- Design, synthesis, evaluation, and molecular modeling studies of indolyl oxoacetamides as potential pancreatic lipase inhibitors
-
A series of indolyl oxoacetamide analogs was synthesized, characterized, and evaluated for their pancreatic lipase inhibitory activity using porcine pancreatic lipase (type II) and 4-nitrophenyl butyrate. Compound 8d exhibited a potent inhibition, with an IC50 value of 4.53 μM, followed by 8c (IC50 = 5.12 μM), compared with the standard drug, orlistat (IC50 = 0.99 μM). Furthermore, analogs 8c and 8d exhibited a reversible competitive inhibition, similar to orlistat. Molecular docking studies of the compounds 7a–f and 8a–f were in agreement with the in vitro results, wherein 8d exhibited a potential MolDock score of ?163.052 kcal/mol. A 10-ns molecular dynamics simulation of 8d complexed with pancreatic lipase confirmed the role of π–π stacking and π–cation interactions with the lid domain and Arg 256, respectively, in stabilizing the ligand at the active site (maximum observed root mean square deviation ≈ 2 ?). The present study led to the identification of novel indolyl oxoacetamides (8a–d) as potential pancreatic lipase inhibitory leads that might further result in enhanced potency through lead optimization.
- Sridhar,Palawat, Saksham,Paul, Atish T.
-
-
Read Online
- Discovery of New 4-Indolyl Quinazoline Derivatives as Highly Potent and Orally Bioavailable P-Glycoprotein Inhibitors
-
The major drawbacks of P-glycoprotein (P-gp) inhibitors at the clinical stage make the development of new P-gp inhibitors challenging and desirable. In this study, we reported our structure-activity relationship studies of 4-indolyl quinazoline, which led to the discovery of a highly effective and orally active P-gp inhibitor, YS-370. YS-370 effectively reversed multidrug resistance (MDR) to paclitaxel and colchicine in SW620/AD300 and HEK293T-ABCB1 cells. YS-370 bound directly to P-gp, did not alter expression or subcellular localization of P-gp in SW620/AD300 cells, but increased the intracellular accumulation of paclitaxel. Furthermore, YS-370 stimulated the P-gp ATPase activity and had moderate inhibition against CYP3A4. Significantly, oral administration of YS-370 in combination with paclitaxel achieved much stronger antitumor activity in a xenograft model bearing SW620/Ad300 cells than either drug alone. Taken together, our data demonstrate that YS-370 is a promising P-gp inhibitor capable of overcoming MDR and represents a unique scaffold for the development of new P-gp inhibitors.
- Chen, Zhe-Sheng,Dai, Qing-Qing,Li, Guo-Bo,Liu, Hong-Min,Liu, Hui,Wang, Bo,Wang, Shaomeng,Yu, Bin,Yuan, Shuo,Zhang, Jing-Ya,Zhang, Xiao-Nan,Zuo, Jia-Hui
-
p. 14895 - 14911
(2021/10/12)
-
- Three-component reactions of 3-arylidene-3h-indolium salts, isocyanides and amines
-
A multicomponent reaction of isocyanides with aryl(indol-3-yl)methylium salts and amines has been found. A series of aryl(indol-3-yl)acetimidamides was obtained in up to 96% yields. In the case of ethyl isocyanoacetate, the reaction is followed by cyclization to form 3,5-dihydro-4H-imidazol-4-one derivatives.
- Nguyen, Hung M.,Golantsov, Nikita E.,Golubenkova, Alexandra S.,Rybakov, Victor B.,Voskressensky, Leonid G.
-
-
- Anti-leukemic properties of aplysinopsin derivative ee-84 alone and combined to bh3 mimetic a-1210477
-
Aplysinopsins are a class of marine indole alkaloids that exhibit a wide range of biological activities. Although both the indole and N-benzyl moieties of aplysinopsins are known to possess antiproliferative activity against cancer cells, their mechanism of action remains unclear. Through in vitro and in vivo proliferation and viability screening of newly synthesized aplysinopsin analogs on myelogenous leukemia cell lines and zebrafish toxicity tests, as well as analysis of differential toxicity in noncancerous RPMI 1788 cells and PBMCs, we identified EE-84 as a promising novel drug candidate against chronic myeloid leukemia. This indole derivative demonstrated drug-likeness in agreement with Lipinski’s rule of five. Furthermore, EE-84 induced a senescent-like phenotype in K562 cells in line with its cytostatic effect. EE-84-treated K562 cells underwent morphological changes in line with mitochondrial dysfunction concomitant with autophagy and ER stress induction. Finally, we demonstrated the synergistic cytotoxic effect of EE-84 with a BH3 mimetic, the Mcl-1 inhibitor A-1210477, against imatinib-sensitive and resistant K562 cells, highlighting the inhibition of antiapoptotic Bcl-2 proteins as a promising novel senolytic approach against chronic myeloid leukemia.
