ABSTRACT
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 = 20 nM.
Subject(s)
Cyclin-Dependent Kinase 5/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Glycogen Synthase Kinase 3 beta/antagonists & inhibitors , Indoles/pharmacology , Cell Line, Tumor , Enzyme Inhibitors/chemistry , Humans , Structure-Activity RelationshipABSTRACT
An efficient synthetic strategy was developed to modulate the structure of the tetrahydropyridine isoindolone (Valmerin) skeleton. 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 docking studies were performed to support medicinal chemistry efforts. A strong GSK3/CDK5 dual inhibitor (38, IC50 GSK3/CDK5 32/84 nM) was obtained. A set of highly selective GSK3 inhibitors was synthesized by fine-tuning structural modifications (29 IC50 GSK3/CDK5 32/320 nM). Antiproliferative effects on cells were correlated with the in vitro kinase activities and the best effects were obtained with lung and colon cell lines.
Subject(s)
Cyclin-Dependent Kinase 5/antagonists & inhibitors , Glycogen Synthase Kinase 3/antagonists & inhibitors , Isoindoles/pharmacology , Piperidines/pharmacology , Protein Kinase Inhibitors/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclin-Dependent Kinase 5/metabolism , Dose-Response Relationship, Drug , Glycogen Synthase Kinase 3/metabolism , Humans , Isoindoles/chemical synthesis , Isoindoles/chemistry , Models, Molecular , Molecular Structure , Piperidines/chemical synthesis , Piperidines/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
Substituted 3,4-dihydro-1,8-naphthyridin-2(1H)-ones have been synthesized with the inverse electron-demand Diels-Alder reaction from 1,2,4-triazines bearing an acylamino group with a terminal alkyne side chain. Alkynes were first subjected to the Sonogashira cross-coupling reaction with aryl halides, the product of which then underwent an intramolecular inverse electron-demand Diels-Alder reaction to yield 5-aryl-3,4-dihydro-1,8-naphthyridin-2(1H)-ones by an efficient synthetic route.
ABSTRACT
The development of CDK and GSK3 inhibitors has been regarded as a potential therapeutic approach, and a substantial number of diverse structures have been reported to inhibit CDKs and GSK-3ß in recent years. Only a few molecules have gone through or are currently undergoing clinical trials as CDK and GSK inhibitors. In this paper, we prepared valmerins, a new family containing the tetrahydropyrido[1,2-a]isoindone core. The fused heterocycle was prepared with a straightforward synthesis that was functionalized by a (het)arylurea. Twelve valmerins inhibited the CDK5 and GSK3 with an IC(50) < 100 nM. A semiquantitative kinase scoring was realized, and a cellular screening was done. At the end of our study, we investigated the in vivo potency of one valmerin. Mice exhibited good tolerance to our lead, which proved its efficacy and clearly blocked tumor growth. Valmerins appear also as good candidates for further development as anticancer agents.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Cyclin-Dependent Kinase 5/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Glycogen Synthase Kinase 3/antagonists & inhibitors , Heterocyclic Compounds/pharmacology , Neoplasms/drug therapy , Animals , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Cycle/drug effects , Enzyme Inhibitors/chemistry , Female , Glycogen Synthase Kinase 3 beta , Heterocyclic Compounds/chemistry , Humans , Mice , Models, Molecular , Phosphorylation/drug effects , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
UNLABELLED: Two efficient reactions were successfully carried out using Animal Bone Meal (ABM) and potassium fluoride or sodium nitrate doped ABMs as new heterogeneous catalysts under very mild conditions. After preparation and characterization of the catalysts, we first report their use in a simple and convenient synthesis of various chalcones by Claisen-Schmidt condensation and then in an aza-Michael addition involving several synthesized chalcones with aromatic amines. All the reactions were carried out at room temperature in methanol; the chalcone synthesis was also achieved in water environment under microwave irradiation. Doping ABM enhances the rate and yield at each reaction. Catalytic activities are discussed and the ability to re-use the ABM is demonstrated. RESULTS: For Claisen-Schmidt the use of ABM alone, yields never exceeded 17%. In each entry, KF/ABM and NaNO3/ABM (79-97%) gave higher yields than using ABM alone under thermic condition. Also the reaction proceeded under microwave irradiation in good yields (72-94% for KF/ABM and 81-97% for NaNO3/ABM) and high purity. For aza-Michael addition the use of ABM doped with KF or NaNO3 increased the catalytic activity remarkably. The very high yields could be noted (84-95% for KF/ABM and 81-94% for NaNO3/ABM). CONCLUSION: The present method is an efficient and selective procedure for the synthesis of chalcones an aza-Michael adducts. The ABM and doped ABMs are a new, inexpensive and attractive solid supports which can contribute to the development of catalytic processes and reduced environmental problems.
