- Novel optimization of valmerins (tetrahydropyrido[1,2- a ]isoindolones) as potent dual CDK5/GSK3 inhibitors
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An efficient synthetic strategy able to modulate the structure of the tetrahydropyridine isoindolone (Valmerin) skeleton was developed. A library of more than 30 novel final structures was generated. Biological activities on CDK5 and GSK3 as well as cellular effects on cancer cell lines were measured for each novel compound. Additionally to support the SAR, a docking study was performed. A potent GSK3/CDK5 dual inhibitor (37, IC50 CDK5/GSK3 35/7 nM) was obtained. Best antiproliferative effects were obtained on lung and prostate cell lines with IC50 Combining double low line 20 nM.
- Ouach, Aziz,Boulahjar, Rajaa,Vala, Christine,Bourg, Stéphane,Bonnet, Pascal,Guguen-Guillouzo, Christiane,Ravache, Myriam,Le Guevel, Rémy,Lozach, Olivier,Lazar, Sa?d,Troin, Yves,Meijer, Laurent,Ruchaud, Sandrine,Akssira, Mohamed,Guillaumet, Gérald,Routier, Sylvain
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p. 311 - 325
(2016/04/05)
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- Modular synthesis and biological activity of pyridyl-based analogs of the potent Class i Histone Deacetylase Inhibitor Largazole
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The formation of a series of analogs containing a pyridine moiety in place of the natural thiazole heterocycle, based on the potent, naturally occurring HDAC inhibitor Largazole has been accomplished. The synthetic strategy was designed modularly to access multiple inhibitors with different aryl functionalities containing both the natural depsipeptide and peptide isostere variant of the macrocycle. The cytotoxicity and biochemical activity of the library of HDAC inhibitors is described herein.
- Clausen, Dane J.,Smith, William B.,Haines, Brandon E.,Wiest, Olaf,Bradner, James E.,Williams, Robert M.
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p. 5061 - 5074
(2015/08/03)
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- Design of glycosyltransferase inhibitors: Pyridine as a pyrophosphate surrogate
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A series of ten glycosyltransferase inhibitors has been designed and synthesized by using pyridine as a pyrophosphate surrogate. The series was prepared by conjugation of carbohydrate, pyridine, and nucleoside building blocks by using a combination of gly
- Wang, Shuai,Cuesta-Seijo, Jose A.,Lafont, Dominique,Palcic, Monica M.,Vidal, Sebastien
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supporting information
p. 15346 - 15357
(2013/11/06)
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- NHC-catalysed highly selective aerobic oxidation of nonactivated aldehydes
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This publication describes a highly selective oxidation of aldehydes to the corresponding acids or esters. The reaction proceeds under metal-free conditions by using N-heterocyclic carbenes as organocatalysts in combination with environmentally friendly oxygen as the terminal oxidation agent.
- Moehlmann, Lennart,Ludwig, Stefan,Blechert, Siegfried
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p. 602 - 607
(2013/04/24)
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- New NO-releasing pharmacodynamic hybrids of losartan and its active metabolite: Design, synthesis, and biopharmacological properties
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In a preliminary work, we reported two NO-sartans, possessing the characteristics of an AT1 antagonist and a "slow NO donor", obtained by adding NO-donor side chains to losartan 1. The NO release from an NO-sartan should be modulated in order to strengthen the antihypertensive activity of the native drug and to ensure additional effects, such as the antiplatelet and anti-ischemic ones. To obtain a collection of proto-typical NO-sartans, showing different rates of NO release, new NO-donor moieties have been linked to 1 or its active metabolite 2 (EXP 3174). Almost all the synthesized compounds exhibited both AT1-antagonist and NO-mediated vasorelaxing properties, with a wide range of NO-releasing rates. Further pharmacological investigation on compound 4a showed that it possessed antihypertensive and cardiac antihypertrophic effects similar to those of the reference AT1-blocking or ACE-inhibiting drugs. Furthermore, the additional anti-ischemic cardio-protective properties and antiplatelet effects of 4a have been preliminarily investigated.
