- Design, synthesis and cytotoxic evaluation of a library of oxadiazole-containing hybrids
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The development of hybrid compounds led to the discovery of new pharmacologically active agents for some of the most critical diseases, including cancer. Herein, we describe a new series of oxadiazole-containing structures designed by a molecular hybridiz
- Camacho, Cristián M.,Pizzio, Marianela G.,Roces, David L.,Boggián, Dora B.,Mata, Ernesto G.,Bellizzi, Yanina,Barrionuevo, Elizabeth,Blank, Viviana C.,Roguin, Leonor P.
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p. 29741 - 29751
(2021/10/07)
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- Mapping the s1 and s1’ subsites of cysteine proteases with new dipeptidyl nitrile inhibitors as trypanocidal agents
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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.
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- Optimization strategy of single-digit nanomolar cross-class inhibitors of mammalian and protozoa cysteine proteases
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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.
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- COMPOSITION COMPRISING OXALAMIDE GELATORS AND VEGETABLE OIL
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The present invention relates to the composition with gelling properties comprising oxalamide gelators of Formula (I) and a vegetable oil. Uses of such composition in the food, cosmetic or pharmaceutical industry are disclosed.
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Page/Page column 13
(2020/07/14)
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- Comprehensive Synthesis of Amino Acid-Derived Thiazole Peptidomimetic Analogues to Understand the Enigmatic Drug/Substrate-Binding Site of P-Glycoprotein
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A novel set of 64 analogues based on our lead compound 1 was designed and synthesized with an initial objective of understanding the structural requirements of ligands binding to a highly perplexing substrate-binding site of P-glycoprotein (P-gp) and their effect on modulating the ATPase function of the efflux pump. Compound 1, a stimulator of P-gp ATPase activity, was transformed to ATPase inhibitory compounds 39, 53, and 109. The ATPase inhibition by these compounds was predominantly contributed by the presence of a cyclohexyl group in lieu of the 2-aminobenzophenone moiety of 1. The 4,4-difluorocyclohexyl analogues, 53 and 109, inhibited the photolabeling by [125I]-IAAP, with IC50 values of 0.1 and 0.76 μM, respectively. Selected compounds were shown to reverse paclitaxel resistance in HEK293 cells overexpressing P-gp and were selective toward P-gp over CYP3A4. Induced-fit docking highlighted a plausible binding pattern of inhibitory compounds in the putative-binding pocket of P-gp. The current study underscores the stringent requirement by P-gp to bind to chemically similar molecules.
- Patel, Bhargav A.,Abel, Biebele,Barbuti, Anna Maria,Velagapudi, Uday Kiran,Chen, Zhe-Sheng,Ambudkar, Suresh V.,Talele, Tanaji T.
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p. 834 - 864
(2018/02/17)
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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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- Total Synthesis of the Post-translationally Modified Polyazole Peptide Antibiotic Goadsporin
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The structurally unique polyazole antibiotic goadsporin contains six heteroaromatic oxazole and thiazole rings integrated into a linear array of amino acids that also contains two dehydroalanine residues. An efficient total synthesis of goadsporin is repo
- Dexter, Hannah L.,Williams, Huw E. L.,Lewis, William,Moody, Christopher J.
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supporting information
p. 3069 - 3073
(2017/03/13)
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- AMIDE COMPOUNDS, METHODS FOR PREPARATION, AND USE THEREOF AS AGENTS FOR THE TREATMENT AND PREVENTION OF DISEASES CAUSED BY RNA- AND/OR DNA-CONTAINING VIRUSES, AND CONCOMITANT DISEASES
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The present invention relates to medicine and includes a method for preventing and treating diseases caused by RNA- and DNA-containing viruses, and concomitant diseases, wherein the method comprises the use of an effective amount of compounds of general formula I or pharmaceutically acceptable salts thereof. The invention also relates to methods for preparing said compounds, pharmaceutical compositions for the prevention or treatment of diseases caused by RNA- and DNA-containing viruses, said compositions comprising an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The invention addresses the object of providing a novel agent effective in the treatment of diseases caused by an RNA-containing virus belonging to the Enterovirus, Metapneumovirus, Pneumovirus, Respirovirus, or Alfa-coronavirus genus, and/or by a DNA-containing virus belonging to the Adenoviridae and/or Herpesviridae family, and in the prevention and treatment of asthma exacerbation, chronic obstructive pulmonary disease, mucoviscidosis, conjunctivitis, gastroenteritis, hepatitis, myocarditis; in the prevention and treatment of rhinorrhea, acute and infectious rhinitis, pharyngitis, nasopharyngitis, tonsillitis, laryngitis, laryngotracheitis, laryngotracheobronchitis, bronchitis, bronchiolitis, pneumonia, or airway obstructive syndrome.