- Song, Sungmi,Kim, Sua,El-Sawy, Eslam R.,Cerella, Claudia,Orlikova-Boyer, Barbora,Kirsch, Gilbert,Christov, Christo,Dicato, Mario,Diederich, Marc
-
-
- Advancing Base-Metal Catalysis: Development of a Screening Method for Nickel-Catalyzed Suzuki-Miyaura Reactions of Pharmaceutically Relevant Heterocycles
-
Interest in replacing palladium catalysts with base metals resulted in the development of a 24-reaction screening platform for identifying nickel-catalyzed Suzuki-Miyaura reaction conditions. This method was designed to be directly applicable to process s
- Goldfogel, Matthew J.,Guo, Xuelei,Gurak, John A.,Joannou, Matthew V.,Meléndez Matos, Jeishla L.,Moffat, William B.,Simmons, Eric M.,Wisniewski, Steven R.
-
supporting information
(2021/08/18)
-
- Transition-Metal-Free and Base-Promoted Carbon-Heteroatom Bond Formation via C-N Cleavage of Benzyl Ammonium Salts
-
A facile and general method for constructing carbon-heteroatom (C-P, C-O, C-S, and C-N) bonds via C-N cleavage of benzyl ammonium salts under transition-metal-free conditions was reported. The combination of t-BuOK and 18-crown-6 enabled a wide range of substituted benzyl ammonium salts to couple readily with different kinds of heteroatom nucleophiles, i.e. hydrogen phosphoryl compounds, alcohols, thiols, and amines. Good functional group tolerance was demonstrated. The scale-up reaction and one-pot synthesis were also successfully performed.
- Liu, Long,Tang, Yuanyuan,Wang, Kunyu,Huang, Tianzeng,Chen, Tieqiao
-
p. 4159 - 4170
(2021/03/09)
-
- Room-Temperature Palladium(II)-Catalyzed Direct 2-Arylation of Indoles with Tetraarylstannanes
-
A palladium(II)-catalyzed direct 2-arylation of indoles by tetraarylstannanes with oxygen (balloon) as the oxidant at room temperature has been developed. Various tetraarylstannanes can be employed as aryl sources for 2-arylation of indoles in up to 89% yield, providing a practical and efficient catalytic protocol for accessing 2-arylindoles.
- Liu, Yuxia,Wang, Chao,Huang, Linjuan,Xue, Dong
-
supporting information
p. 1613 - 1618
(2020/09/15)
-
- The palladium-catalyzed direct C3-cyanation of indoles using acetonitrile as the cyanide source
-
The ligand-free palladium-catalyzed C3-cyanation of indoles via direct C-H functionalization was achieved. This protocol, utilizing CH3CN as a green and readily available cyanide source, produced the desired products in moderate to good yields through transition-metal-catalyzed C-CN bond cleavage. This journal is
- Feng, Kejun,Li, Qiang,Li, Yuanhua,Liu, Bifu,Liu, Min,Zhou, Yongbo
-
supporting information
p. 6108 - 6114
(2020/10/21)
-
- Manganese-Catalyzed Regioselective Dehydrogenative C-versus N-Alkylation Enabled by a Solvent Switch: Experiment and Computation
-
The first base metal-catalyzed regioselective dehydrogenative alkylation of indolines using readily available alcohols as the alkylating reagent is reported. A single air-and moisture-stable manganese catalyst provides access to either C3-or N-alkylated indoles depending on the solvent used. Mechanistic studies indicate that the reaction takes place through a combined acceptorless dehydrogenation and hydrogen autotransfer strategy.
