- Synthesis, anti-inflammatory and antimicrobial activities of new 1,2,4-oxadiazoles peptidomimetics
-
A new series of 1,2,4-oxadizoles 6a-g have been synthesised in good yields using the peptide synthesis strategy. The prepared compounds were tested for anti-inflammatory and antimicrobial activities. The anti-inflammatory activities were determined in the
- Leite, Ana Cristina L.,Vieira, Renata F.,De Faria, Antonio R.,Wanderley, Almir G.,Afiatpour, Parviz,Ximenes, Eulalia Camelo P. A.,Srivastava, Rajendra M.,De Oliveira, Claudia F.,Medeiros,Antunes, Edson,Brondani, Dalci J.
-
-
Read Online
- Synthesis, in vitro ADME profiling and in vivo pharmacological evaluation of novel glycogen phosphorylase inhibitors
-
A small set of indole-2-carboxamide derivatives identified from a high-throughput screening campaign has been described as a novel, potent, and glucose-sensitive inhibitors of glycogen phosphorylase a (GPa). Among this series of compounds, compound 2 exhibited moderate GP inhibitory activity (IC50 = 0.29 μM), good cellular efficacy (IC50 = 3.24 μM for HepG2 cells and IC50 = 7.15 μM for isolated rat hepatocytes), together with good absorption, distribution, metabolism, and elimination (ADME) profiles. The in vivo animal study revealed that compound 2 significantly inhibited an increase of fasting blood glucose level in adrenaline-induced diabetic mice.
- Miao, Guang-xin,Wang, You-de,Yan, Zhi-wei,Zhang, Li-ying
-
-
Read Online
- Mapping the s1 and s1’ subsites of cysteine proteases with new dipeptidyl nitrile inhibitors as trypanocidal agents
-
The cysteine protease cruzipain is considered to be a validated target for therapeutic intervention in the treatment of Chagas disease. A series of 26 new compounds were designed, synthesized, and tested against the recombinant cruzain (Cz) to map its S1/S1′ subsites. The same series was evaluated on a panel of four human cysteine proteases (CatB, CatK, CatL, CatS) and Leishmania mexicana CPB, which is a potential target for the treatment of cutaneous leishmaniasis. The synthesized compounds are dipeptidyl nitriles designed based on the most promising combinations of different moieties in P1 (ten), P2 (six), and P3 (four different building blocks). Eight compounds exhibited a Ki smaller than 20.0 nM for Cz, whereas three compounds met these criteria for LmCPB. Three inhibitors had an EC50 value of ca. 4.0 μM, thus being equipotent to benznidazole according to the antitrypanosomal effects. Our mapping approach and the respective structure-activity relationships provide insights into the specific ligand-target interactions for therapeutically relevant cysteine proteases.
- Cianni, Lorenzo,Lemke, Carina,Gilberg, Erik,Feldmann, Christian,Rosini, Fabiana,Rocho, Fernanda Dos Reis,Ribeiro, Jean F. R.,Tezuka, Daiane Y.,Lopes, Carla D.,de Albuquerque, Sérgio,Bajorath, Jürgen,Laufer, Stefan,Leit?o, Andrei,Gütschow, Michael,Montanariid, Carlos A.
-
-
- Optimization strategy of single-digit nanomolar cross-class inhibitors of mammalian and protozoa cysteine proteases
-
Cysteine proteases (CPs) are involved in a myriad of actions that include not only protein degradation, but also play an essential biological role in infectious and systemic diseases such as cancer. CPs also act as biomarkers and can be reached by active-
- Cianni, Lorenzo,Rocho, Fernanda dos Reis,Rosini, Fabiana,Bonatto, Vinícius,Ribeiro, Jean F.R.,Lameira, Jer?nimo,Leit?o, Andrei,Shamim, Anwar,Montanari, Carlos A.
-
-
- Synthesis and structure-activity relationship of nitrile-based cruzain inhibitors incorporating a trifluoroethylamine-based P2 amide replacement
-
The structure-activity relationship for nitrile-based cruzain inhibitors incorporating a P2 amide replacement based on trifluoroethylamine was explored by deconstruction of a published series of inhibitors. It was demonstrated that the P3 biphenyl substituent present in the published inhibitor structures could be truncated to phenyl with only a small loss of affinity. The effects of inverting the configuration of the P2 amide replacement and linking a benzyl substituent at P1 were observed to be strongly nonadditive. We show that plotting affinity against molecular size provides a means to visualize both the molecular size efficiency of structural transformations and the nonadditivity in the structure-activity relationship. We also show how the relationship between affinity and lipophilicity, measured by high-performance liquid chromatography with an immobilized artificial membrane stationary phase, may be used to normalize affinity with respect to lipophilicity.
- Gomes, Juliana C.,Cianni, Lorenzo,Ribeiro, Jean,dos Reis Rocho, Fernanda,da Costa Martins Silva, Samelyn,Batista, Pedro Henrique Jatai,Moraes, Carolina Borsoi,Franco, Caio Haddad,Freitas-Junior, Lucio H.G.,Kenny, Peter W.,Leit?o, Andrei,Burtoloso, Antonio C.B.,de Vita, Daniela,Montanari, Carlos A.
