- Oxa Analogues of Nexturastat A Demonstrate Improved HDAC6 Selectivity and Superior Antileukaemia Activity
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The acetylome is important for maintaining the homeostasis of cells. Abnormal changes can result in the pathogenesis of immunological or neurological diseases, and degeneration can promote the manifestation of cancer. In particular, pharmacological interv
- Pflieger, Marc,S?nnichsen, Melf,Horstick-Muche, Nadine,Yang, Jing,Schliehe-Diecks, Julian,Sch?ler, Andrea,Borkhardt, Arndt,Hamacher, Alexandra,Kassack, Matthias U.,Hansen, Finn K.,Bhatia, Sanil,Kurz, Thomas
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Read Online
- Asymmetric Phase-Transfer Catalytic aza-Michael Addition to Cyclic Enone: Highly Enantioselective and Diastereoselective Synthesis of Cyclic 1,3-Aminoalcohols
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The highly enantioselective aza-Michael reaction of tert-butyl β-naphthylmethoxycarbamate to cyclic enones has been accomplished by using a new cinchona alkaloid derived C(9)-urea ammonium catalyst under phase-transfer catalysis conditions with up to 98% ee at 0 °C. The resulting aza-Michael adducts can be converted to versatile intermediates by selective deprotection and the cyclic 1,3-aminoalcohols by diastereoselective reduction with up to 32:1, which have been widely used as important pharmacophores in pharmaceutical development.
- Lee, Jaeyong,Ban, Jeong Woo,Kim, Jeongseok,Yang, Sehun,Lee, Geumwoo,Dhorma, Lama Prema,Kim, Mi-Hyun,Ha, Min Woo,Hong, Suckchang,Park, Hyeung-Geun
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supporting information
p. 1647 - 1651
(2022/03/03)
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- Thermodynamic Stability and Speciation of Ga(III) and Zr(IV) Complexes with High-Denticity Hydroxamate Chelators
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Increasing attention has been recently devoted to 89Zr(IV) and 68Ga(III) radionuclides, due to their favorable decay characteristics for positron emission tomography (PET). In the present paper, a deep investigation is presented on Ga(III) and Zr(IV) comp
- Albanese, Valentina,Baldi, Andrea,Fritsky, Igor O.,Guerrini, Remo,Gumienna-Kontecka, Elzbieta,Illuminati, Davide,Mular, Andrzej,Ostrowska, Ma?gorzata,Pacifico, Salvatore,Piasta, Karolina,Remelli, Maurizio,Toporivska, Yuliya
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p. 13332 - 13347
(2021/09/11)
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- Identification and Characterization of AES-135, a Hydroxamic Acid-Based HDAC Inhibitor That Prolongs Survival in an Orthotopic Mouse Model of Pancreatic Cancer
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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, incurable cancer with a 20% 1 year survival rate. While standard-of-care therapy can prolong life in a small fraction of cases, PDAC is inherently resistant to current treatments, and novel therapies are urgently required. Histone deacetylase (HDAC) inhibitors are effective in killing pancreatic cancer cells in in vitro PDAC studies, and although there are a few clinical studies investigating combination therapy including HDAC inhibitors, no HDAC drug or combination therapy with an HDAC drug has been approved for the treatment of PDAC. We developed an inhibitor of HDACs, AES-135, that exhibits nanomolar inhibitory activity against HDAC3, HDAC6, and HDAC11 in biochemical assays. In a three-dimensional coculture model, AES-135 kills low-passage patient-derived tumor spheroids selectively over surrounding cancer-associated fibroblasts and has excellent pharmacokinetic properties in vivo. In an orthotopic murine model of pancreatic cancer, AES-135 prolongs survival significantly, therefore representing a candidate for further preclinical testing.
- Shouksmith, Andrew E.,Shah, Fenil,Grimard, Michelle L.,Gawel, Justyna M.,Raouf, Yasir S.,Geletu, Mulu,Berger-Becvar, Angelika,De Araujo, Elvin D.,Luchman, H. Artee,Heaton, William L.,Bakhshinyan, David,Adile, Ashley A.,Venugopal, Chitra,O'Hare, Thomas,Deininger, Michael W.,Singh, Sheila K.,Konieczny, Stephen F.,Weiss, Samuel,Fishel, Melissa L.,Gunning, Patrick T.
