Project description:Cascade radical cyclization of 1,6-enynes for the construction of biologically important polycyclic γ-lactams and related heterocycles is reported. In these radical cascade processes, three new C-C bonds are formed and transition metals are not required to run these sequences. The mild reaction conditions, broad substrate scope, and the importance of the heterocyclic products render the approach valuable.
Project description:The enantioselective synthesis of nitrogen-containing heterocycles (N-heterocycles) represents a substantial chemical research effort and resonates across numerous disciplines, including the total synthesis of natural products and medicinal chemistry. In this Article, we describe the highly enantioselective palladium-catalysed decarboxylative allylic alkylation of readily available lactams to form 3,3-disubstituted pyrrolidinones, piperidinones, caprolactams and structurally related lactams. Given the prevalence of quaternary N-heterocycles in biologically active alkaloids and pharmaceutical agents, we envisage that our method will provide a synthetic entry into the de novo asymmetric synthesis of such structures. As an entry for these investigations we demonstrate how the described catalysis affords enantiopure quaternary lactams that intercept synthetic intermediates previously used in the synthesis of the Aspidosperma alkaloids quebrachamine and rhazinilam, but that were previously only available by chiral auxiliary approaches or as racemic mixtures.
Project description:The straightforward protonation of lactams by treatment with acid and the full structural characterization of three resulting N-protonated lactams are disclosed. This work provides experimental evidence that N-protonation of amide bonds results in a dramatic increase in nonplanarity about the C-N amide bond. The resulting compounds are discussed in structural, spectroscopic, and reactivity terms. The data suggest that distortion of these amide bonds by approximately 50 degrees is sufficient for their effective N-activation.
Project description:Cancer is one of the major healthcare challenges across the globe. Several anticancer drugs are available on the market but they either lack specificity or have poor safety, severe side effects, and suffer from resistance. So, there is a dire need to develop safer and target-specific anticancer drugs. More than 85% of all physiologically active pharmaceuticals are heterocycles or contain at least one heteroatom. Nitrogen heterocycles constituting the most common heterocyclic framework. In this study, we have compiled the FDA approved heterocyclic drugs with nitrogen atoms and their pharmacological properties. Moreover, we have reported nitrogen containing heterocycles, including pyrimidine, quinolone, carbazole, pyridine, imidazole, benzimidazole, triazole, β-lactam, indole, pyrazole, quinazoline, quinoxaline, isatin, pyrrolo-benzodiazepines, and pyrido[2,3-d]pyrimidines, which are used in the treatment of different types of cancer, concurrently covering the biochemical mechanisms of action and cellular targets.
Project description:The reactions of a series of strained bicyclic and tricyclic one-carbon bridged lactams with organometallic reagents have been investigated. These amides permit isolation of a number of remarkably stable hemiaminals upon nucleophilic addition to the twisted amide bonds present in the lactam precursors. The factors that affect the stability of the resulting bridged hemiaminals are presented. In some cases, the hemiaminals were found to collapse to the open-form amino ketones in a manner expected for traditional carboxylic acid derivatives. Transannular N...C=O interactions were also observed in some nine-membered amino ketones. Additionally, tricyclic bridged lactams were found to react with some nucleophiles that typically react with ketones but not with planar amides. The effect of geometry on the reactivity of amide bonds and the amide bond distortion range that marks the boundary of amide-like and ketone-like carbonyl reactivity of lactams are also discussed.
Project description:Nuclear factor kappa beta (NF-κB) is a transcriptional factor that plays a crucial role in regulating cancer cell proliferation. Therefore, the inhibition of NF-κB activity by small molecules may be beneficial in cancer therapy. In this report, methyl-thiol-bridged oxadiazole and triazole heterocycles were synthesized via click chemistry and it was observed that the lead structure, 2-(((1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-5-(4-methoxybenzyl)-1,3,4-oxadiazole (4c), reduced the viability of MCF-7 cells with an IC50 value of 7.4 µM. Compound 4c also caused concentration-dependent loss of cell viability in chronic myelogenous leukemia (CML) cells. Furthermore, compound 4c inhibited the activation of NF-κB in human CML cells as observed by nuclear translocation and DNA binding assays. Functionally, compound 4c produced PARP cleavage and also suppressed expression of Bcl-2/xl, MMP-9, COX-2, survivin, as well as VEGF, resulting in apoptosis of CML cells. Moreover, ChIP assay showed that compound 4c decreased the binding of COX-2 to the p65 gene promoter. Detailed in silico analysis also indicated that compound 4c targeted NF-κB in CML cells. In conclusion, a novel structure bearing both triazole and oxadiazole moieties has been identified that can target NF-κB in CML cells and may constitute a potential novel drug candidate.
Project description:Medium-bridged twisted amides can be synthesized by the intramolecular Schmidt reaction of 2-azidoalkyl ketones. In these reactions, the regiochemistry of the Schmidt reaction is diverted into a typically disfavored pathway by the presence of an aromatic group at the alpha-position adjacent to the ketone, which stabilizes the predominantly reactive conformation of the azidohydrin intermediate by engaging in a nonbonded cation-pi interaction with the positively charged diazonium cation. This results in the rarely observed rearrangement of the C-C bond distal to the azidoalkyl chain. This reaction pathway also requires the azide-containing tether to be situated in the axial orientation in the key azidohydrin intermediate. Examination of the effect of substitution of aromatic rings on the regiochemistry of the Schmidt reaction shows an increase in the migratory selectivity with more electron-rich aromatic groups. The selectivity is lower when an electron-withdrawing substituent is placed on the aromatic ring. The ability of cation-pi interactions to act as a controlling element decreases when Lewis acids coordinate to substituents on the aromatic ring. The developed version of the Schmidt reaction provides a direct access to a family of medium-bridged twisted amides with a [4.3.1] bicyclic system, compounds which are very difficult to access with use of other currently available methods.
Project description:The chemistry of rare-earth carbene and alkylidene complexes including their synthesis, structure and reaction is a challenging issue because of their high reactivity (or instability) and the lack of synthetic methods. In this work, we report the first synthesis of the bridged bis-alkylidene complexes which feature a 2-butene-1,1,4,4-tetraanion and four Sc-C(sp3) bonds by the reaction of 1,4-dilithio-1,3-butadienes with ScCl3. This reaction proceeds via two key intermediates: an isolable scandacyclopentadiene and a proposed scandacyclopropene. The scandacyclopentadiene undergoes β,β'-C-C bond cleavage to generate the scandacyclopropene, which then dimerizes to afford the bridged bis-alkylidene complex via a cooperative double metathesis reaction. Reaction chemistry study of the bridged bis-alkylidene complex reveals their ligand-based reduction reactivity towards different oxidants such as hexachloroethane, disulfide and cyclooctatetraene.