phenanthroindolizidine and tylophorine

A potassium base-promoted formal [2+2] cycloaddition of 2-acyl-2'-vinyl-1,1'-biaryls was developed to afford benzo-fused polycyclic cyclobutanols in a highly stereoselective manner. We demonstrated synthesis of substituted polycyclic aromatic hydrocarbons and these heterocyclic derivatives via this cyclization, followed by an acid-promoted rearrangement. Furthermore, asymmetric total synthesis of phenanthroindolizidine alkaloid (-)-tylophorine was achieved using our methodology and late-stage asymmetric hydrogenation of a cyclic imine.

Topics: Alkaloids; Cyclization; Cycloaddition Reaction; Heterocyclic Compounds; Hydrogenation; Indolizines; Phenanthrenes; Phenanthrolines; Polycyclic Aromatic Hydrocarbons

A concise and modular synthesis of phenanthroindolizidine alkaloids was achieved by combining iodoaminocylization with a free radical cyclization approach. The route described allowed the preparation of (±)-tylophorine, (±)-antofine, and (±)-deoxypergularinine in six steps. When commercially available l-prolinol was used as a chiral building block, (S)-(+)-tylophorine was also synthesized in 49% yield and >99% ee over five linear steps.

Topics: Alkaloids; Chemistry, Organic; Cyclization; Free Radicals; Indoles; Indolizines; Isoquinolines; Magnetic Resonance Spectroscopy; Phenanthrenes; Phenanthrolines; Pyrrolidines; Stereoisomerism; Structure-Activity Relationship; Temperature

A new asymmetric total synthesis of a phenanthroindolizidine alkaloid (S)-tylophorine is reported, which features a catalytic asymmetric allylation of aldehydes and an unexpected one-pot DMAP promoted isocyanate formation and Lewis acid catalyzed intramolecular cyclization reaction. In addition, White's direct C-H oxidation catalyst system converting monosubstituted olefins to linear allylic acetates was also employed for late-stage transformation.

Topics: Alkaloids; Catalysis; Chemistry, Organic; Cyclization; Indolizines; Isocyanates; Lewis Acids; Phenanthrenes; Phenanthrolines; Pyridines; Stereoisomerism

An efficient stereocontrolled preparation of chiral phenanthroindolizidines is detailed. The synthesis relies on the stereoselective indium-mediated allylation of 2-(phenanthren-9-yl)acetaldehyde derivatives with chiral tert-butylsulfinamide. Chemoselective transformations from the corresponding homoallylic sulfinamine allow the synthesis of the phenanthroindolizidines in only three synthetic operations, without any detectable racemization. Following this procedure, the synthesis of natural (-)-tylophorine was successfully accomplished.

Topics: Alkaloids; Allyl Compounds; Amines; Indolizines; Molecular Structure; Oxidation-Reduction; Phenanthrenes; Phenanthrolines; Stereoisomerism; Sulfonium Compounds

The alkaloid (-)-tylophorine was isolated from a sample of Tylophora indica, and the crude extract was analyzed by HPLC/MS(n) and chiral HPLC/MS. While the literature states that the naturally occurring form of this alkaloid is the R-enantiomer and that its S-antipode is usually not found in nature, we confirmed the hypothesis of Govindachari and Nagarajan that natural levorotatory tylophorine is indeed a nearly racemic mixture with a slight excess of the R-enantiomer.

Topics: Alkaloids; Indolizines; Molecular Structure; Phenanthrenes; Phenanthrolines; Tylophora

Tylophorine, a phenanthroindolizidine alkaloid, is the major medicinal constituent of herb Tylophora indica. Tylophorine treatment increased the accumulation of c-Jun protein, a component of activator protein 1 (AP1), in carcinoma cells. An in vitro kinase assay revealed that the resultant c-Jun phosphorylation was primarily mediated via activated c-Jun N-terminal protein kinase (JNK). Moreover, flow cytometry indicated that ectopically overexpressed c-Jun in conjunction with tylophorine significantly increased the number of carcinoma cells that were arrested at the G1 phase. The tylophorine-mediated downregulation of cyclin A2 protein levels is known to be involved in the primary G1 arrest. Chromatin immunoprecipitation and reporter assays revealed that tylophorine enhanced the c-Jun downregulation of the cyclin A2 promoter activity upon increased binding of c-Jun to the deregulation AP1 site and decreased binding to the upregulation activating transcription factor (ATF) site in the cyclin A2 promoter, thereby reducing cyclin A2 expression. Further, biochemical studies using pharmacological inhibitors and RNA silencing approaches demonstrated that tylophorine-mediated elevation of the c-Jun protein level occurs primarily via two discrete prolonged signaling pathways: (i) the NF-κB/PKCδ_(MKK4)_JNK cascade, which phosphorylates c-Jun and increases its stability by slowing its ubiquitination, and (ii) the PI3K_PDK1_PP2A_eEF2 cascade, which sustains eukaryotic elongation factor 2 (eEF2) activity and thus c-Jun protein translation. To the best of our knowledge, this report is the first to demonstrate the involvement of c-Jun in the anticancer activity of tylophorine and the release of c-Jun translation from a global translational blockade via the PI3K_PDK1_eEF2 signaling cascade.