-
-
- Amidation of carboxylic acids via the mixed carbonic carboxylic anhydrides and its application to synthesis of antidepressant (1S,2R)-tranylcypromine
-
Primary amidations of carboxylic acids 1 or 3 with NH4Cl in the presence of ClCO2Et and Et3N were developed to afford the corresponding primary amides in 22% to quantitative yields. Additionally, we have applied the amidation to the preparation of various amides containing hydroxamic acids and achieved the synthesis of (1S,2R)-tranylcypromine as an antidepressant medicine via Lossen rearrangement.
- Ezawa, Tetsuya,Kawashima, Yuya,Noguchi, Takuya,Jung, Seunghee,Imai, Nobuyuki
-
p. 1690 - 1699
(2017/11/14)
-
- RITA Mimics: Synthesis and Mechanistic Evaluation of Asymmetric Linked Trithiazoles
-
The established cytotoxic agent RITA contains a thiophene-furan-thiophene backbone and two terminal alcohol groups. Herein we investigate the effect of using thiazoles as the backbone in RITA-like molecules and modifying the terminal groups of these trithiazoles, thereby generating 41 unique structures. Incorporating side chains with varied steric bulk allowed us to investigate how size and a stereocenter impacted biological activity. Subjecting compounds to growth inhibition assays on HCT-116 cells showed that the most potent compounds 7d, 7e, and 7h had GI50 values of 4.4, 4.4, and 3.4 μM, respectively, versus RITA (GI50 of 800 nM). Analysis of these compounds in apoptosis assays proved that 7d, 7e, and 7h were as effective as RITA at inducing apoptosis. Evaluating the impact of 7h on proteins targeted by RITA (p53, c-Myc, and Mcl-1) indicated that it acts via a different mechanism of action to that of RITA. RITA suppressed Mcl-1 protein via p53, whereas compound 7h suppressed Mcl-1 expression via an alternative mechanism independent of p53.
- Pietkiewicz, Adrian L.,Zhang, Yuqi,Rahimi, Marwa N.,Stramandinoli, Michael,Teusner, Matthew,McAlpine, Shelli R.
-
supporting information
p. 401 - 406
(2017/04/21)
-
- Synthesis of macrocycles that inhibit protein synthesis: Stereochemistry and structural based studies on sanguinamide B derivatives
-
We report the synthesis of seven new sanguinamide B (SanB) analogues. Substitution of amino acids along the backbone of SanB and testing in HCT-116 colon cancer cell lines identified new biologically active SanB derivatives. These compounds establish a st
- Pietkiewicz, Adrian L.,Wahyudi, Hendra,McConnell, Jeanette R.,McAlpine, Shelli R.
-
p. 6979 - 6982
(2015/02/05)
-
- Mechanistic studies of sanguinamide B derivatives: A unique inhibitor of eukaryotic ribosomes
-
Described are mechanistic studies of two Sanguinamide B (San B) derivatives. These compounds were identified as eukaryotic ribosomal inhibitors. Two biotinylated San B derivatives were synthesized and used to capture protein targets in a pull-down assay.
- Tantisantisom, Worawan,Ramsey, Deborah M.,McAlpine, Shelli R.
-
supporting information
p. 4638 - 4641
(2013/10/08)
-
- Convenient preparation of primary amides via activation of carboxylic acids with ethyl chloroformate and triethylamine under mild conditions
-
Primary amides were easily prepared in 22-99% yields from the corresponding carboxylic acids 1 or 5 with NH4Cl via activation with ClCO 2Et and Et3N. The enantiomers of the corresponding primary amides of Cbz-, Boc-, or Fmoc-α-amino acids can be separated by using a chiral column.
- Noguchi, Takuya,Sekine, Masahiro,Yokoo, Yuki,Jung, Seunghee,Imai, Nobuyuki
-
p. 580 - 582
(2013/07/05)
-
- Synthesis, structurea-activity analysis, and biological evaluation of sanguinamide B analogues
-
We report the first synthesis of sanguinamide B analogues. Substituting N-methylated (N-Me) amino acids, glycine (Gly), and l-or d-phenylalanine (Phe) into the backbone of sanguinamide B showed that only l-and d-Phe residues controlled the macrocycle conf
- Wahyudi, Hendra,Tantisantisom, Worawan,Liu, Xuechao,Ramsey, Deborah M.,Singh, Erinprit K.,McAlpine, Shelli R.
-
p. 10596 - 10616
(2013/02/22)
-
- 2-(N-Benzyl-N-phenylsulfonamido)alkyl amide derivatives as γ-secretase inhibitors
-
A series of (N-benzyl-N-phenylsulfonamido)alkyl amides were developed from classic and parallel synthesis strategies. Compounds with good in vitro and in vivo γ-secretase activity were identified and described.
