- Synthesis and evaluation of 4-cycloheptylphenols as selective Estrogen receptor-β agonists (SERBAs)
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A short and efficient route to 4-(4-hydroxyphenyl)cycloheptanemethanol was developed, which resulted in the preparation of a mixture of 4 stereoisomers. The stereoisomers were separated by preparative HPLC, and two of the stereoisomers identified by X-ray crystallography. The stereoisomers, as well as a small family of 4-cycloheptylphenol derivatives, were evaluated as estrogen receptor-beta agonists. The lead compound, 4-(4-hydroxyphenyl)cycloheptanemethanol was selective for activating ER relative to seven other nuclear hormone receptors, with 300-fold selectivity for the β over α isoform and with EC50 of 30–50 nM in cell-based and direct binding assays.
- Sampathi Perera, K.L.Iresha,Hanson, Alicia M.,Lindeman, Sergey,Imhoff, Andrea,Lu, Xingyun,Sem, Daniel S.,Donaldson, William A.
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Read Online
- Electrochemical Difunctionalization of Terminal Alkynes: Access to 1,4-Dicarbonyl Compounds
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1,4-Dicarbonyl compounds are versatile scaffolds for the heterocycle synthesis, including the Paal-Knorr reaction. Herein, a feasible electrosynthesis method to access 1,4-dicarbonyl compounds has been developed from simple alkynes and 1,3-dicarbonyl compounds. When the undivided cell is combined with the constant current mode, aryl alkynes containing numerous medicinal motifs with 1,3-dicarbonyl esters or ketones react smoothly. External oxidant and catalyst-free conditions conform to the requirements of green synthesis.
- Chen, Siyu,He, Haoyu,Hu, Jiayu,Hu, Jingcheng,Jiao, Ying,Lei, Aiwen,Liu, Xue,Ma, Rui,Wang, Hongfei,Xu, Zhexi,Zeng, Li
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supporting information
(2022/01/04)
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- Enantioselective α-Amination of Acyclic 1,3-Dicarbonyls Catalyzed by N-Heterocyclic Carbene
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Herein, we describe a method for the catalytic enantioselective α-amination of α-substituted acyclic 1,3-ketoamides and 1,3-amidoesters that affords the products possessing N-substituted quaternary stereocenters with a chiral N-heterocyclic carbene (NHC). The reaction is based on the utilization of an intrinsic Br?nsted base characteristic of NHC that enables the catalytic formation of a chiral ion pair comprising the enolate and the azolium ion. A series of challenging open-chain α-substituted 1,3-dicarbonyls are aminated via this method with ee's of ≤99%.
- Santra, Surojit,Maji, Ujjwal,Guin, Joyram
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supporting information
p. 468 - 473
(2020/02/04)
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- Substituted pyrazoloheptylcyclo-5-formamide compound as well as preparation method and application thereof
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The invention discloses a substituted pyrazoloheptylcyclo-5-formamide compound as well as a preparation method and application of the substituted pyrazoloheptylcyclo-5-formamide compound. The structural formula of the substituted pyrazoloheptylcyclo-5-formamide compound is shown as the following formula I (See the specification), wherein in the formula I, n is an integer from 1 to 3, R1 is selected from hydrogen, a phenyl group, a substituted phenyl group, a C1-C4 alkoxy group, a halogenated C1-C4 alkoxy group, a C1-C4 alkyl sulfonyl group, a halogenated C1-C4 alkyl sulfonyl group, a C1-C4 alkyl carbonyl group, a halogenated C1-C4 alkyl carbonyl group, a C1-C4 alkoxy carbonyl group and a halogenated C1-C4 alkoxy carbonyl group, the substituted phenyl group contains one or more substituentgroups, and the substituent group is selected from at least one of halogen, amino, hydroxyl, nitro, cyano, C1-C4 alkyl and C1-C4 alkoxy. The compound is prepared through an amide condensation reaction, and the preparation method is simple. The pyrazoloheptylcyclo-5-formamide compound has an obvious regulation effect on the growth and development of agricultural pests, the pests have the symptoms of individual reduction, epidermis relaxation and development deformity until the pests die finally, and the pyrazoloheptylcyclo-5-formamide compound can be applied to agriculture as an insecticide.
