- Anti-trypanosomal activity of non-peptidic nitrile-based cysteine protease inhibitors
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The cysteine protease cruzipain is considered to be a validated target for therapeutic intervention in the treatment of Chagas disease. Anti-trypanosomal activity against the CL Brener strain of T. cruzi was observed in the 0.1 μM to 1 μM range for three nitrile-based cysteine protease inhibitors based on two scaffolds known to be associated with cathepsin K inhibition. The two compounds showing the greatest potency against the trypanosome were characterized by EC50values (0.12 μM and 0.25 μM) that were an order of magnitude lower than the corresponding Kivalues measured against cruzain, a recombinant form of cruzipain, in an enzyme inhibition assay. This implies that the anti-trypanosomal activity of these two compounds may not be explained only by the inhibition of the cruzain enzyme, thereby triggering a putative polypharmacological profile towards cysteine proteases.
- Burtoloso, Antonio C. B.,de Albuquerque, Sérgio,Furber, Mark,Gomes, Juliana C.,Gon?alez, Cristiana,Kenny, Peter W.,Leit?o, Andrei,Montanari, Carlos A.,Quilles, José Carlos,Ribeiro, Jean F. R.,Rocha, Josmar R.
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Read Online
- Rapid Syntheses of (?)-FR901483 and (+)-TAN1251C Enabled by Complexity-Generating Photocatalytic Olefin Hydroaminoalkylation
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We report a common strategy to facilitate the syntheses of the polycyclic alkaloids (?)-FR901483 (1) and (+)-TAN1251C (2). A divergent synthetic strategy provides access to both natural products through a pivotal spirolactam intermediate (3), which can be accessed on a gram-scale. A photocatalytic olefin hydroaminoalkylation brings together three readily available building blocks and forges the majority of the carbon framework present in 1 and 2 in a single operation, leading to concise total syntheses. The complexity-generating photocatalytic process also provides direct access to novel non-racemic spirolactam scaffolds that are likely to be of interest to early-stage drug discovery programs.
- Reich, Dominik,Trowbridge, Aaron,Gaunt, Matthew J.
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supporting information
p. 2256 - 2261
(2020/01/24)
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- Synthesis, bioactivity, docking and molecular dynamics studies of furan-based peptides as 20s proteasome inhibitors
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Proteasome inhibitors are promising compounds for a number of therapies, including cardiovascular and eye diseases, diabetes, and cancers. We previously reported a series of furanbased peptidic inhibitors with moderate potencies against the proteasome b5 subunit, hypothesizing that the C-terminal furyl ketone motif could form a covalent bond with the catalytic residue, threonine 1. In this context, we describe further optimizations of the furan-based peptides, and a series of dipeptidic and tripeptidic inhibitors were designed and synthesized, aiming at improved potency and better solubility. Most of the tripeptidic inhibitors demonstrated improved potency and selectivity as b5 subunit inhibitors in both enzymatic and cellular assays, and good antineoplastic activities in various tumor cell lines were also observed. However, no inhibitory effects were observed for the dipeptidic compounds, which led us to presume that a noncovalent binding mode is adopted. Docking studies and molecular dynamics simulations were carried out to verify this presumption, with results showing that the distance between the furyl ketone motif and Thr1 is slightly too long to form covalent bond.
- Sun, Qi,Xu, Bo,Niu, Yan,Xu, Fengrong,Liang, Lei,Wang, Chao,Yu, Jiapei,Yan, Gang,Wang, Wei,Jin, Hongwei,Xu, Ping
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p. 498 - 510
(2015/03/18)
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- MODULATORS OF REV-ERB
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The subject matter herein concerns the identification and development of potent synthetic REV-ERB ligands, such as in vivo agonists and antagonists. These compounds allow for characterization of the effects of modulation of this receptor in vivo specifically on circadian behavior and metabolism, and have suitable characteristics for development of medicinal compounds useful for treatment of malconditions such as diabetes, obesity, atherosclerosis, dyslipidemia, a circadian rhythm disorder, coronary artery disease, bipolar disorder, depression, cancer, a sleep disorder, an anxiety disorder, an addiction disorder, a bone-related disorder such osteoporosis, a skeletal muscle disease, e.g., with compromised exercise capacity, or an autoimmune disorder such as psoriasis, multiple sclerosis, inflammatory bowel disease, and others.
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Page/Page column 120
(2015/07/16)
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- OXOAZETIDINE DERIVATIVES, PROCESS FOR THE PREPARATION THEREOF AND USE THEREOF IN HUMAN MEDICINE AND IN COSMETICS
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The present invention relates to novel compounds derived from oxoazetidine corresponding to general formula (I) to the compositions containing same, to the process for preparation thereof and to the use thereof in pharmaceutical or cosmetic compositions.