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supporting information
p. 2651 - 2665
(2019/03/17)
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- NOVEL ALKENYL AND BETA-SUBSTITUTED PHOSPHONATES AS ANTIMICROBIAL AGENTS
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The present disclosure relates to novel compounds, pharmaceutical compositions, and methods for treating or preventing microbial infection caused by parasites or bacteria, such as Plasmodium falciparum or related Plasmodium parasite species and Mycobacterium tuberculosis or related Mycobacterium bacteria species. The compounds are α,β-unsaturated analogs of fosmidomycin and can inhibit deoxyxylulose phosphate reductoisomerase (Dxr) in many microbes, such as P. falciparum.
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Paragraph 0088; 0092; 0116; 0162
(2019/01/17)
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- Acyloxybenzyl and Alkoxyalkyl Prodrugs of a Fosmidomycin Surrogate as Antimalarial and Antitubercular Agents
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Two classes of prodrugs of a fosmidomycin surrogate were synthesized and investigated for their ability to inhibit in vitro growth of P. falciparum and M. tuberculosis. To this end, a novel efficient synthesis route was developed involving a cross metathe
- Courtens, Charlotte,Risseeuw, Martijn,Caljon, Guy,Cos, Paul,Van Calenbergh, Serge
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supporting information
p. 986 - 989
(2018/09/25)
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- MEPicides: α,β-Unsaturated Fosmidomycin Analogues as DXR Inhibitors against Malaria
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Severe malaria due to Plasmodium falciparum remains a significant global health threat. DXR, the second enzyme in the MEP pathway, plays an important role to synthesize building blocks for isoprenoids. This enzyme is a promising drug target for malaria due to its essentiality as well as its absence in humans. In this study, we designed and synthesized a series of α,β-unsaturated analogues of fosmidomycin, a natural product that inhibits DXR in P. falciparum. All compounds were evaluated as inhibitors of P. falciparum. The most promising compound, 18a, displays on-target, potent inhibition against the growth of P. falciparum (IC50 = 13 nM) without significant inhibition of HepG2 cells (IC50 > 50 μM). 18a was also tested in a luciferase-based Plasmodium berghei mouse model of malaria and showed exceptional in vivo efficacy. Together, the data support MEPicide 18a as a novel, potent, and promising drug candidate for the treatment of malaria.
- Wang, Xu,Edwards, Rachel L.,Ball, Haley,Johnson, Claire,Haymond, Amanda,Girma, Misgina,Manikkam, Michelle,Brothers, Robert C.,McKay, Kyle T.,Arnett, Stacy D.,Osbourn, Damon M.,Alvarez, Sophie,Boshoff, Helena I.,Meyers, Marvin J.,Couch, Robin D.,Odom John, Audrey R.,Dowd, Cynthia S.
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supporting information
p. 8847 - 8858
(2018/10/05)
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- Rational Design, Development, and Stability Assessment of a Macrocyclic Four-Hydroxamate-Bearing Bifunctional Chelating Agent for 89Zr
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Zirconium-89 is a positron-emitting radionuclide of high interest for medical imaging applications with positron emission tomography (PET). For the introduction of this radiometal into biologically active targeting vectors, the chelating agent desferrioxa
- Seibold, Uwe,W?ngler, Bj?rn,W?ngler, Carmen
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p. 1555 - 1571
(2017/09/26)
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- Structural Requirements of Histone Deacetylase Inhibitors: SAHA Analogs Modified on the Hydroxamic Acid
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Histone deacetylase (HDAC) proteins have emerged as targets for anti-cancer therapeutics, with several inhibitors used in the clinic, including suberoylanilide hydroxamic acid (SAHA, vorinostat). Because SAHA and many other inhibitors target all or most o
- Bieliauskas, Anton V.,Weerasinghe, Sujith V.W.,Negmeldin, Ahmed T.,Pflum, Mary Kay H.
