (labelled as series b compounds) substantially improved their anti-proliferation capacity towards AML cells. The intracellular thermal shift and LC-MS/MS results implied that Boc enhanced the drug lipophilicity and might be removed under the cancerous acidic environment to release the real pharmacophore, evidenced by the fact that a structurally similar but acidic inert pivaloyl to replace Boc dramatically dropped the cellular anti-proliferation effect. Finally, a benzyl group installed at the amino site to appropriately increase lipophilicity led to trans-4-(2-(benzylamino)-cyclopropyl)-N,N-diethylbenzenesulfonamide a10 that showed better anti-proliferation activity in AML cells and enzymatic inhibition against LSD1. Taken together, our work offers a novel TCP-based structure and provides a prodrug strategy for the discovery of potent LSD1 inhibitors by having appropriate lipophilicity.
Electrochemical Ring-Opening Dicarboxylation of Strained Carbon-Carbon Single Bonds with CO2: Facile Synthesis of Diacids and Derivatization into Polyesters
Liao, Li-Li,Wang, Zhe-Hao,Cao, Ke-Gong,Sun, Guo-Quan,Zhang, Wei,Ran, Chuan-Kun,Li, Yiwen,Chen, Li,Cao, Guang-Mei,Yu, Da-Gang
supporting information, p. 2062 - 2068 (2022/02/10)
Diacids are important monomers in the polymer industry to construct valuable materials. Dicarboxylation of unsaturated bonds, such as alkenes and alkynes, with CO2 has been demonstrated as a promising synthetic method. However, dicarboxylation of C-C single bonds with CO2 has rarely been investigated. Herein we report a novel electrochemical ring-opening dicarboxylation of C-C single bonds in strained rings with CO2. Structurally diverse glutaric acid and adipic acid derivatives were synthesized from substituted cyclopropanes and cyclobutanes in moderate to high yields. In contrast to oxidative ring openings, this is also the first realization of an electroreductive ring-opening reaction of strained rings, including commercialized ones. Control experiments suggested that radical anions and carbanions might be the key intermediates in this reaction. Moreover, this process features high step and atom economy, mild reaction conditions (1 atm, room temperature), good chemoselectivity and functional group tolerance, low electrolyte concentration, and easy derivatization of the products. Furthermore, we conducted polymerization of the corresponding diesters with diols to obtain a potential UV-shielding material with a self-healing function and a fluorine-containing polyester, whose performance tests showed promising applications.
Controllable stereoinversion in DNA-catalyzed olefin cyclopropanationviacofactor modification
Cheng, Yu,Hao, Jingya,Jia, Guoqing,Li, Can,Lu, Shengmei,Miao, Wenhui
, p. 7918 - 7923 (2021/06/16)
The assembly of DNA with metal-complex cofactors can form promising biocatalysts for asymmetric reactions, although catalytic performance is typically limited by low enantioselectivities and stereo-control remains a challenge. Here, we engineer G-quadruplex-based DNA biocatalysts for an asymmetric cyclopropanation reaction, achieving enantiomeric excess (eetrans) values of up to +91% with controllable stereoinversion, where the enantioselectivity switches to ?72% eetransthrough modification of the Fe-porphyrin cofactor. Complementary circular dichroism, nuclear magnetic resonance, and fluorescence titration experiments show that the porphyrin ligand of the cofactor participates in the regulation of the catalytic enantioselectivityviaa synergetic effect with DNA residues at the active site. These findings underline the important role of cofactor modification in DNA catalysis and thus pave the way for the rational engineering of DNA-based biocatalysts.