- Breschi, Maria C.,Calderone, Vincenzo,Digiacomo, Maria,Macchia, Marco,Martelli, Alma,Martinotti, Enrica,Minutolo, Filippo,Rapposelli, Simona,Rossello, Armando,Testai, Lara,Balsamo, Aldo
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p. 2628 - 2639
(2007/10/03)
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- TRICYCLIC DERIVATIVES OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF, THEIR PREPARATIONS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
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The present invention relates to tricyclic derivatives or pharmaceutically acceptable salts thereof, their preparations and pharmaceutical compositions containing them. More precisely, the present invention relates to tricyclic derivatives as colchicine derivatives, pharmaceutically acceptable salts thereof, their preparations and pharmaceutical compositions containing them. Tricyclic derivatives of the present invention show very powerful cytotoxicity to cancer cell lines but were much less toxic than colchicine or taxol, confirmed through animal toxicity test. Tricyclic derivatives of the invention also decrease the volume and weight of a tumor and have a strong angiogenesis inhibiting activity in HUVEC cells. Thus, tricyclic derivatives of the present invention can effectively be used as an anticancer agent, anti-proliferation agent and an angiogenesis inhibitor.
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- Oxo and Non-oxovanadium(IV) Complexes with Oxy-Carboxylate Ligands, and the Structure of VCl2(salen)
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VO(2+) forms complexes of composition VO(L1)(EtOH), VO(HL1)2 and VO(HL2)(H2O) with the lithium or sodium salts of 6-hydroxymethyl-pyridine-2-carboxylic acid (H2L1) and 4,8-dihydroxyquinoline-2-carboxylic acid (H3L2).VCl2(salen/salphen) and VCl2(napgly/nappa) (napgly and nappa are the Schiff bases derived from o-hydroxynaphthaldehyde and glycine or phenylalanine, respectively), prepared from the oxo precursor and SOCl2, react with Li2L1 and the lithium salts of benzilic acid (H2L3) and ortho-hydroxybenzoic acid (H2L4) to yield the non-oxo ("bare") complexes V(salen)L1, V(salen)L3, V(salphen)L3, V(salen)L4, V(napgly)L1, V(nappa)L1 and V(nappa)L4.The complexes have been characterized by IR, EPR and elemental analysis.VOCl2(salen) crystallizes in the monoclinic space group Cc, a = 14.579(3), b = 9.537(2), c = 13.453(3) Angstroem, β = 120.92(3) deg.The molecule exhibits gross distortions from octahedral geometry.An improved synthesis for H2L1 is described. - Keywords: Oxovanadium Compounds, Non-Oxo Complexes of Vanadium
- Vergopoulos, Vassilios,Jantzen, Sven,Julien, Nathalie,Rose, Eric,Rehder, Diether
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p. 1127 - 1136
(2007/10/02)
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- Studies on the hydrogenation of 6-(hydroxymethyl)pyridine-2-carboxylates and its application to the synthesis of 6-(hydroxymethyl)piperidine-2-carboxylic acid derivatives
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The synthesis of the novel amino acid 6-(hydroxymethyl)-2-piperidinecarboxylic acid (1a) and its ethyl ester 1b is reported. In the hydrogenation of 6-(hydroxymethyl)pyridine-2-carboxylates, hydrogenolysis of the alcohol group appeared as an unusual side reaction. Optimization of the reaction conditions allowed us to minimize hydrogenolysis and afforded pure 1.