ABSTRACT
In the two mol-ecules of the asymmetric unit of the title compound, C(12)H(11)N(3)O(4), the seven-membered diazepine ring adopts a boat conformation (with the two phenyl-ene C atoms representing the stern and the methine C atom the prow). The five-membered pyrrole ring, which has an envelope conformation, makes dihedral angles of 60.47â (10) and 54.69â (9)° with the benzene ring of the benzodiazepine unit in the two mol-ecules. In the crystal, inter-molecular N-Hâ¯O hydrogen bonds and π-π stacking inter-actions [centroid-centroid distance = 3.8023â (7)-3.8946â (7)â Å] lead to the formation of a three-dimensional framework.
ABSTRACT
In the title compound, C(25)H(23)N(3)O(3), the seven-membered diazepine ring adopts a boat conformation with the hydroxy-substituted C atom at the prow and fused-ring C atoms at the stern. The crystal packing features C-Hâ¯O, C-Hâ¯π and N-H â¯π inter-actions.
ABSTRACT
In the crystal structure of the title compound, C(11)H(11)NO(3)S, the mol-ecules are linked by inter-molecular C-Hâ¯O hydrogen-bond inter-actions. The heterocyclic thia-zine ring adopts a conformation inter-mediate between twist and boat.
ABSTRACT
All the non-H atoms of the title compound, C(17)H(24)N(2)S, lie almost in a common plane (r.m.s. deviation = 0.049â Å). The octyl chain adopts an all-trans conformation.
ABSTRACT
In the mol-ecule of the title compound, C(12)H(12)N(2)O, the quinoxaline ring is planar with an r.m.s. deviation of 0.007â (15)â Å. The dihedral angle between the quinoxaline and propenyl planes is 82.1â (2)°. The crystal packing is stabilized by offset π-π stacking between the quinoxaline rings [centroid-centroid distance = 3.8832â (9)â Å].
ABSTRACT
The asymmetric unit of the title compound, C(16)H(14)N(2)O, contains three independent mol-ecules. The dihedral angles between the quinoxaline and phenyl planes in the three mol-ecules are 82.58â (8), 85.66â (9) and 85.36â (9)°. The crystal packing is stabilized by C-Hâ¯O and C-Hâ¯N hydrogen bonds.
ABSTRACT
In the title compound, C(15)H(15)N(3), the 1H-pyrazolo-[3,4-b]pyridine system and the phenyl ring are each individually planar, with r.m.s. deviations of 0.017â (2) and 0.011â (2)â Å, respectively; the dihedral angle between the two aromatic systems is 9.33â (10)°. The crystal packing is stabilized by offset π-π stacking between parallel pyrazolo-[3,4-b]pyridine ring systems [face-to-face distance = 3.449â (6)â Å].
ABSTRACT
In the title compound, C(12)H(13)N(3)O(2)S, the oxazolidin ring displays an envelope conformation. The dihedral angle between the benzimidazole ring and the 1,3-oxazolidin-2-one mean plane is 69.85â (13)°. In the crystal, mol-ecules are linked by inter-molecular N-Hâ¯N hydrogen bonds, forming a chain parallel to the b axis.