ABSTRACT
The mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (MNKs 1/2) and their downstream target eIF4E, play a role in oncogenic transformation, progression and metastasis. These results provided rationale for development of first MNKs inhibitors, currently in clinical trials for cancer treatment. Inhibitors of the MNKs/eIF4E pathway are also proposed as treatment strategy for inflammatory conditions. Here we present results of optimization of indazole-pyridinone derived MNK1/2 inhibitors among which compounds 24 and 26, selective and metabolically stable derivatives. Both compounds decreased levels of eIF4E Ser206 phosphorylation (pSer209-eIF4E) in MOLM16 cell line. When administered in mice compounds 24 and 26 significantly improved survival rates of animals in the endotoxin lethal dose challenge model, with concomitant reduction of proinflammatory cytokine levels - TNFα and IL-6 in serum. Identified MNK1/2 inhibitors represent a novel class of immunomodulatory compounds with a potential for the treatment of inflammatory diseases including sepsis.
Subject(s)
Immunologic Factors/chemical synthesis , Indazoles/chemistry , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyridones/chemistry , Shock, Septic/drug therapy , Amino Acid Sequence , Animals , Cytokines/metabolism , Dose-Response Relationship, Drug , Drug Discovery , Endotoxins/metabolism , Eukaryotic Initiation Factor-4E/metabolism , Humans , Immunologic Factors/pharmacology , Mice , Molecular Docking Simulation , Protein Binding , Protein Kinase Inhibitors/pharmacology , Shock, Septic/chemically induced , Signal Transduction , Structure-Activity RelationshipABSTRACT
The UV-induced photochemical reaction of 1α,25-dihydroxy-9-methylene-19-norvitamin D3 has been investigated. The pentacyclic structure of the isolated product has been unequivocally established by X-ray crystallographic analysis. The possible reaction paths of the examined photochemical transformation are discussed. Biological in vivo and in vitro tests proved that the photoproduct is devoid of calcemic activity.
Subject(s)
Hydroxycholecalciferols/chemistry , Hydroxycholecalciferols/radiation effects , Sterols/chemistry , Sterols/radiation effects , Ultraviolet Rays , Crystallography, X-Ray , HL-60 Cells , Humans , Models, Molecular , Molecular Conformation , Photochemical Processes , Sterols/chemical synthesisABSTRACT
Continuing the structure-activity relationship studies in the vitamin D area, we designed and synthesized novel C-9 substituted calcitriol analogues, possessing different nonpolar groups at this position. 9α-Methyl-1α,25-(OH)2D3, both epimers of 9-methylene-10,19-dihydro-1α,25-(OH)2D3 as well as the parent vitamin with the "reversed" triene system, 9-methylene-19-nor-1α,25-(OH)2D3, were obtained from the previtamin D precursors, constructed by either Suzuki-Miyaura, Sonogashira, or Stille couplings of the corresponding A- and C,D-ring fragments. An alternative synthetic path, leading to the latter vitamin and its homologue with 9-ethylidene group, involved formation of dienynes as precursors of the respective 19-norprevitamin D compounds. 9ß-Methyl-19-nor-1α,25-(OH)2D3 was prepared by homogeneous hydrogenation with Wilkinson catalyst, and this analogue was found to be the most active in vitro. Moreover, 9α-methyl-1α,25-(OH)2D3 and 9-methylene-19-nor-1α,25-(OH)2D3 showed some in vitro activity, however, the in vivo assays indicated only weak calcemic potency of these compounds in the intestinal calcium transport.
Subject(s)
Vitamin D/analogs & derivatives , Chromatography, High Pressure Liquid , Crystallography, X-Ray , In Vitro Techniques , Proton Magnetic Resonance Spectroscopy , Vitamin D/chemical synthesis , Vitamin D/chemistry , Vitamin D/pharmacologyABSTRACT
1α,25-(OH)(2)-9α-Methylvitamin D(3) (4), the first known analogue of the natural hormone 1α,25-(OH)(2)D(3) (3) with an alkyl substituent at C-9, and two 1α,25-(OH)(2)-9-methylene-10,19-dihydrovitamin D(3) analogues (7 and 8) with an unprecedented non-natural triene system were synthesized by thermal isomerization of 1α,25-(OH)(2)-9-methylprevitamin D(3) (6). Three alternative approaches (Sonogashira, Stille, or stereoselective dehydration of a tertiary propargyl alcohol) have been successfully used to construct the dienyne precursors of previtamin 6 possessing two methyl groups capable of participating in the [1,7]-sigmatropic hydrogen shift.
Subject(s)
Alkanes/chemistry , Calcitriol/chemical synthesis , Hydroxycholecalciferols/chemical synthesis , Methane/analogs & derivatives , Alkylation , Calcitriol/chemistry , Hydroxycholecalciferols/chemistry , Methane/chemistry , Molecular StructureABSTRACT
9-Alkylidene analogs of 19-nor-1α,25-(OH)2D3 were synthesized, possessing a 'reversed' triene system compared to the natural hormone. The conjugated triene moiety of the novel analogs was constructed by coupling an enyne anion, representing an A-ring synthon, with a 9α-substituted Grundmann ketone derivative. Regioselective dehydration followed by semihydrogenation under Lindlar conditions, provided the desired 9-alkylated 19-norprevitamins which were thermally isomerized to the corresponding 9-methylene and 9-ethylidene analogs of 19-norcalcitriol. It was established that only the former compound had significant binding affinity to the full-length recombinant rat vitamin D receptor. The remaining in vitro studies show very low activity of both analogs. This article is part of a Special Issue entitled 'Vitamin D Workshop'.
Subject(s)
Calcitriol/analogs & derivatives , Animals , Calcitriol/chemical synthesis , Calcitriol/pharmacology , Cell Differentiation/drug effects , Chemistry Techniques, Synthetic , Drug Evaluation, Preclinical , HL-60 Cells , Humans , Rats , Receptors, Calcitriol/metabolism , Structure-Activity Relationship , Transcription, Genetic/drug effectsABSTRACT
Convergent syntheses of three new analogues of 1α,25-dihydroxyvitamin D3 with α-hydroxyalkyl substituents at C12 (4a-c) are described. The A-ring and triene system of each analogue were assembled by a tandem Pd-catalysed intramolecular cyclization and Suzuki-Miyaura coupling process. The stereoselective introduction of substituents at C12 was achieved by Johnson-Claisen rearrangement on allylic alcohol 15 as the key step. This article is part of a Special Issue entitled 'Vitamin D Workshop'.
