- Convenient method for the synthesis of some novel chiral methyl 2-(2-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)propanoate derivatives and biological evaluation of their antioxidant, cytotoxic, and molecular docking properties
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Ten chiral methyl 2-(2-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)propanoate derivatives 6a-6j have been synthesized from optically pure amino methyl phenol 5 and 4-nitrophenyl chloroformate. These derivatives 6a-6j are characterized by 1H NMR, 13C NMR, FT-IR, and HRMS spectral techniques. Optical purity of these derivatives was confirmed by chiral HPLC method. Ten synthesized ester derivatives 6a-6j were screened for their in vitro antioxidant activity. Among the compounds 6b-d and 6h-j have exhibited comparable antioxidant activity with ascorbic acid as a standard. Compounds 6a and 6e-g have shown moderate antioxidant activity. Further, the in vitro cytotoxicity of these compounds were studied through MTT cell proliferation assay in addition the effect on LDH leakage and NO release. Among the derivatives, 6j showed extremely best activity and the IC50 value (12.54 ± 0.71 μM) is very close to doxorubicin (7.2 ± 0.58 μM) as a standard. Compounds 6b, 6h, and 6i showed better inhibition next to compound 6j on the viability of HepG2 cells with an IC50 value (μM) of 56.02 ± 1.4, 41.76 ± 0.58, and 38.17 ± 0.34, respectively. Also, molecular docking studies have been carried out with STAT-3 (PDB ID: 1BG1) and BCL-2 (PDB ID: 4AQ3) proteins against the four active compounds 6b, 6h, 6i, and 6j. The binding energies of the tested compounds were in the range of ?7.76 to ?8.41 kcal/mol, which is very close to doxorubicin (?8.53 kcal/mol) as a standard. These molecular docking results are in good agreement with the in vitro studies.
- Matam, Sivakumar,Kaliyan, Prabakaran,Selvaraj, Loganathan,Muthu, Seenivasa Perumal,Lohanathan, Bharathi Priya,Viswanadhan, Vijaya Padma,Makala, Himesh,Venkatasubramanian, Ulaganathan
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supporting information
p. 569 - 579
(2020/12/11)
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- A DNA-Encoded Chemical Library Incorporating Elements of Natural Macrocycles
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Here we show a seven-step chemical synthesis of a DNA-encoded macrocycle library (DEML) on DNA. Inspired by polyketide and mixed peptide-polyketide natural products, the library was designed to incorporate rich backbone diversity. Achieving this diversity, however, comes at the cost of the custom synthesis of bifunctional building block libraries. This study outlines the importance of careful retrosynthetic design in DNA-encoded libraries, while revealing areas where new DNA synthetic methods are needed.
- Stress, Cedric J.,Sauter, Basilius,Schneider, Lukas A.,Sharpe, Timothy,Gillingham, Dennis
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supporting information
p. 9570 - 9574
(2019/06/24)
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- Strategies to develop selective CB2 receptor agonists from indole carboxamide synthetic cannabinoids
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Activation of the CB2 receptor is an attractive therapeutic strategy for the treatment of a wide range of inflammatory diseases. However, receptor subtype selectivity is necessary in order to circumvent the psychoactive effects associated with activation of the CB1 receptor. We aimed to use potent, non-selective synthetic cannabinoids designer drugs to develop selective CB2 receptor agonists. Simple structural modifications such as moving the amide substituent of 3-amidoalkylindole synthetic cannabinoids to the 2-position and bioisosteric replacement of the indole core to the 7-azaindole scaffold are shown to be effective and general strategies to impart receptor subtype selectivity. 2-Amidoalkylindole 16 (EC50 CB1 > 10 μM, EC50 CB2 = 189 nM) and 3-amidoalkyl-7-azaindole 21 (EC50 CB1 > 10 μM, EC50 = 49 nM) were found to be potent and selective agonists with favourable physicochemical properties. Docking studies were used to elucidate the molecular basis for the observed receptor subtype selectivity for these compounds.
