- Design, synthesis and biological evaluation of novel hamamelitannin analogues as potentiators for vancomycin in the treatment of biofilm related Staphylococcus aureus infections
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Staphylococcus aureus is a frequent cause of biofilm-related infections. Bacterial cells within a biofilm are protected from attack by the immune system and conventional antibiotics often fail to penetrate the biofilm matrix. The discovery of hamamelitannin as a potentiator for antibiotics, recently led to the design of a more drug-like lead. In the present study, we want to gain further insight into the structure–activity relationship (S.A.R.) of the 5-position of the molecule, by preparing a library of 21 hamamelitannin analogues.
- Vermote, Arno,Brackman, Gilles,Risseeuw, Martijn D.P.,Coenye, Tom,Van Calenbergh, Serge
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Read Online
- A concise, efficient and production-scale synthesis of a protected L-lyxonolactone derivative: An important aldonolactone core
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A multikilogram-scale synthesis of L-lyxonolactone-2,3-O-isopropylidene is reported. It proceeds efficiently from an optimized, large-scale, aqueous bromine oxidation of D-ribose to D-ribonolactone including a one-pot isopropylidene formation, and subsequent conversion of the D-ribonolactone-2,3- 0-isopropylidene to L-lyxonolactone-2,3-O-isopropylidene via the derived C 5-mesylate and intramolecular relactonization of the product of aqueous potassium hydroxide cleavage of the D-ribonolactone ring. The inversion of configuration at the C4-chiral center is understood in terms of an intermediating C4-C5-epoxide. The overall process is noteworthy for its operational simplicity, stereochemical integrity, and use of inexpensive chemicals.
- Batra, Hitesh,Moriarty, Robert M.,Penmasta, Raju,Sharma, Vijay,Stanciuc, Gabriela,Staszewski, James P.,Tuladhar, Sudersan M.,Walsh, David A.,Datla, Satyanarayana,Krishnaswamy, Sunderraj
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Read Online
- Design and synthesis of 2,6-disubstituted-4′-selenoadenosine- 5′-N,N-dimethyluronamide derivatives as human A3 adenosine receptor antagonists
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A new series of 4′-selenoadenosine-5′-N,N-dimethyluronamide derivatives as highly potent and selective human A3 adenosine receptor (hA3AR) antagonists, is described. The highly selective A3AR agonists, 4′-selenoadenosine-5′-N-methyluronamides were successfully converted into selective antagonists by adding a second N-methyl group to the 5′-uronamide position. All the syn-thesized compounds showed medium to high binding affinity at the hA3AR. Among the synthe-sized compounds, 2-H-N6-3-iodobenzylamine derivative 9f exhibited the highest binding affinity at hA3AR. (Ki = 22.7 nM). The 2-H analogues generally showed better binding affinity than the 2-Cl analogues. The cAMP functional assay with 2-Cl-N6-3-iodobenzylamine derivative 9l demonstrated hA3AR antagonist activity. A molecular modelling study suggests an important role of the hydrogen of 5′-uronamide as an essential hydrogen bonding donor for hA3AR activation.
- Choi, Hongseok,Jacobson, Kenneth A.,Yu, Jinha,Jeong, Lak Shin
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- Discovery of a novel template, 7-substituted 7-deaza-4′-thioadenosine derivatives as multi-kinase inhibitors
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The development of anticancer drugs remains challenging owing to the potential for drug resistance. The simultaneous inhibition of multiple targets involved in cancer could overcome resistance, and these agents would exhibit higher potency than single-target inhibitors. Protein kinases represent a promising target for the development of anticancer agents. As most multi-kinase inhibitors are heterocycles occupying only the hinge and hydrophobic region in the ATP binding site, we aimed to design multi-kinase inhibitors that would occupy the ribose pocket, along with the hinge and hydrophobic region, based on ATP-kinase interactions. Herein, we report the discovery of a novel 4′-thionucleoside template as a multi-kinase inhibitor with potent anticancer activity. The in vitro evaluation revealed a lead 1g (7-acetylene-7-deaza-4′-thioadenosine) with potent anticancer activity, and marked inhibition of TRKA, CK1δ, and DYRK1A/1B kinases in the kinome scan assay. We believe that these findings will pave the way for developing anticancer drugs.