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p. 373 - 382
(2016/05/19)
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- Structure Property Relationships of Carboxylic Acid Isosteres
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The replacement of a carboxylic acid with a surrogate structure, or (bio)-isostere, is a classical strategy in medicinal chemistry. The general underlying principle is that by maintaining the features of the carboxylic acid critical for biological activity, but appropriately modifying the physicochemical properties, improved analogs may result. In this context, a systematic assessment of the physicochemical properties of carboxylic acid isosteres would be desirable to enable more informed decisions of potential replacements to be used for analog design. Herein we report the structure-property relationships (SPR) of 35 phenylpropionic acid derivatives, in which the carboxylic acid moiety is replaced with a series of known isosteres. The data set generated provides an assessment of the relative impact on the physicochemical properties that these replacements may have compared to the carboxylic acid analog. As such, this study presents a framework for how to rationally apply isosteric replacements of the carboxylic acid functional group.
- Lassalas, Pierrik,Gay, Bryant,Lasfargeas, Caroline,James, Michael J.,Tran, Van,Vijayendran, Krishna G.,Brunden, Kurt R.,Kozlowski, Marisa C.,Thomas, Craig J.,Smith, Amos B.,Huryn, Donna M.,Ballatore, Carlo
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p. 3183 - 3203
(2016/05/19)
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- ANTIBACTERIAL SIDEROMYCINS
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A compound, comprising: an Fe(III)-binding and/or Fe(III)-bound siderophore; one or more optional linker covalently bound to the siderophore; and daptomycin covalently bound to the linker, or, if no linker is present, then to the siderophore; or pharmaceu
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Page/Page column 63
(2016/03/13)
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- Effect of Substituents and Stability of Transient Aluminum-Aminals in the Presence of Nucleophiles
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Disubstituted hydroxylamines are synthesized and used to form aluminum-amide complexes. These reagents mask carbonyl groups in situ via nucleophilic addition. The stability and utility of the aluminum-aminals are presented in the context of selectively controlling nucleophilic addition on substrates with multiple carbonyl groups.
- Barrios, Francis J.,Springer, Brannon C.,Hazlitt, Robert A.,Colby, David A.
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p. 175 - 180
(2015/05/05)
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- Conformational and structural studies of N-methylacetohydroxamic acid and of its mono- and bis-chelated uranium(VI) complexes
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The thermodynamics and kinetics of the cis/trans isomerism of N-methylacetohydroxamic acid (NMAH) and its conjugated base (NMA-) have been reinvestigated in aqueous media by 1H NMR spectroscopy. Hindered rotation around the central C
- Brandès, Stéphane,Sornosa-Ten, Alejandra,Rousselin, Yoann,Lagrelette, Mickael,Stern, Christine,Moncomble, Aurélien,Cornard, Jean-Paul,Meyer, Michel
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p. 164 - 175
(2015/12/18)
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- Biomimetic ferrichrome: Structural motifs for switching between narrow- and broad-spectrum activities in P. putida and E. coli
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A series of novel ferrichrome (FC) analogs was designed based on the X-ray structure of FC in the FhuA transporter of Escherichia coli. Two strategies were employed: the first strategy optimized the overall size and relative orientation of H-bonding inter
- Olshvang, Evgenia,Szebesczyk, Agnieszka,Kozlowski, Henryk,Hadar, Yitzhak,Gumienna-Kontecka, Elzbieta,Shanzer, Abraham
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supporting information
p. 20850 - 20858
(2015/12/11)
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- Condensed derivatives of imidazole useful as pharmaceuticals
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The invention relates to the compounds (I) and their acids and bases salts: wherein: the dotted line indicates a double bond; X is N or C-R1 and Y is N or C-R2, X and Y not being simultaneously N; A is selected from the group consisting of phenyl, naphthyl and (5-11) membered monocyclic or bicyclic unsaturated cycle or heterocycle possibly substituted as defined in the application, and A can also comprise either a further (4-7) membered heterocycle, said heterocycle being a monocycle, fused, saturated or unsaturated, the polycyclic system then comprising up to 14 members and up to 5 heteroatoms selected from N, O and S; B is Hydrogen or a substituent as defined in the application, or B is a (4-10) membered mono or bicyclic saturated or unsaturated heterocycle containing 1-3 heteroatoms selected from N, O and S, and possibly substituted as defined in the application; B not being Hydrogen when X is N and Y is C-R2; R1 is Hydrogen or a substituent as defined in the application; B and R1 cannot be simultaneously Hydrogen; R2 is Hydrogen or Halogen; their preparation, their use in the antibacterial prevention and therapy, alone or in association with antibacterials, antivirulence agents or drugs reinforcing the host innate immunity, and pharmaceutical compositions and associations containing them.