- Moir, Michael,Lane, Samuel,Lai, Felcia,Connor, Mark,Hibbs, David E.,Kassiou, Michael
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supporting information
p. 291 - 309
(2019/07/17)
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- Novel Fubinaca/Rimonabant hybrids as endocannabinoid system modulators
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The discovery of novel modulators of the cannabinoid system is a current topic in medicinal chemistry. In this paper, we report nine novel carboxamides designed as hybrids of Fubinaca family compounds and Rimonabant. These hybrids were obtained by linking the 1-benzyl-2,5-dichloroindazole-3-carboxylic acid to different amino acids bearing a hydrophobic side chain and three different C-terminus. The new chemical entities were tested in vitro to evaluate their bioactivity by means of receptor binding assays and [35S]GTPγS stimulation assays to reveal their affinity and potency. We found that all compounds were able to bind to the cannabinoid receptors in the low nanomolar range with a marked selectivity towards the CB1 cannabinoid receptor. Some of them are full agonists, whereas the others act as partial agonists. These molecules could be potentially used as anti-obesity agents, antiemetic and analgesics.
- Stefanucci, Azzurra,Macedonio, Giorgia,Dvorácskó, Szabolcs,T?mb?ly, Csaba,Mollica, Adriano
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p. 1595 - 1605
(2018/09/14)
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- Quantitative Modeling of Bis(pyridine)silver(I) Permanganate Oxidation of Hydantoin Derivatives: Guidelines for Predicting the Site of Oxidation in Complex Substrates
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The bis(pyridine)silver(I) permanganate promoted hydroxylation of diketopiperazines has served as a pivotal transformation in the synthesis of complex epipolythiodiketopiperazine alkaloids. This late-stage C-H oxidation chemistry is strategically critical to access N-acyl iminium ion intermediates necessary for nucleophilic thiolation of advanced diketopiperazines en route to potent epipolythiodiketopiperazine anticancer compounds. In this study, we develop an informative mathematical model using hydantoin derivatives as a training set of substrates by relating the relative rates of oxidation to various calculated molecular descriptors. The model prioritizes Hammett values and percent buried volume as key contributing factors in the hydantoin series while correctly predicting the experimentally observed oxidation sites in various complex diketopiperazine case studies. Thus, a method is presented by which to use simplified training molecules and resulting correlations to explain and predict reaction behavior for more complex substrates.
- Bischoff, Amanda J.,Nelson, Brandon M.,Niemeyer, Zachary L.,Sigman, Matthew S.,Movassaghi, Mohammad
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supporting information
p. 15539 - 15547
(2017/11/06)
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- Sequential ruthenium catalysis for olefin isomerization and oxidation: Application to the synthesis of unusual amino acids
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How can you use a ruthenium isomerization catalyst twice? A ruthenium-catalyzed sequence for the formal two-carbon scission of allyl groups to carboxylic acids has been developed. The reaction includes an initial isomerization step using commercially available ruthenium catalysts followed by in situ transformation of the complex to a metal-oxo species, which is capable of catalyzing subsequent oxidation reactions. The method enables enantioselective syntheses of challenging α-tri- and tetrasubstituted α-amino acids including an expedient total synthesis of the antiepileptic drug levetiracetam.
- Liniger, Marc,Liu, Yiyang,Stoltz, Brian M.
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supporting information
p. 13944 - 13949
(2017/11/06)
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- Distal Stereocontrol Using Guanidinylated Peptides as Multifunctional Ligands: Desymmetrization of Diarylmethanes via Ullman Cross-Coupling
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We report the development of a new class of guanidine-containing peptides as multifunctional ligands for transition-metal catalysis and its application in the remote desymmetrization of diarylmethanes via copper-catalyzed Ullman cross-coupling. Through design of these peptides, high levels of enantioinduction and good isolated yields were achieved in the long-range asymmetric cross-coupling (up to 93:7 er and 76% yield) between aryl bromides and malonates. Our mechanistic studies suggest that distal stereocontrol is achieved through a Cs-bridged interaction between the Lewis-basic C-terminal carboxylate of the peptides with the distal arene of the substrate.
- Kim, Byoungmoo,Chinn, Alex J.,Fandrick, Daniel R.,Senanayake, Chris H.,Singer, Robert A.,Miller, Scott J.