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Paragraph 0042-0044
(2020/09/09)
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- From cycloheptathiophene-3-carboxamide to oxazinone-based derivatives as allosteric HIV-1 ribonuclease H inhibitors
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The paper focussed on a step-by-step structural modification of a cycloheptathiophene-3-carboxamide derivative recently identified by us as reverse transcriptase (RT)-associated ribonuclease H (RNase H) inhibitor. In particular, its conversion to a 2-aryl-cycloheptathienoozaxinone derivative and the successive thorough exploration of both 2-aromatic and cycloheptathieno moieties led to identify oxazinone-based compounds as new anti-RNase H chemotypes. The presence of the catechol moiety at the C-2 position of the scaffold emerged as critical to achieve potent anti-RNase H activity, which also encompassed anti-RNA dependent DNA polymerase (RDDP) activity for the tricyclic derivatives. Benzothienooxazinone derivative 22 resulted the most potent dual inhibitor exhibiting IC50s of 0.53 and 2.90 μM against the RNase H and RDDP functions. Mutagenesis and docking studies suggested that compound 22 binds two allosteric pockets within the RT, one located between the RNase H active site and the primer grip region and the other close to the DNA polymerase catalytic centre.
- Massari, Serena,Corona, Angela,Distinto, Simona,Desantis, Jenny,Caredda, Alessia,Sabatini, Stefano,Manfroni, Giuseppe,Felicetti, Tommaso,Cecchetti, Violetta,Pannecouque, Christophe,Maccioni, Elias,Tramontano, Enzo,Tabarrini, Oriana
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- Does the Exception Prove the Rule? A Comparative Study of Supramolecular Synthons in a Series of Lactam Esters
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In this paper a series of simple lactam esters and carboxylic acids is studied with respect to their overall conformation and hydrogen bonding patterns. In total, eight lactams featuring Nα-substitution have been synthesized. Additionally, the molecular structures of related lactam esters have been considered. The length of the amide bonds does not seem to be majorly influenced by different substituents unless the electron withdrawing N-Boc-protection group is introduced, resulting in a higher susceptibility toward hydrolytic ring opening. As known from other lactams, the Nα ester moiety of the title compounds can be in an axial or equatorial conformation. Smaller ester groups were found to prefer equatorial positions, while larger ones occupy axial sites. N-substitution seems to promote axial conformations of the respective Nα group, with enantholactams being the only studied exception. In addition to the two common amide packing motifs, i.e., the R2 2 (8) amide dimer (NH···O/NH···O) and the C(4) amide chain, a third graph-set was found: the R2 2(8) NH···O/CH···O=C heterodimer. In general, there seems to be a tendency for medium-sized lactams as well as lactams with small esters to form R2 2 (8) amide dimers. Larger esters and enantholactam esters lead to C(4) amide chains. In this respect the formation of R2 2(8) N - H···O/C-H···O=C heterodimers should be seen as a remarkable exception.
- Weck,Nauha,Gruber
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p. 2899 - 2911
(2019/05/10)
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- Coumarin-dithiocarbamate hybrids as novel multitarget AChE and MAO-B inhibitors against Alzheimer's disease: Design, synthesis and biological evaluation
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A series of new coumarin-dithiocarbamate hybrids were designed and synthesized as multitarget agents for the treatment of Alzheimer's disease. Most of them showed potent and clearly selective inhibition towards AChE and MAO-B. Among these compounds, compound 8f demonstrated the most potent inhibition to AChE with IC50 values of 0.0068 μM and 0.0089 μM for eeAChE and hAChE, respectively. Compound 8g was identified as the most potent inhibitor to hMAO-B, and it is also a good and balanced inhibitor to both hAChE and hMAO-B (0.114 μM for hAChE; 0.101 μM for hMAO-B). Kinetic and molecular modeling studies revealed that 8g was a dual binding site inhibitor for AChE and a competitive inhibitor for MAO-B. Further studies indicated that 8g could penetrate the BBB and exhibit no toxicity on SH-SY5Y neuroblastoma cells. More importantly, 8g did not display any acute toxicity in mice at doses up to 2500 mg/kg and could reverse the cognitive dysfunction of scopolamine-induced AD mice. Overall, these results highlighted 8g as a potential multitarget agent for AD treatment and offered a starting point for design of new multitarget AChE/MAO-B inhibitors based on dithiocarbamate scaffold.