Topics: Activating Transcription Factor 1; Alkaloids; Antineoplastic Agents, Phytogenic; Carcinoma; Cell Line, Tumor; Cyclin A2; Down-Regulation; Elongation Factor 2 Kinase; Eukaryotic Initiation Factors; G1 Phase Cell Cycle Checkpoints; Hep G2 Cells; Humans; Indolizines; JNK Mitogen-Activated Protein Kinases; MAP Kinase Signaling System; NF-kappa B; Phenanthrenes; Phenanthrolines; Phosphatidylinositol 3-Kinases; Phosphorylation; Promoter Regions, Genetic; Protein Kinase C-delta; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-jun; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; RNA Interference; RNA, Small Interfering; Transcription Factor AP-1; Tylophora

The discovery and development of new, highly potent anti-coronavirus agents and effective approaches for controlling the potential emergence of epidemic coronaviruses still remains an important mission. Here, we identified tylophorine compounds, including naturally occurring and synthetic phenanthroindolizidines and phenanthroquinolizidines, as potent in vitro inhibitors of enteropathogenic coronavirus transmissible gastroenteritis virus (TGEV). The potent compounds showed 50% maximal effective concentration (EC₅₀) values ranging from 8 to 1468 nM as determined by immunofluorescent assay of the expression of TGEV N and S proteins and by real time-quantitative PCR analysis of viral yields. Furthermore, the potent tylophorine compounds exerted profound anti-TGEV replication activity and thereby blocked the TGEV-induced apoptosis and subsequent cytopathic effect in ST cells. Analysis of the structure-activity relations indicated that the most active tylophorine analogues were compounds with a hydroxyl group at the C14 position of the indolizidine moiety or at the C3 position of the phenanthrene moiety and that the quinolizidine counterparts were more potent than indolizidines. In addition, tylophorine compounds strongly reduced cytopathic effect in Vero 76 cells induced by human severe acute respiratory syndrome coronavirus (SARS CoV), with EC₅₀ values ranging from less than 5 to 340 nM. Moreover, a pharmacokinetic study demonstrated high and comparable oral bioavailabilities of 7-methoxycryptopleurine (52.7%) and the naturally occurring tylophorine (65.7%) in rats. Thus, our results suggest that tylophorine compounds are novel and potent anti-coronavirus agents that may be developed into therapeutic agents for treating TGEV or SARS CoV infection.

Topics: Alkaloids; Animals; Antiviral Agents; Apocynaceae; Chlorocebus aethiops; Coronavirus Infections; Cytopathogenic Effect, Viral; Dose-Response Relationship, Drug; Gastroenteritis, Transmissible, of Swine; Indolizines; Phenanthrenes; Phenanthrolines; Quinolizines; Rats; Rats, Sprague-Dawley; Severe Acute Respiratory Syndrome; Severe acute respiratory syndrome-related coronavirus; Structure-Activity Relationship; Swine; Transmissible gastroenteritis virus; Tylophora; Vero Cells

The total synthesis of alkaloids phenanthroindolizidine 1a, tylophorine 1b, and phenanthroquinolizidine 1c, has been achieved in 46%, 49%, and 42% overall yield, respectively, starting from the corresponding phenanthrene-9-carboxaldehyde. Compound exhibited potent inhibition activity in three human cancer cell lines, with IC(50) values ranging from 104 to 130 nM. The structure-activity relations of these alkaloids and some of their synthetic intermediates against the three cell lines were also described.

Topics: Alkaloids; Antineoplastic Agents; Biochemistry; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Indolizines; Phenanthrenes; Phenanthrolines; Quinolizines; Structure-Activity Relationship