ABSTRACT
Lysine methyltransferases are important regulators of epigenetic signaling and are emerging as a novel drug target for drug discovery. This work demonstrates the positioning of novel 1,5-oxaza spiroquinone scaffold into selective SET and MYND domain-containing proteins 2 methyltransferases inhibitors. Selectivity of the scaffold was identified by epigenetic target screening followed by SAR study for the scaffold. The optimization was performed iteratively by two-step optimization consisting of iterative synthesis and computational studies (docking, metadynamics simulations). Computational binding studies guided the important interactions of the spiro[5.5]undeca scaffold in pocket 1 and Lysine channel and suggested extension of tail length for the improvement of potency (IC50: up to 399 nM). The effective performance of cell proliferation assay for chosen compounds (IC50: up to 11.9 nM) led to further evaluation in xenograft assay. The potent compound 24 demonstrated desirable in vivo efficacy with growth inhibition rate of 77.7% (4 fold decrease of tumor weight and 3 fold decrease of tumor volume). Moreover, mirosomal assay and pharmacokinetic profile suggested further developability of this scaffold through the identification of major metabolites (dealkylation at silyl group, reversible hydration product, the absence of toxic quinone fragments) and enough exposure of the testing compound 24 in plasma. Such spiro[5.5]undeca framework or ring system was neither been reported nor suggested as a modulator of methyltransferases. The chemo-centric target positioning and structural novelty can lead to potential pharmacological benefit.
Subject(s)
Aza Compounds/pharmacology , Enzyme Inhibitors/pharmacology , Epigenesis, Genetic/drug effects , Histone-Lysine N-Methyltransferase/antagonists & inhibitors , Quinones/pharmacology , Spiro Compounds/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Aza Compounds/chemical synthesis , Aza Compounds/chemistry , Cell Survival/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Epigenesis, Genetic/genetics , Female , HEK293 Cells , Histone-Lysine N-Methyltransferase/genetics , Histone-Lysine N-Methyltransferase/metabolism , Humans , Male , Mammary Neoplasms, Experimental/drug therapy , Mammary Neoplasms, Experimental/metabolism , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Inbred BALB C , Mice, Inbred ICR , Mice, Nude , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Molecular Docking Simulation , Molecular Structure , Quinones/chemical synthesis , Quinones/chemistry , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Structure-Activity RelationshipABSTRACT
The cycloisomerization of 1,8-enynes in the presence of platinum(II) chloride was developed to generate bicyclic nitrogen-containing heterocycle species via 6- endo-dig cyclization and [3,3]-sigmatropic rearrangement in acceptable to good yields. The related control experiments and preliminary mechanistic studies indicate a plausible mechanism involving 1,6- endo-dig aminoplatination of the alkyne and allylic [3,3]-sigmatropic rearrangement with total inversion of the allylic moiety.
ABSTRACT
The 1:1 zwitterionic intermediates obtained from the reaction between isoquinoline, quinoline, pyridine, or N-methylimidazole with activated acetylenes are trapped by ethyl pyruvate to produce highly functionalized fused [1,3]oxazines in good yields.