Crystal structure, DFT and Hirshfeld surface analysis of N-acetyl-t-3-methyl-r-2,c-6-diphenylpiperidine

In the title compound [systematic name: 1-(3-methyl-2,6-diphenylpiperidin-1-yl)ethanone], C20H23NO, the piperidine ring adopts a distorted boat conformation, while the phenyl rings subtend a dihedral angle 65.1 (2)°. In the crystal, molecules are linked by C—H...O hydrogen bonds into chains extending along the b-axis direction. The DFT/B3LYP/6–311 G(d,p) method was used to determine the HOMO–LUMO energy levels. A Hirshfeld surface analysis was conducted to verify the contributions of the different intermolecular interactions, indicating that the important contributions to the crystal packing are from H...H (73.2%), C...H (18.4%) and O...H (8.4%) interactions.

Crystal structure and Hirshfeld surface analysis of 3-(hydroxymethyl)-3-methyl-2,6-diphenylpiperidin-4-one

A new synthesis of the title compound, C19H21NO2, was developed with good yield and purity using the reaction of 4-hydroxy-3-methyl-2-butanone, benzaldehyde and ammonium acetate in glacial acetic acid as a solvent. The central piperidine ring adopts a chair conformation, and its least-squares basal plane forms dihedral angles of 85.71 (11) and 77.27 (11)° with the terminal aromatic rings. In the crystal, the molecules are linked by O—H...O and C—H...O hydrogen bonds into double ribbons. The Hirshfeld surface analysis shows that the most important contributions are from H...H (68%), C...H/H...C (19%) and O...H/H...O (12%) interactions.

Cytotoxic Tumour-Selective 1,5-Diaryl-3-Oxo-1,4-Pentadienes Mounted on a Piperidine Ring

A series of 3,5-bis(benzylidene)-4-piperidones 2a-u were prepared as candidate cytotoxic agents. In general, the compounds are highly toxic to human gingival carcinoma (Ca9-22), human squamous carcinoma-2 (HSC-2) and human squamous carcinoma-4 (HSC-4) neoplasms, but less so towards non-malignant human gingival fibroblast (HGF), human periodontal ligament fibroblast (HPLF) and human pulp cells (HPC), thereby demonstrating tumour-selective toxicity. A further study revealed that most of the compounds in series 2 were more toxic to the human Colo-205 adenocarcinoma cell line (Colo-205), human HT29 colorectal adenocarcinoma cells (HT-29) and human CEM lymphoid cells (CEM) neoplasms than towards non-malignant human foreskin Hs27 fibroblast line (Hs27) cells. The potency of the cytotoxins towards the six malignant cell lines increased as the sigma and sigma star values of the aryl substituents rose. Attempts to condense various aryl aldehydes with 2,2,6,6-tetramethyl-4-piperidone led to the isolation of some 1,5-diaryl-1,4-pentadien-3-ones. The highest specificity for oral cancer cells was displayed by 2e and 2r. In the case of 2r, its selective toxicity exceeded that of doxorubicin and melphalan. The enones 2k, m, o have the highest SI values towards colon cancer and leukemic cells. Both 2e,r inhibited mitosis and increased the subG1 population (with a transient increase in G2/M phase cells). Slight activation of caspase-3, based on the cleavage of poly(ADP-ribose)polymerase (PARP) and procaspase 3, was detected.

Application of Oxidative Ring Opening/Ring Closing by Reductive Amination Protocol for the Stereocontrolled Synthesis of Functionalized Azaheterocycles