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Page/Page column 56
(2010/06/11)
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- MELANOCORTIN RECEPTOR ANTAGONIST COMPOUNDS, PROCESS FOR PREPARING THEM AND USE THEREOF IN HUMAN MEDICINE AND COSMETICS
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The present invention relates to novel melanocortin receptor antagonist compounds corresponding to the general formula (I) below, to compositions containing them, to the process for preparing them and to their use in pharmaceutical or cosmetic compositions.
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Page/Page column 23
(2010/06/11)
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- MELANOCORTIN RECEPTOR MODULATORS, PROCESS FOR PREPARING THEM AND USE THEREOF IN HUMAN MEDICINE AND COSMETICS
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The present invention relates to novel melanocortin receptor modulators corresponding to the general formula (I) to compositions containing them, to the process for preparing them and to their use in pharmaceutical or cosmetic compositions.
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Page/Page column 42-43
(2010/06/11)
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- Total synthesis of (-)-apratoxin A, 34-epimer, and its oxazoline analogue
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A concise and convergent total synthesis of the highly cytotoxic marine natural product apratoxin A is accomplished by an 18-step linear sequence. The high sensitivity of the thiazoline, bearing an adjacent β-hydroxyl group at the C35-position, results in
- Numajiri, Yoshitaka,Takahashi, Takashi,Doi, Takayuki
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experimental part
p. 111 - 125
(2010/07/06)
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- RCM approach for the total synthesis of cryptophycin-24 (Arenastatin A)
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An efficient total synthesis of cryptophycin-24 (arenastatin A) is reported, which features two novel synthetic strategies, the use of a RCM reaction to form the macrocycle, and the introduction of the styrene epoxide moiety prior to the macrocyclization
- Tripathy, Narendra K.,Georg, Gunda I.
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p. 5309 - 5311
(2007/10/03)
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- Synthesis and biological activity of new potential agonists for the human adenosine A2A receptor
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New adenosine derivatives have been synthesized and tested as putative agonists of adenosine receptors. Compounds 2-6 derive from the introduction of several types of substituents (electron donating, electron withdrawing, and halogens) in the para-position of the phenyl ring of the parent compound 1, and compound 7 lacks the hydroxyl group of amino alcohol 1. In radioligand binding assays using recombinant human A1, A2A, A2B, and A3 receptors, all compounds showed very low or negligible affinity for A1 and A2B receptors but compounds 3, 5, and 7 displayed a remarkably potent affinity for the A2A receptor with Ki values of 1-5 nM. Bromo derivative 3 displayed a selectivity A1/A2A = 62 and A3/A2A = 16 whereas the presence of a hydroxyl group (compound 5) improved the selectivity of A 1/A2A and A3/A2A to 120- and 28-fold, respectively. When the methoxy derivative 4 lacks the hydroxyl group on the side chain (compound 7), the binding affinity for A2A is increased to 1 nM, improving selectivity ratios to 356- and 100-fold against A1 and A3, respectively. In Chinese hamster ovary cells transfected with human A2A and A2B receptors, most compounds showed a remarkable activity for the A2A receptor, except chloro derivative 2, with EC50 values ranging from 1.4 to 8.8 nM. The compounds behaved as good A2A agonists, and all were more selective than 5′-(N-ethylcarboxamino)adenosine (NECA), with A2B/A 2A ratios of cAMP accumulation ranging from 48 for compound 2 to 666 for compound 7 while the corresponding A2B/A2A ratio for NECA was only 9. Compounds 1, 3, 5, and 7 also displayed higher selectivities than NECA up to 100-fold in isolated aortas of rat and guinea pig. In guinea pig tracheal rings precontracted by carbachol, compounds 2 and 4 were more potent than adenosine (100-fold) and NECA (10-fold), whereas compounds I and 7 displayed similar effects to NECA. Pretreatment of the tracheal rings with A2, A2A, and A2B receptor antagonists 3,7-dimethyl-L-propargylxanthine, 8-(3-chlorostyryl)caffeine, and alloxazine produced a marked inhibition of the tracheal relaxations induced by compounds 1, 2, and 4, but none of the compounds showed selectivity toward any of the adenosine receptors.
- Bosch, M. Pilar,Campos, Francisco,Niubó, Itziar,Rosell, Gloria,Díaz, J. Luis,Brea,Loza, M. Isabel,Guerrero, Angel
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p. 4041 - 4053
(2007/10/03)
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- An aldol-based approach to the synthesis of the antibiotic anisomycin
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Chemical equation presented A new approach to the synthesis of the antibiotic anisomycin is reported that relies upon a key aldol disconnection. The glycolate aldol coupling proceeds in 75% yield and with >95% diastereoselectivity, which allows the 13-step synthesis to proceed in 35% overall yield.