- Borghs, Jannik C.,Zubar, Viktoriia,Zubar, Viktoriia,Azofra, Luis Miguel,Sklyaruk, Jan,Rueping, Magnus,Rueping, Magnus
-
supporting information
p. 4222 - 4227
(2020/06/04)
-
- Palladium-Catalyzed C-N Cross-Coupling of NH-Heteroarenes and Quaternary Ammonium Salts via C-N Bond Cleavage
-
In this paper, we extend the substrate class of Buchwald-Hartwig amination to quaternary ammonium salts. In the presence of Pd(OAc)2 and t-BuXPhos, the coupling of aryl- or arylmethyltrimethylammonium triflates with NH-heteroarenes via C-N bond cleavage affords the desired N-aryl or N-arylmethyl heteroarenes in moderate to excellent yields.
- Chen, Hongyi,Yang, Hongqin,Li, Nutao,Xue, Xinghua,He, Ze,Zeng, Qingle
-
p. 1679 - 1685
(2019/08/20)
-
- Catalytic Electrophilic C?H Borylation Using NHC?Boranes and Iodine Forms C2-, not C3-, Borylated Indoles
-
Activation of N-heterocyclic carbene boranes (NHC?BH3) by I2 enables the metal-free catalytic C?H borylation of heteroarenes with formation of H2 as the by-product in a process that uses only bench stable precursors. The borylation of indoles using NHC?BH3/I2 produces C2-borylated indoles exclusively in contrast to other catalytic electrophilic C?H borylation methods. Mechanistic studies indicate that this is due to C3 to C2 boron migration facilitated by the absence of exogenous Br?nsted bases. Thus this C?H borylation methodology proceeds under sufficiently Br?nsted acidic conditions to enable the thermodynamic C2-borylated indole isomer to be formed instead of the C3 borylated-isomer. This demonstrates that electrophilic C?H borylation can be used to access a wider range of borylated regioisomers than reported to date.
- McGough, John S.,Cid, Jessica,Ingleson, Michael J.
-
supporting information
p. 8180 - 8184
(2017/06/23)
-
- Regiocontrolled Direct C?H Arylation of Indoles at the C4 and C5 Positions
-
An effective and practical strategy has been established for the direct and site-selective arylation of indoles at the C4 and C5 positions with the aid of a readily accessible, cheap, and removable pivaloyl directing group at the C3 position. This transfo
- Yang, Youqing,Gao, Pan,Zhao, Yue,Shi, Zhuangzhi
-
supporting information
p. 3966 - 3971
(2017/03/27)
-
- Chiral Pincer Carbodicarbene Ligands for Enantioselective Rhodium-Catalyzed Hydroarylation of Terminal and Internal 1,3-Dienes with Indoles
-
Catalytic enantioselective addition of N-heteroarenes to terminal and internal 1,3-dienes is reported. Reactions are promoted by 5 mol % of Rh catalyst supported by a new chiral pincer carbodicarbene ligand that delivers allylic substituted arenes in up to 95% yield and up to 98:2 er. Mechanistic and X-ray evidence is presented that supports that the reaction proceeds via a Rh(III)-η3-allyl.
- Marcum, Justin S.,Roberts, Courtney C.,Manan, Rajith S.,Cervarich, Tia N.,Meek, Simon J.
-
supporting information
p. 15580 - 15583
(2017/11/14)
-
- HISTONE DEMETHYLASE INHIBITORS
-
The present invention relates generally to compositions and methods for treating cancer and neoplastic disease. Provided herein are substituted pyrido[3,4-d]pyrimidin-4-one derivative compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibition of histone demethylase. Furthermore, the subject compounds and compositions are useful for the treatment of cancer, such as prostate cancer, breast cancer, bladder cancer, lung cancer and/or melanoma and the like.
- -
-
Paragraph 00168
(2016/04/09)
-
- Frustrated Lewis Pair Catalyzed Dehydrogenative Oxidation of Indolines and Other Heterocycles
-
An acceptorless dehydrogenation of heterocycles catalyzed by frustrated Lewis pairs (FLPs) was developed. Oxidation with concomitant liberation of molecular hydrogen proceeded in high to excellent yields for N-protected indolines as well as four other substrate classes. The mechanism of this unprecedented FLP-catalyzed reaction was investigated by mechanistic studies, characterization of reaction intermediates by NMR spectroscopy and X-ray crystal analysis, and by quantum-mechanical calculations. Hydrogen liberation from the ammonium hydridoborate intermediate is the rate-determining step of the oxidation. The addition of a weaker Lewis acid as a hydride shuttle increased the reaction rate by a factor of 2.28 through a second catalytic cycle.