- He, Qi,Liu, Jing,Lan, Jin-Shuai,Ding, Jiaoli,Sun, Yongbing,Fang, Yuanying,Jiang, Neng,Yang, Zunhua,Sun, Liyuan,Jin, Yi,Xie, Sai-Sai
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supporting information
p. 512 - 528
(2018/09/29)
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- A new series of cycloalkane-fused coumarin sulfonates: Synthesis and in vitro antiproliferative screening
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In this paper, we report the synthesis of 14 new cycloalkane-fused tricyclic coumarin sulfonate derivatives. They were examined for in vitro anticancer activity against NCI-57 cancer cell line panel of nine different cancer types. Among all the target analogs, compounds 1c, 1e, and 1n showed the highest activities. Compound 1e exerted the highest percentage growth inhibition (91.91%) against SNB-75 CNS cancer cell line at 10 μM concentration and was more active than carmustineagainst this cell line. Compound 1c also showed strong activity against HT29 colon, ACHN renal, and PC-3 prostate cancer cell lines. Furthermore, compound 1n was selective toward the HT29 colon cancer cell line. Compounds 1c, 1e, and 1n showed superior selectivity against cancer cell lines compared to the noncancerous RAW 264.7 macrophages. The in silico predictions estimate the oral bioavailability, which is in compliance with Lipinski's rule of five.
- El-Gamal, Mohammed I.,Baek, Daejin,Oh, Chang-Hyun
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p. 184 - 191
(2016/02/26)
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- Synthesis of New Tricyclic and Tetracyclic Fused Coumarin Sulfonate Derivatives and Their Inhibitory Effects on LPS-Induced Nitric Oxide and PGE2 Productions in RAW 264.7 Macrophages: Part 2
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The synthesis of a new series of 21 fused coumarin derivatives is described, and the biological evaluation of their in vitro antiinflammatory effects as inhibitors of lipopolysaccharide (LPS)-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production in RAW 264.7 macrophages. The target compounds 1a–u were first tested for cytotoxicity to determine a non-toxic concentration for antiinflammatory screening, so that the inhibitory effects against NO and PGE2 production would not be caused by cytotoxicity. Compounds 1f and 1p were the most active PGE2 inhibitors with IC50 values of 0.89 and 0.95 μM, respectively. Western blot and cell-free COX-2 screening showed that their effects were due to inhibition of both COX-2 protein expression and COX-2 enzyme activity. Their IC50 values against the COX-2 enzyme were 0.67 and 0.85 μM, respectively, which is more potent than etoricoxib. The selectivity indexes of compounds 1f and 1p against COX-2 compared to COX-1 were 41.1 and 42.5, respectively. Compound 1f showed strong inhibitory effects at 5 μM concentration on COX-2 mRNA expression in LPS-induced RAW 264.7 macrophages. Moreover, the tricyclic compounds 1l and 1n as well as the tetracyclic analog 1u were the most potent NO inhibitors, with one-digit micromolar IC50 values. They showed dose-dependent inhibition of inducible nitric oxide synthase (iNOS) protein expression. The tetracyclic derivative 1u was the most potent inhibitor of NO production. It also exhibited a strong inhibitory effect on iNOS mRNA expression in LPS-induced RAW 264.7 macrophages.
- El-Gamal, Mohammed I.,Lee, Woo-Seok,Shin, Ji-Sun,Oh, Chang-Hyun,Lee, Kyung-Tae,Choi, Jungseung,Myoung, Nohsun,Baek, Daejin
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p. 853 - 863
(2016/11/09)
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- Ethyl Lithiodiazoacetate: Extremely Unstable Intermediate Handled Efficiently in Flow
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Ethyl diazoacetate (EDA) is one of the most prominent diazo reagents. It is frequently used in metal–carbene-type reactions. However, EDA can also be used as a nucleophile under base catalysis. Whilst the addition of EDA to aldehydes can be performed using organic bases, the addition of EDA to other carbonyl electrophiles requires the use of organometallics such as lithium diisopropylamide (LDA). The generated ethyl lithiodiazoacetate is highly reactive and decomposes rapidly, even at low temperatures. Herein, we report a continuous flow protocol that overcomes the problems associated with the instantaneous decomposition of ethyl lithiodiazoacetate. The addition of ethyl lithiodiazoacetate to ketones provides direct access to tertiary diazoalcohols in good yields.