- An, Seungchan,Byun, Woong Sub,Jeong, Lak Shin,Kim, Gibae,Kim, Minjae,Ko, Hyejin,Kwon, Eun-Ji,Kwon, Jee Youn,Lee, Hyuk Woo,Lee, Sang Kook,Mashelkar, Karishma K.,Noh, Minsoo,Sung, Kisu,Tripathi, Sushil K.,Yum, Yun A.
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- Stereoselective synthesis of selenium-containing glycoconjugates via the mitsunobu reaction
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A simple and efficient route for the synthesis of new glycoconjugates has been developed. The approach acts as a model for a mini-library of compounds with a deoxy-selenosugar core joined to a polyphenolic moiety with well-known antioxidant properties. An unexpected stereocontrol detected in the Mitsunobu key reaction led to the most attractive product showing a natural Dconfiguration. Thus, we were able to obtain the target molecules from the commercially available D-ribose via a shorter and convenient sequence of reactions.
- Cermola, Flavio,De Nisco, Mauro,Manfra, Michele,Pedatella, Silvana,Serpico, Luigia
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- Antioxidant composition comprising marliolide derivatives
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The present invention relates to a marliolide derivative and an antioxidant composition containing the same as an active component, wherein the marliolide derivative increases the expression of a transcription factor Nrf2 that regulates the expression of an antioxidant-related protein without cytotoxicity, thereby increasing the expression of HO-1 and NQO1, which are antioxidant-related proteins. In addition, since the marliolide derivative is confirmed to inhibit the oxidation of DNA and lipids induced by TPA that induces oxidative stress, a composition containing the marliolide derivative can be provided as the antioxidant composition.(AA) Compound 1 (10 andmu;M)COPYRIGHT KIPO 2019
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Paragraph 0039-0041; 0054-0057
(2019/11/23)
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- Practical synthesis of 4′-selenopurine nucleosides by combining chlorinated purines and ‘armed’ 4-selenosugar
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The synthesis of a variety of chemically modified oligonucleotides requires the development of a practical synthetic method for its building block, i.e., nucleoside analogs. The one-pot Pummerer-like reaction using hypervalent iodine in combination with 6-chloropurine and an ‘armed’ 4-selenosugar bearing an electron-donating group at the 2-position gave the desired 4′-seleno-6-chloropurine derivative in higher yield as compared to the previous method using a ‘disarmed’ 4-selenosugar bearing an electron-withdrawing group at the 2-position. In addition, the use of 2,6-dichloropurine as a nucleobase transformable into guanine skeleton enabled an effective Pummerer-like reaction followed by isomerization to the desired N9 isomer under the acidic conditions. This Pummerer-like reaction between chlorinated purine bases and an ‘armed’ 4-selenosugar is advantageous because it affords 4′-selenopurine nucleosides in one-pot without the need for isolation of the unstable selenoxide derivative.
- Ishii, Kazuki,Saito-Tarashima, Noriko,Ota, Masashi,Yamamoto, Seigi,Okamoto, Yasuko,Tanaka, Yoshiyuki,Minakawa, Noriaki
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supporting information
p. 6589 - 6594
(2016/09/23)
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- HAMAMELITANNIN ANALOGUES AND USES THEREOF
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The present invention relates to hamamelitannin analogues, pharmaceutical compositions comprising the same, and combinations thereof with anti-microbial agents such as antibiotics or disinfectants. It in particular relates to the use of the compounds, compositions and combinations according to this invention in human or veterinary medicine, more in particular for use in the prevention and/or treatment of bacterial infections, such as Staphylococcusaureus infections, in humans or animals.