- Maier, Alexander F. G.,Tussing, Sebastian,Schneider, Tobias,Fl?rke, Ulrich,Qu, Zheng -Wang,Grimme, Stefan,Paradies, Jan
-
p. 12219 - 12223
(2016/10/13)
-
- Asymmetric catalysis with substitutionally labile yet stereochemically stable chiral-at-metal iridium(III) complex
-
A metal-coordination-based high performance asymmetric catalyst utilizing metal centrochirality as the sole element of chirality is reported. The introduced substitutionally labile chiral-at-metal octahedral iridium(III) complex exclusively bears achiral
- Huo, Haohua,Fu, Chen,Harms, Klaus,Meggers, Eric
-
supporting information
p. 2990 - 2993
(2014/03/21)
-
- Gold(I)-catalyzed rearrangement of alkynylaziridine indoles for the synthesis of spiro-tetrahydro-β-carbolines
-
Functionalized spiro-tetrahydro-β-carbolines were formed by an efficient gold(I)-catalyzed rearrangement reaction of alkynylaziridine indoles. The reaction involved a Friedel-Crafts type intramolecular reaction of alkynylaziridine indoles, following by hydroamination of aminoallene intermediate.
- Yang, Yan-Fang,Li, Lian-Hua,He, Yu-Tao,Luo, Jian-Yi,Liang, Yong-Min
-
supporting information
p. 702 - 707
(2014/02/14)
-
- C2-selective direct alkynylation of indoles
-
The first C2-selective alkynylation of indoles using the hypervalent iodine reagent triisopropylsilylethynyl-1,2-benziodoxol-3(1H)-one (TIPS-EBX) with Pd(II) as a catalyst is described. This convenient and robust method gives a single-step access to substituted alkynyl indoles with very high C2 selectivity. The reaction is orthogonal to classical Pd(0) cross-coupling reactions, as it is tolerant to bromide and iodide substituents. The used silyl protecting group can be easily removed to give terminal acetylenes.
- Tolnai, Gergely L.,Ganss, Stephanie,Brand, Jonathan P.,Waser, Jerome
-
supporting information
p. 112 - 115
(2013/03/28)
-
- General and efficient synthesis of 2,3-unsubstituted indoles catalyzed by acidic mesoporous molecular sieves
-
A general and efficient method for the synthesis of 2,3-unsubstituted indoles has been established by the intramolecular cyclization of N-benzyl 2-anilinoacetals. Acidic mesoporous molecular sieve (MCM-41-SO3H) has shown excellent catalytic activity on this transformation, and the 2,3-unsubstituted indoles bearing 7-substituent or strong electron-withdrawing substituents also could be achieved by this protocol. Moreover, the heterogeneous catalyst, MCM-41-SO3H, could be conveniently recovered and reused without obvious loss of the catalytic activity. This work will provide an economic and environmental-benign method for the construction of various indole derivatives.
- Sun, Nan,Hong, Lingfen,Huang, Fang,Ren, Hong,Mo, Weimin,Hu, Baoxiang,Shen, Zhenlu,Hu, Xinquan
-
p. 3927 - 3933
(2013/06/27)
-
- Synthesis of indole and biindolyl triflones: Trifluoromethanesulfonylation of indoles with Tf2O/TTBP (2,4,6-tri- tert -butylpyridine) system
-
A convenient synthesis of indole triflones is reported. N-Alkyl, aryl and N-H indole triflones were obtained in 82-96% yields by the Tf2O/TTBP System. Biindolyl triflones were accessed in 51-81% yields for the first time by simple treatment of the resulting indole triflones with a base and without any use of organometallic chemistry. An environmentally friendly solvent, Solkane 365/227, can be substituted for this process without any loss of efficiency.
- Xu, Xiu-Hua,Liu, Guo-Kai,Azuma, Ayaka,Tokunaga, Etsuko,Shibata, Norio
-
supporting information; experimental part
p. 4854 - 4857
(2011/11/06)
-
- Palladium-catalyzed direct and regioselective C-H bond functionalization/ oxidative acetoxylation of indoles
-
The first general examples of palladium-catalyzed direct and selective oxidative C3-acetoxylation of indoles are presented. The mild reaction conditions (70 °C and with weak base, KOAc) in this indole C-H-acetoxylation are notable.