- Müller, Simon T. R.,Hokamp, Tobias,Ehrmann, Svenja,Hellier, Paul,Wirth, Thomas
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supporting information
p. 11940 - 11942
(2016/08/16)
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- Quantification of the Nucleophilic Reactivities of Cyclic β-Keto Ester Anions
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Kinetics of the reactions of enolate anions derived from acyclic and cyclic β-keto esters with benzhydrylium ions and quinone methides have been determined photometrically in dimethyl sulfoxide solution at 20 C. The reactions follow second-order rate laws: first-order with respect to the electrophile and first-order with respect to the enolate. Reactions conducted in the presence of 18-crown-6 ether and in the presence of variable concentrations of K+ allowed the influence of ion-pairing on the nucleophilic reactivities of the various enolate ions to be determined quantitatively. Enolate ions derived from oxocycloalkanecarboxylic esters show reactivities similar to those of their acyclic analogue. Enolate ions derived from δ-lactones are less nucleophilic, which is explained by the enforced (E) conformation of the corresponding esters.
- Corral-Bautista, Francisco,Mayr, Herbert
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supporting information
p. 7594 - 7601
(2016/01/25)
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- Synthesis of tricyclic fused coumarin sulfonates and their inhibitory effects on LPS-induced nitric oxide and PGE2 productions in RAW 264.7 macrophages
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The regulations of NO and PGE2 productions are research topics of interest in the field of antiinflammatory drug development. In the present study, a series of tricyclic fused coumarin sulfonate derivatives was synthesized and evaluated for their abilities to inhibit NO and PGE2 productions in LPS-induced RAW 264.7 macrophages. Among all the target compounds, compound 1g possessing p-(trifluoromethyl)phenyl and fused cycloheptane moieties showed the highest inhibitory effects on NO and PGE 2 productions. Compound 1g not only inhibited COX-2 activity but also reduced expressions of COX-2 and iNOS. Furthermore, ADME profiling showed that compounds 1g, 1j, 1m, and 1n are estimated to be orally bioavailable.
- Jang, Hyeon-Lok,El-Gamal, Mohammed I.,Choi, Hye-Eun,Choi, Ho-Yeong,Lee, Kyung-Tae,Oh, Chang-Hyun
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p. 571 - 575
(2014/01/23)
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- Synthesis, in vitro antiproliferative activity, and in silico studies of fused tricyclic coumarin sulfonate derivatives
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A series of fused tricyclic coumarin sulfonate derivatives was synthesized. Their in vitro antiproliferative activities against a panel of 57 human cancer cell lines of nine different cancer types were tested at the NCI. Compounds 1e, 1f, 1h, 1i, and 1o showed the highest mean percentage of inhibition values over the 57 cell line panel at 10 μM, and they were further tested in 5-dose testing mode to determine their IC50 values. Compounds 1e, 1f, and 1o were more selective against leukemia and colon cancer subpanels, while compounds 1h and 1i showed broad-spectrum anticancer activities. Compounds 1e, 1f, 1h, 1i, and 1o demonstrated high selectivity towards cancer cell lines than RAW 264.7 macrophages. Compound 1h exerted lethal effect over NCI-H522 NSCLC, SK-MEL-5 melanoma, and A498 renal cancer cell lines with percentage of inhibition values of 114.10%, 103.23%, and 100.52% at 10 μM concentration, respectively. Moreover, the IC50 value of compound 1o against HT29 colon cancer cell line was 532 nM. Compounds 1e, 1f, 1h, 1i, and 1o were tested for inhibitory effect over cyclooxygenase-2 (COX-2) enzyme as a possible mechanism of action. Furthermore, in silico studies were conducted to check the compliance of those five compounds with Lipinski's rule of five, and hence estimate their oral bioavailability.