Synthesis of ruthenium–dithiocarbamate chelates bearing diphosphine ligands and their use as latent initiators for atom transfer radical additions
Aldin, Mohammed Zain,Delaude, Lionel,Zaragoza, Guillermo
supporting information, (2021/08/03)
Nine representative [Ru(S2CNEt2)2(diphos)] complexes were prepared in almost quantitative yields (91–97%) from [RuCl2(p-cymene)]2, sodium diethyldithiocarbamate trihydrate, and a diphosphine (dppm, dppe, dppp, dppb, dpppe, dppen, dppbz, dppf, or DPEphos), using a novel, straightforward, one-pot procedure. The recourse to a monomodal microwave reactor was instrumental in reaching the thermodynamic equilibria favoring the targeted monometallic trichelates. All the products were fully characterized by using various analytical techniques and the molecular structures of seven of them were determined by X-ray crystallography. NMR, XRD, and IR spectroscopies evidenced a significant contribution of the thioureide resonance form Et2N+=CS22– to the electronic structure of the 1,1-dithiolate ligand. MS/MS spectrometry showed the formation of phosphine-free [Ru(S2CNEt2)2]+ cations in the gas phase, except when starting from [Ru(S2CNEt2)2(dppbz)]. The activity of the nine complexes was probed in three different catalytic processes, viz., the cyclopropanation of styrene with ethyl diazoacetate, the synthesis of vinyl esters from benzoic acid and 1-hexyne, and the atom transfer radical addition (ATRA) of carbon tetrachloride and methyl methacrylate. In the first two reactions, the saturated trichelates were poorly efficient. This was most likely due to their high stability, which prevented the formation of coordinatively unsaturated species. Contrastingly, with a turnover number of 2000 and an initial turnover frequency of 2080 h–1 for a 0.05 mol% catalyst loading, the [Ru(S2CNEt2)2(dppm)] complex emerged as a very robust, latent ATRA initiator, whose activity matched or outperformed those displayed by the most efficient ruthenium catalysts described so far.
Catalytic cyclopropanation, antimicrobial, and DFT properties of some chelated transition metal(II) complexes
Ababneh, Taher S.,Al-Dawood, Lina A.,Al-Momani, Waleed M.,Hijazi, Ahmed K.,Taha, Ziyad A.
, (2020/12/25)
Transition Metal (II) complexes of general formula [MII(NH2C2H4NH2)3][B(C6F5)4]2 (1-6), where (M= Mn, Fe, Co, Ni, Cu, Zn) have been synthesized and characterized in the solid state and in solution using elemental, thermogravimetric analysis, EPR, 11B-NMR and IR spectroscopy. All complexes were used as catalysts for the cyclopropanation reaction with a variety of olefins. Excellent yields up to 93% were obtained using complex 5. All prepared complexes were used as anti-bacterial agents against different types of bacteria (Gram-negative and Gram-positive), and as anti-fungal agents. Complex 6 showed the highest activity with MIC value of 8 μg/mL against Staphylococcus aureus (Gram-positive bacteria), and of 16 μg/mL against candida albicans. To get more insights into their structural features, molecular geometries of all prepared complexes were fully optimized using density functional theory calculations at the M06-2X/6-311+G** level of theory.
Noncanonical Heme Ligands Steer Carbene Transfer Reactivity in an Artificial Metalloenzyme**
Dunkelmann, Daniel,Hayashi, Takahiro,Hilvert, Donald,Mittl, Peer R. E.,Ota, Yusuke,Pott, Moritz,Tinzl, Matthias
supporting information, p. 15063 - 15068 (2021/06/09)
Changing the primary metal coordination sphere is a powerful strategy for tuning metalloprotein properties. Here we used amber stop codon suppression with engineered pyrrolysyl-tRNA synthetases, including two newly evolved enzymes, to replace the proximal histidine in myoglobin with Nδ-methylhistidine, 5-thiazoylalanine, 4-thiazoylalanine and 3-(3-thienyl)alanine. In addition to tuning the heme redox potential over a >200 mV range, these noncanonical ligands modulate the protein's carbene transfer activity with ethyl diazoacetate. Variants with increased reduction potential proved superior for cyclopropanation and N–H insertion, whereas variants with reduced Eo values gave higher S–H insertion activity. Given the functional importance of histidine in many enzymes, these genetically encoded analogues could be valuable tools for probing mechanism and enabling new chemistries.