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supporting information
p. 7939 - 7945
(2016/07/07)
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- Enantioselective α-Alkylation of Aldehydes by Photoredox Organocatalysis: Rapid Access to Pharmacophore Fragments from β-Cyanoaldehydes
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The combination of photoredox catalysis and enamine catalysis has enabled the development of an enantioselective α-cyanoalkylation of aldehydes. This synergistic catalysis protocol allows for the coupling of two highly versatile yet orthogonal functionalities, allowing rapid diversification of the oxonitrile products to a wide array of medicinally relevant derivatives and heterocycles. This methodology has also been applied to the total synthesis of the lignan natural product (-)-bursehernin. A combination of photoredox catalysis and enamine catalysis has enabled the development of an enantioselective cyanoalkylation of aldehydes. This synergistic catalysis protocol makes possible the coupling of two highly versatile yet orthogonal functionalities.
- Welin, Eric R.,Warkentin, Alexander A.,Conrad, Jay C.,MacMillan, David W. C.
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supporting information
p. 9668 - 9672
(2015/08/11)
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- Hepatitis C Virus Inhibitors
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The present disclosure is generally directed to antiviral compounds, and more specifically directed to combinations of compounds which can inhibit the function of the NS5A protein encoded by Hepatitis C virus (HCV), compositions comprising such combinations, and methods for inhibiting the function of the NS5A protein.
- -
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Paragraph 1379-1380
(2015/02/25)
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- COMBINATIONS OF HEPATITIS C VIRUS INHIBITORS
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The present disclosure is generally directed to antiviral compounds, and more specifically directed to combinations of compounds which can inhibit the function of the NS5A protein encoded by Hepatitis C virus (HCV), compositions comprising such combinations, and methods for inhibiting the function of the NS5A protein.
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Page/Page column 497; 498
(2015/02/02)
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- Substituted 2-hydroxy-N-(arylalkyl)benzamides induce apoptosis in cancer cell lines
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Variously substituted 2-hydroxy-N-(arylalkyl)benzamides were prepared and screened for antiproliferative and cytotoxic activity in cancer cell lines in vitro. Five compounds, out of 33 showed single-digit micromolar IC50 values against several human cancer cell lines. One of the most potent compounds N-((R)-1-(4-chlorophenylcarbamoyl)-2-phenylethyl)-5-chloro-2-hydroxybenzamide (6k) reduced proliferation and induced apoptosis in the melanoma cell line G361 in a dose-dependent manner, as shown by decrease in 5-bromo-2′- deoxyuridine incorporation and increase in several apoptotic markers, including subdiploid population increase, activation of caspases and site-specific poly-(ADP-ribose)polymerase (PARP) cleavage.
- Imramovsky, Ale?,Jorda, Radek,Pauk, Karel,?ezní?ková, Eva,Du?ek, Jan,Hanusek, Ji?í,Kry?tof, Vladimír
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p. 253 - 259
(2013/10/01)
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- Tridentate ligands derived from L-tert-Leucine for the Cu(II) mediated asymmetric Henry reaction
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Chiral tridentate Schiff base ligands were prepared from L-tert-Leucine and used as catalysts in the asymmetric Henry reaction in the presence of Cu(II) ions. Moderate enantiomeric excesses (up to 66%) and yields (up to 76%) of the desired β-nitroalcohols were obtained. TUeBITAK.
- Korkmaz, Neslihan,Astley, Demet,Astley, Stephen T.
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experimental part
p. 361 - 374
(2012/02/01)
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- Probing the efficiency of N-heterocyclic carbene promoted O- to C-carboxyl transfer of oxazolyl carbonates
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(Chemical Equation Presented) Screening of a range of azolium salts, bases and solvents for reactivity indicates that triazolinylidenes, generated in situ with KHMDS in THF, promote the Steglich rearrangement of oxazolyl carbonates with high catalytic efficiency (typical reaction time 5 min at 1.5 mol % NHC). This protocol shows wide substrate applicability, even allowing the efficient generation of vicinal quaternary centers. An improved experimental procedure is also described that allows a simplified one-pot reaction protocol to be employed with similarly high catalytic efficiency.
- Thomson, Jennifer E.,Campbell, Craig D.,Concellon, Carmen,Duguet, Nicolas,Rix, Kathryn,Slawin, Alexandra M. Z.,Smith, Andrew D.