- El-Gamal, Mohammed I.,Oh, Chang-Hyun
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- Phosphate tricyclic coumarin analogs as steroid sulfatase inhibitors: Synthesis and biological activity
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In the present work, we report convenient methods for the synthesis and biological evaluation of phosphate tricyclic coumarin derivatives as potential steroid sulfatase inhibitors. The described synthesis includes the straightforward preparation of 7-hydroxy-2,3-dihydro-1H-cyclopenta[c]chromen-4-one, 3-hydroxy-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one and 3-hydroxy-8,9,10,11-tetrahydro-7H-cyclohepta[c]chromen-6-one modified with various phosphate moieties. The inhibitory effects of the synthesized compounds were tested on STS isolated from human placenta as well as the MCF-7, MDA-MB-231 and MDA-MB-435S cancer cell lines. Most of the new STS inhibitors possessed IC50 values between 21 to 159 μM. In the course of our investigation, the largest inhibitory effects in the STS enzyme assays were observed for the three compounds 9p, 9r and 9s, with IC50 values of 36.4, 37.8 and 21.5 μM, respectively (IC50 value of 1.0 μM for the 665-COUMATE used as a reference). The compound 9r, exhibited the highest potency against MCF-7, an estrogen receptor positive (ER+) cell line, with a GI50 value of 24.7 μM. The structure-activity relationships of the synthesized coumarin derivatives with the STS enzyme are discussed.
- Kozak, Witold,Dasko, Mateusz,Maslyk, Maciej,Pieczykolan, Jerzy S.,Gielniewski, Bartlomiej,Rachon, Janusz,Demkowicz, Sebastian
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p. 44350 - 44358
(2014/12/10)
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- Expedient construction of the [7-5-5] all-carbon tricyclic core of the daphniphyllum alkaloids daphnilongeranin B and daphniyunnine D
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A synthetic strategy for the construction of the [7-5-5] all-carbon tricyclic core of numerous calyciphylline A-type Daphniphyllum alkaloids has been developed using a key intramolecular Pauson-Khand reaction. A subsequent base-mediated double-bond migration and a regio-and stereoselective radical late stage allylic oxygenation provide access to the substitution patterns of daphnilongeranin B and daphniyunnine D.
- Darses, Benjamin,Michaelides, Iacovos N.,Sladojevich, Filippo,Ward, John W.,Rzepa, Paula R.,Dixon, Darren J.
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supporting information; experimental part
p. 1684 - 1687
(2012/06/30)
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- Enamine-mediated addition of aldehydes to cyclic enones
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The O-trimethylsilylated α,α-diphenylprolinol-catalyzed addition of aldehydes to cyclic unsaturated enones is described. The apparently unusual stereochemical outcome is discussed. Copyright
- Schietroma, Daniele M. Scarpino,Monaco, Mattia R.,Visca, Valerio,Insogna, Susanna,Overgaard, Jacob,Bella, Marco
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supporting information; experimental part
p. 2648 - 2652
(2011/12/04)
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- Metal-mediated two-atom carbocycle enlargement in aqueous medium
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The indium and tin-mediated carbonyl allylations of 1,3-dicarbonyl compounds have been studied in aqueous medium. The study led to the development of a novel two-atom carbocycle-enlargement in water. Five-, six-, seven-, eight-, and twelve-membered rings are enlarged by two carbon atoms into seven-, eight-, nine-, ten-, and fourteen-membered ring derivatives respectively. Tetralone derivatives are similarly expanded to 6-8 fused ring systems; and indanone derivates are expanded to 5-7 fused ring systems. The use of both indium and zinc as the metal mediators provided the ring expansion products successfully. The use of water as a solvent was found to be essential for the ring expansion reaction.
- Li, Chao-Jun,Chen, Dong-Li,Lu, Yue-Qi,Haberman, John X.,Mague, Joel T.
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p. 2347 - 2364
(2007/10/03)
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- Activated cycloheptenone dienophiles. A versatile approach to 6,7-fused ring targets
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Several 2-carbalkoxy-2-cyclohepten-1-ones were prepared and their Diels-Alder characteristics examined in order to develop a facile general approach to the synthesis of cycloheptane ring-containing polycyclic natural products.Substitution pattern on the seven-membered ring was found to greatly affect the Diels-Alder behavior.In addition, some extraordinary facial stereoselectivity was observed.Key words: Diels-Alder reaction, 2-carbalkoxy-2-cyclohepten-1-ones, 6,7-fused ring system.
- Liu, Hsing-Jang,Yeh, Wen-Lung,Browne, Eric N. C.
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p. 1135 - 1147
(2007/10/03)
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