ABSTRACT
We report a new method for the regiodivergent dearomative (3 + 2) reaction between 3-substituted indoles and oxyallyl cations. Access to both regioisomeric products is possible and is contingent on the presence or absence of a bromine atom on the substituted oxyallyl cation. In this way, we are able to prepare molecules that contain highly-hindered, stereodefined, vicinal, quaternary centers. Detailed computational studies employing energy decomposition analysis (EDA) at the DFT level establishes that regiochemical control arises from either reactant distortion energy or orbital mixing and dispersive forces, depending on the oxyallyl cation. Examination of the Natural Orbitals for Chemical Valence (NOCV) confirms that indole acts as the nucleophilic partner in the annulation reaction.
ABSTRACT
We previously described the development of a DNA-alkylating compound that showed selective toxicity in breast cancer cells. This compound contained an estrogen receptor α (ERα)-binding ligand and a DNA-binding/methylating component that could selectively methylate the N3-position of adenines at adenine-thymine rich regions of DNA. Herein, we describe mechanistic investigations that demonstrate that this class of compounds facilitate the translocation of the ERα-compound complex to the nucleus and induce the expression of ERα target genes. We confirm that the compounds show selective toxicity in ERα-expressing cells, induce ERα localization in the nucleus, and verify the essential role of ERα in modulating the toxicity. Minor alterations in the compound structure significantly affects the DNA binding ability, which correlates to the DNA-methylating ability. These studies demonstrate the utility of DNA-alkylating compounds to accomplish targeted inhibition of the growth of specific cancer cells; an approach that may overcome shortcomings of currently used chemotherapy agents.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Cell Line, Tumor , Cell Survival/drug effects , DNA Methylation , Drug Delivery Systems , Drug Design , Estradiol/administration & dosage , Estradiol/pharmacology , Female , Humans , MCF-7 Cells , Models, Molecular , Molecular Dynamics Simulation , Molecular Structure , Structure-Activity RelationshipABSTRACT
The nucleophile-intercepted Beckmann fragmentation (NuBFr) has the potential to be broadly applicable to the synthesis of indoline alkaloid-based natural products. However, the reaction has not been widely adopted, in part, because of limitations associated with the availability of appropriate promoter-Nu reagents. We have devised a stereospecific Ag(I)-promoted reaction for functionalizing NuBFr products to give novel compositions of matter that may be useful in synthesis and medicinal chemistry. With unhindered amine nucleophiles, structurally unique [2.2.2]-bicycloamidines are generated. We also disclose for the first time detailed density functional theory studies, which shed light on the mechanism of the NuBFr and Ag-promoted substitution reaction that supports an unusual aziridinium ion as a key intermediate.
Subject(s)
Alkaloids , Density Functional TheoryABSTRACT
We describe the first examples of nucleophile-intercepted Beckmann fragmentations of indoline oximes. This reaction uses MsCl as a promoter to give cyano chlorides and is believed to proceed through an aziridinium intermediate via a double stereoinvertive process. Mechanistic insights have led to the further discovery that oxygen, nitrogen, and bromide nucleophiles can be employed for this fragmentation by the use of other promoters. We envision that these products may be useful in the syntheses of members of the akuammiline and koumine families of indoline alkaloids.