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Page/Page column 149; 150
(2016/01/25)
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- RIBONUCLEIC ACIDs WITH 4'-THIO-MODIFIED NUCLEOTIDES AND RELATED METHODS
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Disclosed are messenger RNA molecules and related compositions incorporating a 4'-thio modification in the furanose ring of at least one nucleotide residue, and methods of using these mRNAs to produce an encoded therapeutic protein invivo and to treat or prevent diseases or disorders. In certain embodiments, the 4'-thio modified mRNA provides for enhanced stability and/or reduced immunogenicity in in vivo therapies.
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Paragraph 0132
(2014/10/04)
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- ANTIVIRAL AZASUGAR-CONTAINING NUCLEOSIDES
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Disclosed are compounds comprising an azasugar attached to a heterocyclic base, including pharmaceutically acceptable salts thereof, suitable for use in inhibiting viral RNA polymerase activity or viral replication, and treating viral infections. The compounds are characterized, in part, by favorable pharmacokinetics for the active pharmaceutical ingredient, particularly in conjunction with enteral administration, including, in particular, oral administration. Also disclosed are pharmaceutical compositions comprising one or more compounds mentioned above, or pharmaceutically acceptable salts thereof, as well as methods for preparing same. Also provided are methods for inhibiting viral RNA polymerase activity, viral replication, and treating viral infections.
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Page/Page column 94-95
(2014/06/11)
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- Structure-activity relationships of 2′-modified-4′- selenoarabinofuranosyl-pyrimidines as anticancer agents
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Based on the potent anticancer activity of the D-arabino-configured cytosine nucleoside ara-C, novel 2′-substituted-4′- selenoarabinofuranosyl pyrimidines 3a-3u, comprising azido, fluoro, and hydroxyl substituents at C-2′ were designed, synthesized, and evaluated for anticancer activity. The 2′-azido group was stereoselectively introduced by the Mitsunobu reaction using diphenylphosphoryl azide (DPPA), and the 2′-fluoro group was stereoselectively introduced through the double inversions of stereochemistry via the episelenium intermediate, which was formed by the participation of the selenium atom. Among the compounds tested, the 2′-fluoro derivative 3t (X = NH2, Y = H, R = F) was found to be the most potent anticancer agent and showed more potent anticancer activity than the control, ara-C in all tested human cancer cell lines (HCT116, A549, SNU638, T47D, and PC-3) except the leukemia cell lines (K562). The anticancer activity of the 2′-substituted-4′-selenonucleosides is in the following order: 2′-F > 2′-OH > 2′-N3.
- Kim, Jin-Hee,Yu, Jinha,Alexander, Varughese,Choi, Jung Hee,Song, Jayoung,Lee, Hyuk Woo,Kim, Hea Ok,Choi, Jungwon,Lee, Sang Kook,Jeong, Lak Shin
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p. 208 - 225
(2014/07/08)
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- COMPOSITIONS AND METHODS FOR INHIBITING VIRAL POLYMERASE
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Provided are compounds of Formula (I) as described herein. Compounds of Formula (I) are useful in methods of inhibiting viral RNA polymerase activity and viral replication. Also provided are pharmaceutical compositions comprising compounds of Formula (I), as well as methods of treating viral infections using compounds of Formula (I).
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Page/Page column 75; 76
(2013/11/05)
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- A heterogeneous Pd-Bi/C catalyst in the synthesis of l-lyxose and l-ribose from naturally occurring d-sugars
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A critical step in the synthesis of the rare sugars, l-lyxose and l-ribose, from the corresponding d-sugars is the oxidation to the lactone. Instead of conventional oxidizing agents like bromine or pyridinium dichromate, it was found that a heterogeneous catalyst, Pd-Bi/C, could be used for the direct oxidation with molecular oxygen. The composition of the catalyst was optimized and the best results were obtained with 5:1 atomic ratio of Pd:Bi. The overall yields of the five-step procedure to l-ribose and l-lyxose were 47% and 50%, respectively. The synthetic procedure is advantageous from the viewpoint of overall yield, reduced number of steps, and mild reaction conditions. Furthermore, the heterogeneous oxidation catalyst can be easily separated from the reaction mixture and reused with no loss of activity.