- Bolos,Gubert,Anglada,Perez,Sacristan,Ortiz
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p. 1493 - 1496
(2007/10/02)
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- Metal Ion Effects in Intramolecular Reactions. Effects of Divalent Metal Ions on Intramolecular Acetamido Group Participation in Ester Hydrolysis
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The hydrolysis reactions of a series of esters of α-acetamidocinnamic acid proceed with formation of an oxazolinone intermediate.In 50percent dioxane-H2O (v/v) at 50 deg C, an oxazolinone can be observed spectrophotometrically in the OH- catalyzed cyclization reactions of the α-acetamido-substituted esters with leaving groups of pKa 12.4 or less.In comparison with the OH- catalyzed hydrolysis of the corresponding cinnamate esters, the rate enhancement due to the presence of the acetamido group is a factor of 200 with the trifluoroethyl ester and increases to 2x1E6 with the p-nitrophenyl ester.The plot of log kOH vs ?, the Hammett substituent constant, is linear and has a slope (ρ) of 2.7 (1.8 when ?- is employed) for the cyclization reactions of the phenolic esters, but the ρ value is only 1.4 for the OH- catalyzed hydrolysis of the corresponding cinnamates.The slope of log kOH vs the pKa of the leaving group for the cyclization of the α-acetamidocinnamic acid derivatives, βlg, is -0.9.Thus, there must be considerable C-O bond breaking in the critical transition state for oxazolinone formation.In H2O as the solvent, 6-carboxy-2-pyridylmethyl α-(N-acetylamino)cinnamate and the corresponding 2-pyridylmethyl derivative cyclize rapidly to the oxazolinone with KOH (5xE4)-fold larger than that for hydrolysis of 2-pyridylmethyl cinnamate, even though the leaving group is an aliphatic alcohol.There is significant metal ion catalysis in the cyclization reactions with Cu2+, Ni2+, Co2+ or Zn2+.The binding of the metal ions to the 6-carboxy-substituted derivative is very strong, and saturation occurs at metal ion concentrations less than 0.01 M.A saturating concentration of Cu2+ (0.001 M) enhances the rate of cyclization by a factor of 5x1E4.Thus, the total rate enhancement provided by bifunctional catalysis (Cu2+ and the neighboring acetamido group) is 1E9-fold.Metal ion binding to 2-pyridylmethyl α-(N-acetylamino)cinnamate is weak, but nevertheless, the second-order rate constants kOH are similar to those of the 6-carboxy-substituted ester at equal metal ion concentrations.The metal ions must exert their catalytic effect by stabilizing the leaving group alcohol in the transition state.This appears to be a general mechanism for metal ion catalysis of reactions in which C-O bond breaking is the rate-determining step.
- Fife, Thomas H.,Przystas, Theodore J.,Pujari, Mahesh P.
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p. 8157 - 8163
(2007/10/02)
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- Effects of Divalent Metal Ions on Hydrolysis of Esters of 2-(Hydroxymethyl)picolinic Acid. Metal Ion Catalysis of the Carboxyl, Hydroxide Ion, and Water Reaction
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The effects of divalent metal ions (Cu2+, Ni2+, Co2+, and Zn2+) on the hydrolysis reactions of phthalate, succinate, and acetate esters of 2-(hydroxymethyl)picolinic acid have been determined at 50 deg C.With these esters the metal ion saturates at low metal ion concentration (4 with Ni2+ to 106 with Co2+.A pH-independent reaction also occurs in the case of the phthalate monoester which is associated with the neighboring carboxyl nucleophilic reaction.Rate enhancements of 102-104 are obtained in this reaction at saturating concentrations of Ni2+, Co2+, and Cu2+.Rate constants in the Ni2+ and Co2+ catalyzed reaction are closely similar to those for 2-pyridylmethyl hydrogen phthalate with which metal ion binding is weak.Thus, metal ion catalysis of the nucleophilic reaction, which occurs through leaving group stabilization in the transition state, is not appreciably enhanced by increased strength of binding to the reactant.Such a reaction does not occur with Cu2+ in hydrolysis of succinate monoester, showing that when the leaving group is poor, steric fit of the nucleophile and the carbonyl must be excellent for a nucleophilic mechanism to occur even through the leaving group can be greatly stabilized by a metal ion, i.e., there cannot be degrees of freedom for rotation of the nucleophile away from the carbonyl.At pH obsd is pH independent in the Cu2+-catalyzed hydrolysis of the succinate and acetate esters due to a metal ion promoted water catalyzed reaction.Thus, three different mechanisms for metal ion catalysis can be observed in hydrolysis of esters of 2-(hydroxymethyl)picolinic acid: (1) catalysis of a neighboring carboxyl nucleophilic reaction, (2) metal ion promoted OH- catalysis, and (3) metal ion promoted water catalysis.The first of these mechanisms is dependent upon the strength of binding of the metal ion to the leaving oxygen in the transition state, whereas the latter two mechanisms are facilitated by strength of bindind to the reactant.
- Fife, Thomas H.,Przystas, Theodore J.
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p. 2251 - 2257
(2007/10/02)
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