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p. 2784 - 2791
(2008/09/20)
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- Photochemistry of N-Phthaloyl α-Amino Acid Esters: A New Approach to β,γ-Unsaturated α-Amino Acid, Dihydrobenzazepinedione, and Pyrrolizidinone Derivatives
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The N-phthaloyl-α-amino acid methyl esters of 2-aminobutyric acid (2a), valine (2b), norvaline (2c), tert-leucine (2d), isoleucine (2e), allo-isoleucine (2f), leucine (2g), methionine (2h), alanine (2i), and phenylalanine (2k) were synthesized in enantiomerically pure form via the N-phthaloyl-α-amino acids (1a-k), and their photochemistry was studied.Except 2i and 2k, which proved to be photostable, all compounds were converted into three types of products, depending on the substitution pattern: a) isomerization products (derivatives of β,γ-unsaturated α-amino acids) 3a, b, c, and e, b) ring expansion products (benzazepinedione esters) 4a and c, and c) cyclization products (5d from the tert-leucine derivative 2d).High diastereoselectivities (d.r. >95:5) were observed for all reactions except the transformations of the 2-aminobutyric acid derivative 2a.The absolute configuration of the α-stereogenic center was retained during photolysis, as proven for the isodehydrovaline (type a product) 3b.PCC oxidation (to give 7b) and hydrogenation afforded 2b with an optical rotation comparable to the starting material.Treatment of 3b with an acid or a base led to epimerization (3b') or isomerization of the C=C bond (6b), respectively.The diastereomeric dihydrobenzazepinedione esters 4a, b were formed with d.r. = 33:67 (cis:trans) and in 60percent yield during photolysis of 2a.The isoleucine derivative 2e, however, was converted into the cis isomer 4a with high diastereoselectivity (d.r. >95:5), whereas the corresponding allo substrate 2f was only converted into the trans-isomer 4b.Ethylene was extruded during irradiation of the latter substrates and during irradiation of the norvaline derivative 2c, whereas propene extrusion from the leucine derivative 2g led to the formation of the unsubstituted type b product 4c.The methionine derivative 1h was the only N-phthaloylamino acid which did not show photodecarboxylation, instead two ξ-hydrogen abstraction products were formed: the hydroxy acid 9h and the tetracylic lactone 10h.The methionine ester 2h was only converted into the ring expansion products 11h, h' presumably by a photo electron transfer step.The chronology of the double hydrogen transfer reaction (γ- followed by δ-H abstraction, leading to type a products) was determined by using the deuterium labeled compound (+/-)-2b.Key Words: Photochemistry / α-Amino acids / Amino acids, β,γ-unsaturated / Photoisomerization / Benzazepinedione esters / Selectivity, enantio-, diastereo-
- Griesbeck, Axel G.,Mauder, Harald,Mueller, Ingrid
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p. 2467 - 2476
(2007/10/02)
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- Synthesis of Optically Active 1,3,2-Oxazaphospholidine 2-Sulfides and 1,3,2-Benzodioxaphosphorin 2-Sulfides
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The optical isomers of ten kinds of insecticidal 1,3,2-oxazaphospholidine 2-sulfides (OS) and two kinds of 1,3,2-benzodioxaphosphorin 2-sulfides (BS), including the commercial insecticide salithion, were synthesized in high optical purity by using two optically active aryl methyl phosphorochloridothionates (AMPC) as chiral two-step phosphorylating reagents.Their configurations were assigned according to the reaction mechanism and supported by proton NMR information.
- Wu, Shao-Yong,Hirashima, Akinori,Kuwano, Eiichi,Eto, Morifusa
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p. 537 - 548
(2007/10/02)
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- Synthesis, enzymic degradation, lipophilic properties, and biological activity of [D-alanine2, t-butylglycine 5]enkephalin amide
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L-C(a)-t-Butylglycine (Bug), its amide, methyl ester, and N(a)-t-butoxycarbonyl derivative were prepared by an asymmetric synthesis, and the Hansch side-chain hydrophobic (lipophilicity) parameter determined. A new enkephalin analogue, H . Tyr-D-Ala-Gly-Phe-Bug . HN2 was synthesized which is pharmacologically active in two in vitro assays and strongly resistant against a number of enzymes in vitro.
- Fauchere,Petermann
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p. 824 - 831
(2007/10/02)
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