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Paragraph 0409
(2015/09/23)
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- HETEROBICYCLIC COMPOUNDS AS BETA-LACTAMASE INHIBITORS
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The present invention is directed to compounds which are beta-lactamase inhibitors. The compounds and their pharmaceutically acceptable salts, are useful in combination with beta-lactam antibiotics, or alone, for the treatment of bacterial infections, including infections caused by drug resistant organisms, including multi-drug resistant organisms. The present invention includes compounds according to formula (Ia): or a pharmaceutically acceptable salt thereof, wherein the values of R1, R 2, R 3 and R 4 are described herein.
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Page/Page column 150; 151
(2013/10/22)
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- Lewis acid-mediated radical cyclization: Stereocontrol in cascade radical addition-cyclization-trapping reactions
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An efficient approach for achieving radical cyclizations by using hydroxamate ester as a coordination tether with Lewis acid was studied. The chiral Lewis acid-mediated cascade radical addition-cyclization-trapping reaction proceeded smoothly with good en
- Miyabe, Hideto,Asada, Ryuta,Takemoto, Yoshiji
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supporting information; scheme or table
p. 3519 - 3530
(2012/05/20)
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- NEW INHIBITORS OF CYCLOPHILINS AND USES THEREOF
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The present invention relates to a compound of formula (I): Formula (I), wherein: - n is 0, 1 or 2; - A is in particular CH or N; - X is in particular CO, SO2, CS, and R1 is in particular H, - R2 is a group of formula NR3R4 or OR5, R3 and R4 being in particular H, and R5 an alkyl group, - R6 is in particular H or an alkyl group, and - R7 is in particular an aryl group, for its use in the prevention and/or the treatment of viral pathologies or infections.
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Page/Page column 96-97
(2011/07/09)
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- 2-Aminohydroxamic acid derivatives as inhibitors of Bacillus cereus phosphatidylcholine preferred phospholipase C PC-PLCBc
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Phosphatidylcholine preferring phospholipase C (PC-PLC) is an important enzyme that plays a key role in a variety of cellular events and lipid homoeostases. Bacillus cereus phospholipase C (PC-PLCBc) has antigenic similarity with the elusive mammalian PC-PLC, which has not thus far been isolated and purified. Therefore the discovery of inhibitors of PC-PLC Bc is of current interest. Here, we describe the synthesis and biological evaluation of a new type of compounds inhibiting PC-PLCBc. These compounds have been designed by evolution of previously described 2-aminohydroxamic acid PC-PLCBc inhibitors that block the enzyme by coordination of the zinc active site atoms present in PC-PLCBc [Gonzalez-Roura, A.; Navarro, I.; Delgado, A.; Llebaria, A.; Casas, J. Angew. Chem. Int. Ed. 2004, 43, 862]. The new compounds maintain the zinc coordinating groups and possess an extra trimethylammonium function, linked to the hydroxyamide nitrogen by an alkyl chain, which is expected to mimic the trimethylammonium group of the phosphatidylcholine PC-PLCBc substrates. Some of the compounds described inhibit the enzyme with IC 50's in the low micromolar range. Unexpectedly, the most potent inhibitors found are those that possess a trimethylammonium group but have chemically blocked the zinc coordinating functionalities. The results obtained suggest that PC-PLCBc inhibition is not due to the interaction of compounds with the phospholipase catalytic zinc atoms, but rather results from the inhibitor cationic group recognition by the PC-PLCBc amino acids involved in choline lipid binding.