- Fan, Ao,Jaenicke, Stephan,Chuah, Gaik-Khuan
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supporting information; experimental part
p. 7720 - 7726
(2011/12/04)
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- LONG CHAIN N-ALKYL COMPOUNDS AND OXA-DERIVATIVES THEREOF AND USE AS ANTIVIRAL COMPOSITIONS
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Long chain N-alkyl amino and imino compounds, oxa-substituted derivatives thereof, and pharmaceutical compositions including such compounds are described. The long chain N-alkyl group is a C8-C16 alkyl group. The long chain N-alkyl compounds and oxa-substituted derivatives thereof can be used in the treatment of viral infections, in particular hepatitis B virus or hepatitis C virus, in a cell or an individual. For example, the long chain N-alkyl compounds or oxa-substituted derivatives thereof can be derived from piperidines, pyrrolidines, phenylamines, pyridines, pyrroles, or amino acids.
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Page/Page column 12
(2008/06/13)
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- Looking glass inhibitors: Efficient synthesis and biological evaluation of D-deoxyfuconojirimycin
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1,6-Dideoxygalactostatin, the mirror image of 1-deoxy-L-fuconojirimycin, was efficiently prepared from 2,3-O-isopropylidene-L-lyxonolactone in four steps and evaluated as a glycosidase inhibitor.
- Bleriot, Yves,Gretzke, Dirk,Kruelle, Thomas M.,Butters, Terry D.,Dwek, Raymond A.,Nash, Robert J.,Asano, Naoki,Fleet, George W.J.
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p. 2713 - 2718
(2007/10/03)
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- Deoxyiminoalditols from aldonolactones - V. Preparation of the four stereoisomers of 1,5-dideoxy-1,5-iminopentitols. Evaluation of these iminopentitols and three 1,5-dideoxy-1,5-iminoheptitols as glycosidase inhibitors
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The four stereoisomeric 1,5-dideoxy-1,5-iminopentitols with D-arabino - (D-lyxo-) (3), ribo- (9), L-lyxo- (L-arabino-) (13) and xylo- (18) configurations were synthesized. The corresponding aldonolactones (1, 7 and 11) or aldonic acid ester (15b) having a leaving group at C-5 gave by reaction with aqueous ammonia, the 5-amino-5-deoxy-1,5-lactams, 2, 8, 12 and 17, respectively. Reduction of the lactam function using sodium borohydride/acetic or trifluoroacetic acid, or borane dimethyl sulfide complex yielded the iminopentitols. The compounds 3, 9, 13 and 18, together with the three 1,5-dideoxy-1,5-iminoheptitols 19, 20 and 21 were tested for inhibition of the glycosidase activities present in an extract from human liver. Compound 18 was a potent and 19 a moderately good inhibitor of β-glucosidase. Compound 3 together with 19, 20 and 21, all having D-arabino-configuration at the hydroxy-substituted carbon atoms, were good inhibitors of α-L-fucosidase.
- Godskesen, Michael,Lundt, Inge,Madsen, Robert,Winchester, Bryan
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p. 1857 - 1865
(2007/10/03)
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- Stereoselective transformations leading to pentono -1, 4-lactones
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The readily available 2, 3-O-isopropylidene-D-erythrose has been stereoselectively transformed into L-ribono and D/L lyxonolactone derivatives via dihydroxylation, iodolactonisation and epoxidation. Also D-ribono-1,4-lactone was converted into L-lyxono-1,
- Rao, B. Venkateswara,Lahiri, Saswata
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p. 975 - 984
(2007/10/03)
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- First synthesis of aldopentono-1,4-thiolactones
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A convenient synthesis of enantiomerically pure aldopentono-1,4- thiolactones is described. Thus, 4-thio-D-ribono-1,4-lactone (12) has been prepared from D-gulono-1,4-lactone (1), via its 2,3-O-isopropylidene derivative 3. The 5,6-glycol system of 3 was o
- Varela,Zunszain
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p. 7860 - 7864
(2007/10/02)
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