The current Account gives an insight into the synthesis of some N-heterocyclic β-amino acid derivatives and various functionalized saturated azaheterocycles accessed from substituted cycloalkenes via ring C=C bond oxidative cleavage followed by ring closing across double reductive amination. The ring-cleavage protocol has been accomplished according to two common approaches: a) Os-catalyzed dihydroxylation/NaIO4 vicinal diol oxidation and b) ozonolysis. A comparative study on these methodologies has been investigated. Due to the everincreasing relevance of organofluorine chemistry in drug research as well as of the high biological potential of β-amino acid derivatives several illustrative examples to the access of various fluorine-containing piperidine or azepane β-amino acid derivatives are also presented in the current Account.1 Introduction2 Olefin-Bond Transformation by Oxidative Ring Cleavage3 Synthesis of Saturated Azaheterocycles via Oxidative Ring-Opening/Ring-Closing Double Reductive Amination3.1 Importance of Fluorine-Containing Azaheterocycles in Pharmaceutical Research3.2 Synthesis of Azaheterocyclic Amino Acid Derivatives with a Piperidine or Azepane Framework through Oxidative Ring Opening/Reductive Amination3.2.1 Synthesis of Piperidine β-Amino Esters3.2.2 Synthesis of Azepane β-Amino Esters3.2.3 Synthesis of Fluorine-Containing Piperidine γ-Amino Esters3.3 Synthesis of Tetrahydroisoquinoline Derivatives through Oxidative Ring Opening/Reductive Amination Protocol3.4 Synthesis of Functionalized Benzazepines through Reductive Amination3.4.1 Synthesis of Benzo[c]azepines3.4.2 Synthesis of Benzo[d]azepines3.5 Synthesis of Various N-Heterocycles via Ozonolysis/Reductive Amination3.5.1 Synthesis of Compounds with an Azepane Ring3.5.2 Synthesis of Piperidine β-Amino Acids and Piperidine-Fused β-Lactams3.5.3 Synthesis of γ-Lactams with a Piperidine Ring3.5.4 Synthesis of other N-Heterocycles4 Summary and Outlook5 List of Abbreviations

A flexible approach to the synthesis of type II and III lepadin alkaloids

A flexible approach to both the type II and III lepadin alkaloids is developed for the first time. A key Diels−Alder reaction based on a novel chiral ketolactone dienophile is employed to obtain the desirable all-cis-trisubstituted cyclohexene with excellent regio- and stereoselectivity. As the subsequent closure of the piperidine ring is devised at the N1 and C2 position via a intramolecular nucleophilic amination, the two stereochemical types of lepadin frameworks with the opposite configuration at C2 can be conveniently accessible from a common intermediate. By the approach, lepadins D, E (type II) and F (type III) are stereoselectively synthesized from ethyl L-lactate.

Synthesis and Antinociceptive activity of Newly Modified Amine analogs of Phencyclidine in Mice

Background: Phencyclidine (PCP, I) and its substituted analogs are significant and broadly abused psychotomimetic drugs that affect the central nervous system. They show many pharmacological properties due to the presence of specific receptors in the brain. Aim and Objective: Methyl group, despite strong electron-donating and characters of dipole moments, were placed on various positions of phenyl and amine moieties of Phencyclidine along with the substitution of benzylamine, piperazine, and aniline derivatives in place of piperidine ring of Phencyclidine to create novel compounds of the core with analgesic properties. Material and methods: For evaluation of the Analgesic activities of newly synthesized compounds, they were screened by tests of tail immersion (thermal) and formalin (chemical) pains. The obtained data with the control and PCP groups were compared too. Results: The outcomes indicated that some new compounds have more antinociceptive effects than PCP in tail immersion and formalin tests. In the tail immersion test, the methyl piperazine analog (III) shows more efficacy than others. In the formalin test, none of the compounds are as effective as phencyclidine at the earliest time-point, but compounds IV and V do show more effective during the second stage of formalin pain. Conclusion: It can be concluded that the methyl-piperazine analog of phencyclidine was the best candidate to decrease acute thermal and benzylamine derivatives were suitable candidates to reduce chemical pains.

Anticancer Activity of Half-Sandwich Ru, Rh and Ir Complexes with Chrysin Derived Ligands: Strong Effect of the Side Chain in the Ligand and Influence of the Metal

An important challenge in the field of anticancer chemotherapy is the search for new species to overcome the resistance of standard drugs. An interesting approach is to link bioactive ligands to metal fragments. In this work, we have synthesized a set of p-cymene-Ru or cyclopentadienyl-M (M = Rh, Ir) complexes with four chrysin-derived pro-ligands with different -OR substituents at position 7 of ring A. The introduction of a piperidine ring on chrysin led to the highly cytotoxic pro-ligand HL4 and its metal complexes L4-M (SW480 and A549 cell lines, cytotoxic order: L4-Ir > L4-Ru ≈ L4-Rh). HL4 and its complexes induce apoptosis and can overcome cis-platinum resistance. However, HL4 turns out to be more cytotoxic in healthy than in tumor cells in contrast to its metal complexes which displayed higher selectivity than cisplatin towards cancer cells. All L4-M complexes interact with double stranded DNA. Nonetheless, the influence of the metal is clear because only complex L4-Ir causes DNA cleavage, through the generation of highly reactive oxygen species (1O2). This result supports the hypothesis of a potential dual mechanism consisting of two different chemical pathways: DNA binding and ROS generation. This behavior provides this complex with a great effectivity in terms of cytotoxicity.