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Paragraph 0178; 0179
(2017/07/14)
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- Gastrin releasing peptide receptor-directed radioligands based on a bombesin antagonist: Synthesis, 111in-labeling, and preclinical profile
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Novel bombesin (BBN) antagonists were synthesized by coupling the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) to H-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (JMV594) through linkers of increasing number of (βAla)x residues (x = 1-3). Labeling with 111In afforded the respective radiotracers in high purity and high specific activity. Bioconjugate affinity for the gastrin releasing peptide receptor (GRPR) as determined against [125I-Tyr4]BBN was high (IC50 values in the lower nanomolar range). Radioligands poorly internalized in PC-3 cells at 37 C. Radiopeptides remained >60% intact 5 min after entering the bloodstream of healthy mice. After injection in SCID mice bearing human PC-3 xenografts all analogues showed high tumor uptake and rapid background clearance via the kidneys into urine. Interestingly, pancreatic uptake, albeit GRPR-specific, declined rapidly with time. 111In-DOTA- (βAla)2-JMV594 achieved the highest tumor values among the group (17.0 ± 2.8%ID/g vs. 8-10%ID/g, respectively, at 4 h pi) indicating that the (βAla)2-linker favors in vivo interaction of radiopeptides with the GRPR.
- Marsouvanidis, Panteleimon J.,Nock, Berthold A.,Hajjaj, Bouchra,Fehrentz, Jean-Alain,Brunel, Luc,M'Kadmi, Céline,Van Der Graaf, Linda,Krenning, Eric P.,Maina, Theodosia,Martinez, Jean,De Jong, Marion
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p. 2374 - 2384
(2013/05/21)
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- Synthesis of gem-diamino acid derivatives by a Hofmann rearrangement
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Starting from commercially available N-protected l-α-amino acids, N,N′-protected gem-diaminic units were obtained by a two-step methodology. A Hofmann reaction performed using a primary alcohol as the solvent to trap the isocyanate intermediate represents the key step of the new synthetic procedure. Then, the methodology was applied to α-carbamoyl α′-carboxyl aziridines, also functionalized with l-α-amino esters and stable gem-diaminic units characterized by an aziridine ring and by a retro-peptide modification were obtained. The use of the latter units in the retro-peptide chemistry allows to obtain modified peptides containing an aziridine ring able to behave as an electrophilic site and as a biomimetic structural analog of proline.
- Aresu, Emanuele,Fioravanti, Stefania,Gasbarri, Simona,Pellacani, Lucio,Ramadori, Federico
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p. 977 - 982
(2013/07/05)
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- NOVEL PYRIDINE DERIVATIVES
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The invention relates to a compound of formula (I) wherein R1 to R4 are defined as in the description and in the claims. The compound of formula (I) can be used as a medicament.
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Page/Page column 54
(2013/02/27)
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- PYRIDIN- 2 -AMIDES USEFUL AS CB2 AGONISTS
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The invention relates to a compound of formula (I) wherein R1 to R4 are defined as in the description and in the claims. The compound of formula (I) can be used as a medicament.