- González-Bulnes, Patricia,González-Roura, Albert,Canals, Daniel,Delgado, Antonio,Casas, Josefina,Llebaria, Amadeu
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supporting information; experimental part
p. 8549 - 8555
(2011/02/25)
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- A dramatic effect of double bond configuration in N-oxy-3-aza Cope rearrangements-a simple synthesis of functionalised allenes
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The first examples of low temperature N-oxy-3-aza Cope rearrangements, leading to functionalised allenes are described, where the Z-configuration of the enaminic double bond in the rearranging system proves critical.
- Pinto, Luis F.V.,Glória, Paulo M.C.,Gomes, Mário J.S.,Rzepa, Henry S.,Prabhakar, Sundaresan,Lobo, Ana M.
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scheme or table
p. 3446 - 3449
(2009/09/25)
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- A latent oxazoline electrophile for N-O-C bond formation in pseudomonine biosynthesis
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Nitrogen-heteroatom bonds figure prominently in the structural, chemical, and functional diversity of natural products. In the case of Pseudomonas siderophore pseudomonine, an N-O hydroxamate linkage is found uncommonly configured in an isoxazolidinone ri
- Sattely, Elizabeth S.,Walsh, Christopher T.
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supporting information; body text
p. 12282 - 12284
(2009/02/05)
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- Identification of a gene cluster that directs putrebactin biosynthesis in Shewanella species: PubC catalyzes cyclodimerization of N-Hydroxy-N- succinylputrescine
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Putrebactin is a dihydroxamate iron chelator produced by the metabolically versatile marine bacterium Shewanella putrefaciens. It is a macrocyclic dimer of N-hydroxy-N-succinyl-putrescine (HSP) and is structurally related to desferrioxamine E, which is a
- Kadi, Nadia,Arbache, Simon,Song, Lijiang,Oves-Costales, Daniel,Challis, Gregory L.
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supporting information; experimental part
p. 10458 - 10459
(2009/02/05)
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- A METHOD OF PREPARING ENANTIOMERS OF INDOLE-2,3-DIONE-3-OXIME DERIVATIVES
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The present invention is directed to a method of preparing enantiomers of indole-2,3-dione-3-oxime derivatives.
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- Significance of hydrogen bonding at the S1′ subsite of calpain I
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α-Ketohydroxamates were synthesized as bioisosteres of α-ketoamides. The α-ketohydroxamates were generally more potent than the corresponding α-ketoamides. The potency of the compounds suggests that hydrogen bonding and steric bulk of substituents on the nitrogen atom of the ketoamide moiety influence calpain inhibition.
- Donkor, Isaac O.,Zheng, Xiaozhang,Han, Jie,Lacy, Calvin,Miller, Duane D.
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p. 1753 - 1755
(2007/10/03)
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- Inhibitors of protein isoprenyl transferases
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Compounds having the formula or a pharmaceutically acceptable salt thereof wherein R1is (a) hydrogen, (b) loweralkyl, (c) alkenyl, (d) alkoxy, (e) thioalkoxy, (f) halo, (g) haloalkyl, (h) aryl-L2—, and (i) heterocyclic-L2—; R2is selected from (a) (b) —C(O)NH—CH(R14)—C(O)OR15, (d) —C(O)NH—CH(R14)—C(O)NHSO2R16, (e) —C(O)NH—CH(R14)-tetrazolyl, (f) —C(O)NH-heterocyclic, and (g) —C(O)NH—CH(R14)—C(O)NR17R18; R3is substituted or unsubstituted heterocyclic or aryl, substituted or unsubstituted cycloalkyl or cycloalkenyl, and —P(W)RR3RR3′; R4is hydrogen, lower alkyl, haloalkyl, halogen, aryl, arylakyl, heterocyclic, or (heterocyclic)alkyl; L1is absent or is selected from (a) —L4—N(R5)—L5—, (b) —L4—O—L5—, (c) —L4—S(O)n—L5— (d) —L4—L6—C(W)—N(R5)—L5—, (e) —L4—L6—S(O)m—N(R5)—L5—, (f) —L4—N(R5)—C(W)—L7—L5—, (g) —L4—N(R5)—S(O)p—L7—L5—, (h) optionally substituted alkylene, (i) optionally substituted alkenylene, (j) optionally substituted alkynylene (k) a covalent bond, (l) and (m) are inhibitors of protein isoprenyl transferases. Also disclosed are protein isoprenyl transferase inhibiting compositions and a method of inhibiting protein isoprenyl transferases.