- Hulme, Alison N.,Rosser, Edward M.
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p. 265 - 267
(2007/10/03)
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- Total Synthesis of (-)-FR901483
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The first synthesis of the immunosuppressant (-)-FR901483 (1) has been accomplished in 2% overall yield from O-methyltyrosine methyl ester (31) in 22 steps establishing the absolute stereochemistry of the natural product. A 1,3-dipolar cycloaddition of ni
- Snider, Barry B.,Lin, Hong
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p. 7778 - 7786
(2007/10/03)
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- New renin inhibitors containing aliphatic or aromatic amides at the C-terminus
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Five renin inhibitors, Iva-Pro-Phe(4-OMe)-MeLeu-Sta-εAhx-IAA (18), Iva-εAhx-Phe(4-OMe)-MeLeu-Sta-εAhx-IAA (23), H-εAhx-Phe(4-OMe)-His-Sta-εAhx-FBZA (36), H-εAhx-Phe(4-OMe)-His-Sta-εAhx-MBZA (45), and H-Phe (4-OMe)-His-Sta-εAhx-FBZA (48) have been synthesized in search of structures of improved biological properties. All synthesized inhibitors were resistant to chymotrypsin activity. Inhibitors 18 and 23 were insoluble in buffers, pH 7.4 and 2.0, 36, 45 and 48 were very good soluble in buffer pH 2.0 and poorly in buffer pH 7.4. Experimentally determined 1-octanol/pH 7.4 buffer partition coefficients (log P) of 36, 45 and 48 were above 1. Log P values of 18, 23, 36, 45 and 48 were 6.57, 6.91, 2.48, 2.09 and 2.00 respectively. The inhibitory potency in vitro of 18, 23, 36, 45 and 48 expressed as IC50 was 7.5 · 10-5, 5.0 · 10-6, 7.5 · 10-3, 1.0 · 10-4 and 2.5 · 10-5 M/l respectively.
- Paruszewski,Jaworski,Tautt,Dudkiewicz
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p. 206 - 209
(2007/10/03)
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- Synthesis of Non-proteinogenic Amino-Acid Methyl Esters with Acid-Sensitive Side Chains from a Chiral Glycine Derivative
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A superior chiral glycine derivative 1 (tert-butyl 2-(tert-butyl)-4-methoxy-2,5-dihydro-1,3-imidazole-1-carboxylate, BDI) for the synthesis of acid-sensitive and highly hindered α-amino-acid methyl esters is readily available by resolution methods.The heterocycle 1 is alkylated once and twice in the 5-position with very high diastereoselectivity, and the resulting products (2, 3) are hydrolyzed under very mild conditions to give methyl esters of the corresponding amino acids (6-10).
- Hoffmann, Matthias,Seebach, Dieter
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- Synthesis of novel C2-symmetric and pseudo C2-symmetric based diols, epoxides and dideoxy derivatives of HIV protease inhibitors
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The Julia's olefination reaction between the sulfone derivative (10) and the aldehyde (13) (both obtained from L-phenylalanine) followed by debenzylation led to the formation (2S,5S,3E)-2,5-bis-[(1,1-dimethyl ethoxy)-carbonyl]amino-1,6-diphenylhex-3-ene (
- Gurjar, Mukund K.,Pal, Shashwati,Rama Rao,Pariza, Richard J.,Chorghade, Mukund S.
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p. 4769 - 4778
(2007/10/03)
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- A β-Lactam Framework as a β-Alanyl Dication Equivalent: New Synthesis of α-Amino Acid N-carboxy Anhydrides (NCAs) Derived from β-Substituted Alanines
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Optically pure 4-formyl-3-hydroxy β-lactams are transformed into 4-methylaryl and 4-(2-ethylaryl) derivatives and converted into β-substituted alanine-derived NCAs through oxidation and Baeyer-Villiger rearrangement of the resulting α-keto β-lactams.
- Palomo, Claudio,Aizpurua, Jesus M.,Ganboa, Inaki,Maneiro, Elena,Odriozola, Beatriz
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p. 1505 - 1508
(2007/10/02)
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- A NEW PROTECTING GROUP FOR AMINES. SYNTHESIS OF ANTICAPSIN FROM L-TYROSINE
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An acid and base-stable, nucleophile-resistant protecting group for primary amines and α-amino acids is described which has been used in a synthesis of the title compound.
- Laguzza, Bennett C.,Ganem, Bruce
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p. 1483 - 1486
(2007/10/02)
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