antofine and tylophorine

Phenanthroindolizidines, such as antofine and tylophorine, are a family of natural alkaloids isolated from different species of

Topics: Alkaloids; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; CHO Cells; Cricetulus; Drug Screening Assays, Antitumor; HEK293 Cells; Humans; Indoles; Indolizines; MCF-7 Cells; Molecular Structure; Phenanthrenes; Phenanthrolines; Prodrugs; Quaternary Ammonium Compounds; Structure-Activity Relationship; Tumor Hypoxia

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 collective asymmetric synthesis of phenanthroindolizidine and phenanthroquinolizidine alkaloids (-)-antofine, (-)-cryptopleurine, (-)-tylophorine, and (-)-tylocrebrine was achieved by means of a reaction sequence involving efficient generation of chiral homoallylic amine intermediates by asymmetric allylation of the corresponding tert-butanesulfinyl imine. From these intermediates, the pyrrolidine and piperidine rings were constructed by means of an intramolecular SN2 substitution reaction and a ring-closing metathesis reaction, respectively. The unusual C5-methoxy-substituted phenanthrene moiety of (-)-tylocrebrine was generated by means of an InCl3-catalyzed cycloisomerization reaction of an o-propargylbiaryl compound.

Topics: Alkaloids; Butanes; Indoles; Indolizines; Isomerism; Molecular Structure; Phenanthrenes; Phenanthrolines; Stereoisomerism; Sulfonamides

Topics: Alkaloids; Alkynes; Carbon; Catalysis; Cyclization; Heterocyclic Compounds, 4 or More Rings; Hydrogen; Indoles; Indolizines; Isoquinolines; Phenanthrenes; Phenanthrolines; Pyridones; Rhodium; Stereoisomerism

Nineteen new phenanthrene-based tylophorine analogues with various functional groups on the piperidine moiety were designed, synthesized, and evaluated for in vitro anticancer activity against four human tumor cell lines. Analogues 15 and 21 showed approximately 2-fold enhanced inhibitory activity as compared with our prior lead compound (PBT-1). Analogues 23 and 24 with S- and R-configured substituents, respectively, at the piperidine 3'-position exhibited comparable cytotoxicity to that of PBT-1. Furthermore, mechanistic studies to investigate the effects of the new compounds on Akt protein in lung cancer cells and the NF-kB signaling pathway suggested that the compounds may exert their inhibitory activity on tumor cells through inhibition of activation of both Akt and NF-kB signaling pathway.

Topics: Alkaloids; Antineoplastic Agents; Cell Line, Tumor; Drug Design; Drug Screening Assays, Antitumor; Humans; Indoles; Indolizines; Models, Molecular; Molecular Conformation; NF-kappa B; Phenanthrenes; Phenanthrolines; Piperidines; Proto-Oncogene Proteins c-akt; Signal Transduction; Stereoisomerism; Structure-Activity Relationship

C9-Substituted phenanthrene-based tylophorine derivatives (PBTs) (13-36) were synthesized and evaluated as in vitro anticancer agents against the human A549 lung cancer cell line. Twelve active compounds were further examined against DU-145 (prostate), ZR-751 (breast), KB (nasopharyngeal), and KB-Vin (multidrug resistant KB subline) human cancer cell lines. They showed potent cytotoxic activity against both wild type and matched multidrug resistant KB cell lines, and displayed notable selectivity toward DU-145 (prostate) and ZR-751 (breast) cancer cell lines. The mode of action of this class may be distinctly different from that of other cancer chemotherapeutic compounds. Three PBT analogs were also evaluated in a murine model. Compound 24b showed modest in vivo antitumor activity against human A549 xenograft in nude mice as well as potent in vitro cytotoxic activity, and thus, is a promising anticancer lead compound.

Topics: Alkaloids; Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Indolizines; Male; Mice; Mice, Nude; Neoplasm Transplantation; Phenanthrenes; Structure-Activity Relationship; Transplantation, Heterologous

A concise, efficient and modular approach to the tylophora alkaloids is described, a family of potent cytotoxic agents that are equally effective against drug sensitive and multidrug resistant cancer cell lines. The advantages of the chosen route are illustrated by the total syntheses of the phenanthroquinolizidine cryptopleurine (1) and the phenanthroindolizidines (-)-antofine (2), (-)-tylophorine (3), and their only recently isolated congener (-)-ficuseptine C (4). The key steps consist in a Suzuki cross-coupling between a (commercial) boronic acid and a simple aryl-1,2-dihalide followed by elaboration of the resulting products into the corresponding 2-alkynyl-biphenyl derivatives 27, 33, 41 and 46. The latter undergo PtCl2-catalyzed cycloisomerizations with formation of the functionalized phenanthrenes 28, 34, 42 and 47, which were transformed into the targeted alkaloids by a deprotection/Pictet-Spengler annulation tandem. Due to the flexibility and robust character of this approach, it might enable a systematic exploration of the pharmacological profile of this promising class of bioactive natural products.

Topics: Alkaloids; Antineoplastic Agents, Phytogenic; Indoles; Indolizines; Phenanthrenes; Phenanthrolines