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Page/Page column 117; 118
(2013/02/27)
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- Synthesis of sansalvamide A peptidomimetics: Triazole, oxazole, thiazole, and pseudoproline containing compounds
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Peptidomimetic-based macrocycles typically have improved pharmacokinetic properties over those observed with peptide analogs. Described are the syntheses of 13 peptidomimetic derivatives that are based on active sansalvamide A structures, where these analogs incorporate heterocycles (triazoles, oxazoles, thiazoles, or pseudoprolines) along the macrocyclic backbone. The syntheses of these derivatives employ several approaches that can be applied to convert a macrocyclic peptide into its peptidomimetic counterpart. These approaches include peptide modifications to generate the alkyne and azide for click chemistry, a serine conversion into an oxazole, a Hantzsch reaction to generate the thiazole, and protected threonine to generate the pseudoproline derivatives. Furthermore, we show that two different peptidomimetic moieties, triazoles, and thiazoles, can be incorporated into the macrocyclic backbone without reducing cytotoxicity: triazole and thiazole.
- Davis, Melinda R.,Singh, Erinprit K.,Wahyudi, Hendra,Alexander, Leslie D.,Kunicki, Joseph B.,Nazarova, Lidia A.,Fairweather, Kelly A.,Giltrap, Andrew M.,Jolliffe, Katrina A.,McAlpine, Shelli R.
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experimental part
p. 1029 - 1051
(2012/02/15)
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- Carbamates of 4′-demethyl-4-deoxypodophyllotoxin: Synthesis, cytotoxicity and cell cycle effects
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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
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supporting information; experimental part
p. 7355 - 7358
(2012/02/04)
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- Isoselenocyanates derived from Boc/Z-amino acids: Synthesis, isolation, characterization, and application to the efficient synthesis of unsymmetrical selenoureas and selenoureidopeptidomimetics
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Isoselenocyanates derived from Boc/Z-amino acids are prepared by the reaction of the corresponding isonitriles with selenium powder in presence of triethylamine at reflux. The utility of these new classes of isoselenocyanates in the preparation of selenoureidodipeptidomimetics possessing both amino as well as carboxy termini has been accomplished. The 1H NMR analysis confirmed that the protocol involving the conversion of isonitriles to isoselenocyanates and their use as coupling agents in assembling selenoureido derivatives is free from racemization.
- Chennakrishnareddy, Gundala,Nagendra, Govindappa,Hemantha, Hosahalli P.,Das, Ushati,Guru Row, Tayur N.,Sureshbabu, Vommina V.
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supporting information; experimental part
p. 6718 - 6724
(2010/09/30)
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- Parallel synthesis of an oligomeric imidazole-4, 5-dicarboxamide library
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A library of oligomeric compounds was synthesized based on the imidazole-4, 5-dicarboxylic acid scaffold along with amino acid esters and chiral diamines derived from amino acids. The final compounds incorporate nonpolar amino acids (Leu, Phe, Trp), polar amino acids (Ser, Asp, Arg), and neutral amino acids (Gly, Ala), and were designed to be useful in screening for inhibitors of protein-protein interactions. Many of the protected and deprotected oligomers show evidence of conformational isomers persistent at room temperature in aqueous solution. A total of 317 final oligomers, out of 441 targeted compounds, were obtained in high analytical purity and of sufficient quantity to submit them for high-throughput screening as part of the NIH Roadmap.
- Xu, Zhigang,DiCesare, John C.,Baures, Paul W.
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supporting information; experimental part
p. 248 - 254
(2010/08/19)
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- Synthesis of Boc-amino tetrazoles derived from α-amino acids
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A simple route for the synthesis of Boc-protected tetrazole analogs of amino acids starting from Nα-Boc amino acids has been described. The [2 + 3] cycloaddition of Boc-α-amino nitrile and sodium azide in the presence of a catalytic amount of zinc bromide yielded the desired tetrazoles in good yields and purity. All the compounds obtained have been characterized by 1H and 13C-NMR and mass spectral studies. Copyright Taylor & Francis Group, LLC.