- Choy, Pui Ying,Lau, Chak Po,Kwong, Fuk Yee
-
supporting information; experimental part
p. 80 - 84
(2011/03/22)
-
- Pd-catalyzed direct and selective C-H functionalization: C3-acetoxylation of indoles
-
Direct functionalization of C-H bonds has been a hot topic in organic chemistry during recent years. Arenes-one of the most abundant chemical motifs-usually have multiple C-H bonds. Although, some examples of direct functionalizations of arenes have been
- Liu, Qiang,Li, Gang,Yi, Hong,Wu, Pan,Liu, Jie,Lei, Aiwen
-
supporting information; experimental part
p. 2353 - 2357
(2011/04/24)
-
- Selective ruthenium-catalyzed N-alkylation of indoles by using alcohols
-
(Chemical Equation Presentation) Alcohols for alkylation! The first homogeneous-catalyzed N-alkylations of indoles with aliphatic alcohols proceed under transfer hydrogenation conditions. By the use of the Shvo catalyst and p-toluenesulfonic acid (PTSA) t
- Baehn, Sebastian,Imm, Sebastian,Mevius, Kathleen,Neubert, Lorenz,Tillack, Annegret,Williams, Jonathan M. J.,Beller, Matthias
-
supporting information; experimental part
p. 3590 - 3593
(2010/07/05)
-
- Enantioselective Friedel-Crafts alkylations of α,β-unsaturated 2-acyl imidazoles catalyzed by bis(oxazolinyl)pyridine-scandium(III) triflate complexes
-
An enantioselective Friedel-Crafts alkylation with α,β-unsaturated 2-acyl imidazoles and electron-rich aromatic nucleophiles catalyzed by bis(oxazolinyl)pyridine-scandium(III) triflate complexes has been accomplished. These α,β-unsaturated 2-acyl imidazol
- Evans, David A.,Fandrick, Keith R.,Song, Hyun-Ji
-
p. 8942 - 8943
(2007/10/03)
-
- Enantioselective indole Friedel-Crafts alkylations catalyzed by bis(oxazolinyl)pyridine-scandium(III) triflate complexes
-
A highly enantioselective Friedel-Crafts alkylation of electron-rich aromatic nucleophiles catalyzed by scandium(III) triflate-pyridyl(bis)oxazoline complexes has been accomplished. The reaction involves α,β-unsaturated acyl phosphonates as electrophiles and primarily substituted indoles as nucleophiles. The reactive acyl phosphonate product is converted to the corresponding ester or amide in good overall yield by adding an alcohol or amine directly to the reaction mixture. Copyright
- Evans, David A.,Scheidt, Karl A.,Fandrick, Keith R.,Lam, Hon Wai,Wu, Jimmy
-
p. 10780 - 10781
(2007/10/03)
-
- Indole inhibitors of human nonpancreatic secretory phospholipase A2. 3. Indole-3-glyoxamides
-
The preceding papers of this series detail the development of functionalized indole-3-acetamides as inhibitors of hnps-PLA2. We describe here the extension of the structure-activity relationship to include a series of indole-3-glyoxamide derivatives. Functionalized indole-3-glyoxamides with an acidic substituent appended to the 4- or 5-position of the indole ring were prepared and tested as inhibitors of hnps-PLA2. It was found that the indole-3-glyoxamides with a 4-oxyacetic acid substituent had optimal inhibitory activity. These inhibitors exhibited an improvement in potency over the best of the indole-3-acetamides, and LY315920 (6m) was selected for evaluation clinically as an hnps-PLA2 inhibitor.
- Draheim, Susan E.,Bach, Nicholas J.,Dillard, Robert D.,Berry, Dennis R.,Carlson, Donald G.,Chirgadze, Nickolay Y.,Clawson, David K.,Hartley, Lawrence W.,Johnson, Lea M.,Jones, Noel D.,McKinney, Emma R.,Mihelich, Edward D.,Olkowski, Jennifer L.,Schevitz, Richard W.,Smith, Amy C.,Snyder, David W.,Sommers, Cynthia D.,Wery, Jean-Pierre
-
p. 5159 - 5175
(2007/10/03)
-
- One-Pot Synthesis of Indoles from 1-Benzyl-2,3-dihydroindoles
-
A facile one-pot dehydrodebenzylation of 1-benzyl-2,3-dihydroindoles to indoles uses 10percent palladium on carbon as catalyst and ammonium formate as hydrogen donor in methanol.
- Kiguchi, Toshiko,Kuninobu, Naoko,Takahashi, Yoshiko,Yoshida, Yukiyo,Naito, Takeaki,Ninomiya, Ichiya
-
p. 778 - 781
(2007/10/02)
-