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- Synthesis of O-alkylhydroxylamines by electrophilic amination of alkoxides
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The 3-trichloromethyloxaziridine 7 reacts smoothly with lithium alkoxides, derived from a representative range of alcohols, transferring an NHBoc function to the oxygen to provide good to excellent yields of N-Boc-O- alkylhydroxylamines 8-16 by this new O-amination protocol.
- Foot, Oliver F.,Knight, David W.
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p. 975 - 976
(2007/10/03)
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- Oligonucleotide analogs with an amino acid or a modified amino alcohol residue
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The present invention provides various novel oligonucleotide analogs having one or more properties that make the subject compounds superior to conventional oligonucleotides for use in procedures employing oligonucleotides. The compounds of the invention are oligonucleotide analogs in which the furanose ring of a naturally occurring nucleic acid is replaced with an amino acid or a modified amino alcohol residue. Some embodiments of the novel compounds of the invention are particularly useful for the antisense control of gene expression. The compounds of the invention may also be used as nucleic acid hybridization probes or as primers. Another aspect of the invention is to provide monomeric precursors of the oligonucleotide analogs of the invention. These monomeric precursors may be used to synthesize the subject polynucleotide analogs. Another aspect of the invention is to provide formulations of the subject polynucleotide analogs that are designed for the treatment or prevention of disease conditions. Yet another aspect of the invention is to provide methods for treating or preventing diseases, particularly viral infections and cell growth disorders. The subject disease treatment methods comprise the step of administering an effective amount of the subject polynucleotide analogs for use as antisense inhibitors.
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- Synthesis of enantiomerically pure aziridine-2-imides by cyclization of chiral 3-benzyloxyamino imide enolates
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Aziridine-2-imides are prepared both in high yield and high diastereoselectivity from chiral 3'-benzyloxyamino imides 2, 3, and 8 by treatment with triethylamine in the presence of either TiCl4 or AlMe2Cl. 2 and 3 are easily obtained
- Bongim,Cardillo,Gentilucci,Tomasini
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p. 9148 - 9159
(2007/10/03)
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- HETEROARYL DERIVATIVES OF MONOCYCLIC BETA-LACTAM ANTIBIOTICS
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Antibacterial activity is exhibited by novel compounds having the formula where R1, R2, and M are as defined herein and X is ?(CH2)n? wherein n is 0, 1, 2, 3 or 4 or CR3R4 wherein R3 and R4 are the same or different and each is hydrogen, ?CH3 or ?C2H5 or R3 and R4 taken together with the carbon atom to which they are attached form a 3, 4, 5, 6 or 7-membered cycloalkyl ring
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- Heteroaryl derivatives of monocyclic beta-lactam antibiotics
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Compounds having the formula STR1 exhibiting antibacterial activity.
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- SUBSTITUTED HYDROXYUREAS
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The present invention relates to substituted hydroxyureas. These compounds inhibit the enzyme 5-lipoxygenase. In addition, certain of the compounds also inhibit the enzyme-cyclooxygenase. The compounds are useful for treating asthma, allergies, arthritis, posoriasis, ischemia, dermatitis, inflammation and/or broncho-constriction and/or inflammatory diseases of the eye.
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- ALKYLATION OF N-BENZYLOXYUREAS AND CARBAMATES
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N-benzyloxyureas and orthogonically protected N-hydroxycarbamates can be alkylated in high yields and subsequently deprotected to provide N-alkyl hydroxyureas and hydroxylamines.
- Sulsky, Richard,Demers, James P.
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