- Sureshbabu, Vommina V.,Naik, Shankar A.,Nagendra
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experimental part
p. 395 - 406
(2009/06/06)
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- A simple synthesis of imide-dipeptides
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We report a simple approach to synthesize a new class of imide-dipeptides. This approach is mild, and the starting materials are the easily accessible amino acid derivatives. The imide-dipeptides were synthesized from the coupling of an amide and a 4-nitrophenyl activating ester of an amino acid. The acidic proton of the first amide was removed by 1 equivalent of n-butyl lithium to afford the corresponding amide anion which then reacted with the activating ester to give the desired imide derivatives. Georg Thieme Verlag Stuttgart.
- Ke, Damei,Zhan, Chuanlang,Li, Xiao,Li, Alexander D. Q.,Yao, Jiannian
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experimental part
p. 1506 - 1510
(2009/12/24)
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- Ammonium salts from polymer-bound N-hydroxysuccinimide as solid-supported reagents for EDC-mediated amidations
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New ammonium and alkylammonium salts derived from a polymeric N-hydroxysuccinimide (P-HOSu) have been prepared and used for the amidation of carboxylic acids and amino acids mediated by 1-ethyl-3-(3′-dimethylamino-propyl)carbodiimide hydrochloride (EDC). These polymer-supported ammonium salts afforded the corresponding amides in good yield, without detectable α-racemization and with easy recovery of the P-HOSu after the amidation reaction, being especially suitable for the amidation of Fmoc-protected amino acids.
- Chinchilla, Rafael,Dodsworth, David J.,Nájera, Carmen,Soriano, José M.
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p. 463 - 466
(2007/10/03)
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- Synthesis, anti-inflammatory and antimicrobial activities of new 1,2,4-oxadiazoles peptidomimetics
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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.
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p. 719 - 724
(2007/10/03)
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- Solid-phase synthesis of oligourea peptidomimetics
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A procedure for the solid-phase synthesis of oligourea peptidomimetics starting from Boc-protected monomers is described. The compounds are prepared on Tentagel resin and can be obtained selectively rather as the C-terminal free acids with UV irradiation
- Boeijen, Astrid,Liskamp, Rob M. J.
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p. 2127 - 2135
(2007/10/03)
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- PROTEASE INHIBITORS
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Disclosed herein is a compound of the formula STR1 known as 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-[4-(N,N-dimethylaminomethyl) benzyloxy]carbonyl-L-leucinyl]carbohydrazide; and pharmaceutically acceptable salts, hydrates and solvates thereof.
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- 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
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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.
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p. 7115 - 7118
(2007/10/02)
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- Efficient, racemization-free amidation of protected amino acids
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N-tert-Butoxycarbonyl derivatives of L-leucine, S-benzyl-L-cysteine and N(τ)-(2,4-dinitrophenyl)-L-histidine were amidated with crystalline ammonium, methylammonium, and ethylammonium salts of 3-hydroxy-1,2,3-benzotriazin-4(3H)-one and N-hydroxy-succinimi
- Somlai,Szokan,Balaspiri
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p. 285 - 287
(2007/10/02)
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- Convenient Synthesis of N-Protected Amino Acid Amides
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Boc- or Z-amino acids were conveniently amidated at room temperature by a one-pot procedure employing ammonium hydrogencarbonate and N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline in yields of 81-96percent.The benzyl ester-type protector for the side chains of aspartic acid and glutamic acid was not affected by the procedure.
- Nozaki, Sukekatsu,Muramatsu, Ichiro
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p. 2647 - 2648
(2007/10/02)
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- DESIGN AND SYNTHESIS OF A MULTI-DETACHABLE BENZHYDRYLAMINE-RESIN FOR SOLID PHASE PEPTIDE SYNTHESIS
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Peptides with C-terminal α-carboxamides were synthesized from a multi-detachable benzhydrylamine-resin containing a Boc-(4-acetoxy)benzhydrylamine handle of unambiguous origin.The peptides bound to the new resin are stable to trifluoroacetic acid, but are cleavable by hydrogen fluoride, base and nucleophiles to give unprotected or protected peptide fragments.
- Tam, James P.,DiMarchi, Richard D.,Merrifield, R. B.
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p. 2851 - 2854
(2007/10/02)
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