A metabolic regulon reveals early and late acting enzymes in neuroactive Lycopodium alkaloid biosynthesis

Plants synthesize many diverse small molecules that affect function of the mammalian central nervous system, making them crucial sources of therapeutics for neurological disorders. A notable portion of neuroactive phytochemicals are lysine-derived alkaloids, but the mechanisms by which plants produce these compounds have remained largely unexplored. To better understand how plants synthesize these metabolites, we focused on biosynthesis of the Lycopodium alkaloids that are produced by club mosses, a clade of plants used traditionally as herbal medicines. Hundreds of Lycopodium alkaloids have been described, including huperzine A (HupA), an acetylcholine esterase inhibitor that has generated interest as a treatment for the symptoms of Alzheimer’s disease. Through combined metabolomic profiling and transcriptomics, we have identified a developmentally controlled set of biosynthetic genes, or potential regulon, for the Lycopodium alkaloids. The discovery of this putative regulon facilitated the biosynthetic reconstitution and functional characterization of six enzymes that act in the initiation and conclusion of HupA biosynthesis. This includes a type III polyketide synthase that catalyzes a crucial imine-polyketide condensation, as well as three Fe(II)/2-oxoglutarate–dependent dioxygenase (2OGD) enzymes that catalyze transformations (pyridone ring-forming desaturation, piperidine ring cleavage, and redox-neutral isomerization) within downstream HupA biosynthesis. Our results expand the diversity of known chemical transformations catalyzed by 2OGDs and provide mechanistic insight into the function of noncanonical type III PKS enzymes that generate plant alkaloid scaffolds. These data offer insight into the chemical logic of Lys-derived alkaloid biosynthesis and demonstrate the tightly coordinated coexpression of secondary metabolic genes for the biosynthesis of medicinal alkaloids.

The crystal structures, Hirshfeld surface analyses and energy frameworks of 8-{1-[3-(cyclopent-1-en-1-yl)benzyl]piperidin-4-yl}-2-methoxyquinoline and 8-{4-[3-(cyclopent-1-en-1-yl)benzyl]piperazin-1-yl}-2-methoxyquinoline

The title compounds, 8-{1-[3-(cyclopent-1-en-1-yl)benzyl]piperidin-4-yl}-2-methoxyquinoline, C27H30N2O (I), and 8-{4-[3-(cyclopent-1-en-1-yl)benzyl]piperazin-1-yl}-2-methoxyquinoline, C26H29N3O (II), differ only in the nature of the central six-membered ring: piperidine in I and piperazine in II. They are isoelectronic (CH cf. N) and isotypic; they both crystallize in the triclinic space group P\overline{1} with very similar unit-cell parameters. Both molecules have a curved shape and very similar conformations. In the biaryl group, the phenyl ring is inclined to the cyclopentene mean plane (r.m.s. deviations = 0.089 Å for I and 0.082 Å for II) by 15.83 (9) and 13.82 (6)° in I and II, respectively, and by 67.68 (6) and 69.47 (10)°, respectively, to the mean plane of the quinoline moiety (r.m.s. deviations = 0.034 Å for I and 0.038 Å for II). The piperazine ring in I and the piperidine ring in II have chair conformations. In the crystals of both compounds, molecules are linked by C—H...π interactions, forming chains in I and ribbons in II, both propagating along the b-axis direction. The principal contributions to the overall Hirshfeld surfaces involve H...H contacts at 67.5 and 65.9% for I and II, respectively. The major contribution to the intermolecular interactions in the crystals is from dispersion forces (E dis), reflecting the absence of classical hydrogen bonds.