Controlling the Activity of a Caged Cobalt-Porphyrin-Catalyst in Cyclopropanation Reactions with Peripheral Cage Substituents
Mouarrawis, Valentinos,Bobylev, Eduard O.,de Bruin, Bas,Reek, Joost N. H.
supporting information, p. 2890 - 2898 (2021/07/09)
In this study, three novel cubic cages were synthesized and utilized to encapsulate a catalytically active cobalt(II) meso-tetra(4-pyridyl)porphyrin guest. The newly developed caged catalysts (Co-G@Fe8(Zn-L ? 1)6, Co-G@Fe8(Zn-L ? 2)6 and Co-G@Fe8(Zn-L ? 3)6) can be easily synthesized and differ in exo-functionalization, which are either none, polar or apolar groups. This leads to a different polarity of the peripheral environment surrounding the cage, which affects the (relative) local concentration of the substrates surrounding the cage and hence indirectly influences the substrate availability of the catalysis embedded in the active site of the caged catalyst systems. The resulting increased local substrate concentrations give rise to higher catalytic activities of the respective caged catalyst in metalloradical catalyzed cyclopropanation reactions. Interestingly, the catalytic activity is the highest when the apolar cage catalyst (Co-G@Fe8(Zn-L ? 1)6) is used, and lowest with the polar analog (Co-G@Fe8(Zn-L ? 3)6). In addition, the catalytic activity of the cage without exo-functionalities (Co-G@Fe8(Zn-L ? 2)6) is nearly two times lower than that of Co-G@Fe8(Zn-L ? 1)6 and three times higher than that of Co-G@Fe8(Zn-L ? 3)6, which further demonstrates the effect of the peripheral functionalities on the cyclopropanation reaction.
Synthesis, structure and reactivity of iridium complexes containing a bis-cyclometalated tridentate C^N^C ligand
Cheng, Shun-Cheung,Cheung, Wai-Man,Chong, Man-Chun,Ko, Chi-Chiu,Leung, Wa-Hung,Sung, Herman H.-Y.,Williams, Ian D.
, p. 8512 - 8523 (2021/06/28)
In an effort to synthesize cyclometalated iridium complexes containing a tridentate C^N^C ligand, transmetallation of [Hg(HC^N^C)Cl] (1) (H2C^N^C = 2,6-bis(4-tert-butylphenyl)pyridine) with various organoiridium starting materials has been studied. The treatment of1with [Ir(cod)Cl]2(cod = 1,5-cyclooctadiene) in acetonitrile at room temperature afforded a hexanuclear Ir4Hg2complex, [Cl(κ2C,N-HC^N^C)(cod)IrHgIr(cod)Cl2]2(2), which features Ir-Hg-Ir and Ir-Cl-Ir bridges. Refluxing2with sodium acetate in tetrahydrofuran (thf) resulted in cyclometalation of the bidentate HC^N^C ligand and formation of trinuclear [(C^N^C)(cod)IrHgIr(cod)Cl2] (3). On the other hand, refluxing [Ir(cod)Cl]2with1and sodium acetate in thf yielded [Ir(C^N^C)(cod)(HgCl)] (4). Chlorination of4with PhICl2gave [Ir(C^N^C)(cod)Cl]·HgCl2(5·HgCl2) that reacted with tricyclohexylphosphine to yield Hg-free [Ir(C^N^C)(cod)Cl] (5). Chloride abstraction of5with silver(i) triflate (AgOTf) gave [Ir(C^N^C)(cod)(H2O)](OTf) (6) that can catalyze the cyclopropanation of styrene with ethyl diazoacetate. Reaction of1and [Ir(CO)2Cl(py)] (py = pyridine) with sodium acetate in refluxing thf afforded [Ir(C^N^C)(HgCl)(py)(CO)] (7), in which the carbonyl ligand is coplanar with the C^N^C ligand. On the other hand, refluxing1with (PPh4)[Ir(CO)2Cl2] and sodium acetate in acetonitrile gave [Ir(C^N^C)(κ2C,N-HC^N^C)(CO)] (8), the carbonyl ligand of which istransto the pyridyl ring of the bidentate HC^N^C ligand. Upon