- Parker, Michael F.,Barten, Donna M.,Bergstrom, Carl P.,Bronson, Joanne J.,Corsa, Jason A.,Dee, Michael F.,Gai, Yonghua,Guss, Valerie L.,Higgins, Mendi A.,Keavy, Daniel J.,Loo, Alice,Mate, Robert A.,Marcin, Larry R.,McElhone, Katharine E.,Polson, Craig T.,Roberts, Susan B.,MacOr, John E.
-
p. 6828 - 6831,4
(2020/09/02)
-
- Synthesis of the thiazole-thiazoline fragment of largazole analogues
-
The thiazole - thiazoline fragment of the marine natural product largazole, a potent histone deacetylase 1 inhibitor, has been synthesized in five steps. The methodology provides rapid access to thiazole-4-carbonitrile, thiazole-4-carbimidate, thiazole -
- Diness, Frederik,Nielsen, Daniel S.,Fairlie, David P.
-
experimental part
p. 9845 - 9851
(2012/01/02)
-
- Carbamates of 4′-demethyl-4-deoxypodophyllotoxin: Synthesis, cytotoxicity and cell cycle effects
-
In an attempt to generate compounds with superior bioactivity and reduced toxicity, 12 carbamates of 4′-demethyl-4-deoxypodophyllotoxin, N-(1-oxyl-4′-demethyl- 4-deoxypodophyllic)-α-amino acids amides, were synthesized and evaluated for antiproliferative activity and cell cycle effects. These synthesized compounds proved to be more hydrophilic, as well as improved or comparable in vitro cytotoxicities against four cell lines (A-549, HeLa, SiHa, and HL-60) compared with either parent DPT or anti-cancer drug VP-16. Furthermore, flow cytometric analysis exhibited that N-(1-oxyl-4′- demethyl-4-deoxypodophyllic)-d-α-methine amide (15f) induced cell cycle arrest in the G2/M phase in A-549 cells.
- Chen, Shi-Wu,Gao, Yuan-Yu,Zhou, Ni-Ni,Liu, Jie,Huang, Wen-Ting,Hui, Ling,Jin, Yan,Jin, Yong-Xin
-
supporting information; experimental part
p. 7355 - 7358
(2012/02/04)
-
- Enantiopure trans -3-arylaziridine-2-carboxamides: Preparation by bacterial hydrolysis and ring-openings toward enantiopure, unnatural D -α-amino acids
-
Several racemic trans-3-arylaziridine-2-carboxamides were prepared and then resolved by Rhodococcus rhodochrous IFO 15564-catalyzed hydrolysis. The resulting enantiopure (2R,3S)-3-arylaziridine-2-carboxamides are adequate substrates to undergo fully stereoselective nucleophilic ring-openings at the C-3 ring position to finally yield enantiopure, unnatural d-α- aminocarboxylic acids. Experimental evidence is provided that suggests the fate of the (2S,3R)-3-arylaziridine-2-carboxylic acids concomitantly formed during the resolution processes. In this context, the similar bacterial resolution of racemic 1-arylaziridine-2-carboxamides and -carbonitriles, previously investigated by our research group, has been partially re-examined.
- Moran-Ramallal, Roberto,Liz, Ramon,Gotor, Vicente
-
experimental part
p. 6614 - 6624
(2010/11/17)
-
- The preparation of optically active α-amino 4H-[1,2,4]oxadiazol-5-ones from optically active α-amino acids
-
Optically active α-amino 4H-[1,2,4]oxadiazol-5-ones (oxadiazolones) were prepared from optically active α-amino acids in five synthetic steps. The oxadiazolone moiety serves as a bioisosteric replacement for the carboxylic acid. Incorporation of an α-amino oxadiazolone into a representative dipeptide mimic is described.
- Mangette, John E.,Johnson, Matthew R.,Le, Van-Duc,Shenoy, Rajesh A.,Roark, Howard,Stier, Michael,Belliotti, Thomas,Capiris, Thomas,Guzzo, Peter R.
-
experimental part
p. 9536 - 9541
(2009/12/28)
-
- Design, Synthesis, Molecular Modeling Studies, and Calpain Inhibitory Activity of Novel α-Ketoamides Incorporating Polar Residues at the P 1′-Position
-
A series of novel α-ketoamides incorporating stereoisomeric residues with different electronic properties at the P1′-position were synthesized to study the electronic requirements for inhibitor binding to the S1′-subsite of calpain I
- Donkor, Isaac O.,Han, Jie,Zheng, Xiaozhang
-
-
- Activation of carboxylic acids by pyrocarbonates. Application of di-tert-butyl pyrocarbonate as condensing reagent in the synthesis of amides of protected amino acids and peptides
-
Amides formation from protected amino acids and peptides was achieved in an easy and convenient one-pot procedure using di-tert-butyl pyrocarbonate as activating agent in the presence of pyridine and ammonium hydrogencarbonate. The method gave good yields and did not induce racemization during the amidation of urethane protected amino acids.
- Pozdnev, Vladimir F.
-
p. 7115 - 7118
(2007/10/02)
-