irradiation with UV light8in thf was isomerized to8′, in which the carbonyl istransto a phenyl group of the bidentate HC^N^C ligand. The isomer pair8and8′exhibited emission at 548 and 514 nm in EtOH/MeOH at 77 K with lifetime of 84.0 and 64.6 μs, respectively. Protonation of8withp-toluenesulfonic acid (TsOH) afforded the bis(bidentate) tosylate complex [Ir(κ2C,N-HC^N^C)2(CO)(OTs)] (9) that could be reconverted to8upon treatment with sodium acetate. The electrochemistry of the Ir(C^N^C) complexes has been studied using cyclic voltammetry. Reaction of [Ir(PPh3)3Cl] with1and sodium acetate in refluxing thf led to isolation of the previously reported compound [Ir(κ2P,C-C6H4PPh2)2(PPh3)Cl] (10). The crystal structures of2-5,8,8′,9and10have been determined.
Selective carbene transfer to amines and olefins catalyzed by ruthenium phthalocyanine complexes with donor substituents
Cailler, Lucie P.,Kroitor, Andrey P.,Martynov, Alexander G.,Gorbunova, Yulia G.,Sorokin, Alexander B.
supporting information, p. 2023 - 2031 (2021/02/26)
Electron-rich ruthenium phthalocyanine complexes were evaluated in carbene transfer reactions from ethyl diazoacetate (EDA) to aromatic and aliphatic olefins as well as to a wide range of aromatic, heterocyclic and aliphatic amines for the first time. It was revealed that the ruthenium octabutoxyphthalocyanine carbonyl complex [(BuO)8Pc]Ru(CO) is the most efficient catalyst converting electron-rich and electron-poor aromatic olefins to cyclopropane derivatives with high yields (typically 80-100%) and high TON (up to 1000) under low catalyst loading and nearly equimolar substrate/EDA ratio. This catalyst shows a rare efficiency in the carbene insertion into amine N-H bonds. Using a 0.05 mol% catalyst loading, a high amine concentration (1 M) and 1.1 eq. of EDA, a number of structurally divergent amines were selectively converted to mono-substituted glycine derivatives with up to quantitative yields and turnover numbers reaching 2000. High selectivity, large substrate scope, low catalyst loading and practical reaction conditions place [(BuO)8Pc]Ru(CO) among the most efficient catalysts for the carbene insertion into amines.
Generation of Diazomethyl Radicals by Hydrogen Atom Abstraction and Their Cycloaddition with Alkenes
Dong, Kuiyong,Doyle, Michael P.,Su, Yong-Liang,Zheng, Haifeng
supporting information, p. 18484 - 18488 (2021/07/20)
A general catalytic methodology for the synthesis of pyrazolines from α-diazo compounds and conjugated alkenes is reported. The direct hydrogen atom transfer (HAT) process of α-diazo compounds promoted by the tert-butylperoxy radical generates electrophilic diazomethyl radicals, thereby reversing the reactivity of the carbon atom attached with the diazo group. The regiocontrolled addition of diazomethyl radicals to carbon-carbon double bonds followed by intramolecular ring closure on the terminal diazo nitrogen and tautomerization affords a diverse set of pyrazolines in good yields with excellent regioselectivity. This strategy overcomes the limitations of electron-deficient alkenes in traditional dipolar [3+2]-cycloaddition of α-diazo compounds with alkenes. Furthermore, the straightforward formation of the diazomethyl radicals provides umpolung reactivity, thus opening new opportunities for the versatile transformations of diazo compounds.
