title: Simplification of antitumoral phenanthroindolizidine alkaloids: short synthesis of cytotoxic indolizidinone and pyrrolidine analogs.
abstract: Hydroxylated seco-analogs of cytotoxic phenanthroindolizidine alkaloids were prepared in good yields from inexpensive 4-hydroxyproline derivatives, in just two steps. Thus, a sequential oxidative radical scission-oxidation was used for the direct conversion of the proline derivative into a 2-(2-aryl-oxoethyl)pyrrolidine with a variety of aryl and heteroaryl groups. The 4R-stereogenic center allowed ready isomer separation, and stereocontrol in the introduction of new chains (interestingly, the 2,4-cis isomers predominated). In the second step, a cyclization reaction afforded alkaloid analogs with an indolizidinone core; a partial isomerization took place but the isomers were readily purified. Then the cytotoxic activity of the bicyclic indolizidinones and the simpler pyrrolidine derivatives was compared against tumorogenic human neuronal SHSY-5Y and breast cancer MCF7 cells. All the biphenyl derivatives displayed a potent activity (one derivative caused >80% cell death in both tumor lines at micromolar dosis), being comparable in the pyrrolidine and indolizidinone series.
authors.affiliation: Instituto de Productos Naturales y Agrobiología del CSIC, Avda. Astrofísico Francisco Sánchez 3, 38206 La Laguna, Tenerife, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Miguélez
authors.forename: Alicia
authors.initials: A
authors.lastname: Boto
authors.forename: Raquel
authors.initials: R
authors.lastname: Marín
authors.forename: Mario
authors.initials: M
authors.lastname: Díaz
mesh_terms: D000470:Alkaloids / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D006801:Humans; D007212:Indolizines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D061986:MCF-7 Cells; D010618:Phenanthrolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011759:Pyrrolidines / Q000737:chemistry*
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D007212:Indolizines; D010618:Phenanthrolines; D011759:Pyrrolidines; C521640:phenanthroindolizidine; C032519:pyrrolidine
keywords: (diacetoxyiodo)benzene; 80 W; 80 watts; Alkaloid; Ar; Ar-M; Boc; CNS; CO(2)CMe(3); Cytotoxicity; DIB; DMEM; DMSO; Dubelcco's modified Eagle medium; EtOAc; FBS; HRMS; Indolizidine; MHz; NMR; NOESY; Nu; OTMS; Ph; SAR; Sequential process; Synthetic methodology; TLC; TMS; Ts; VEH; aryl; aryl-metal; br; broad signal (e.g. br s = broad singlet, br d = broad doublet, br b = broad band); central nervous system; diastereomeric ratio; dimethylsulfoxide; dr; ethyl acetate; fetal bovine serum; high-resolution mass spectrometry; megahertz; melting point; mp; nuclear Overhauser effect spectroscopy; nuclear magnetic resonance; nucleophile; p; phenyl; probability; structure–activity relationships; tetramethylsilane; thin-layer chromatography; toluenesulfonyl (TsOH is toluenesulfonic acid); trimethylsilyloxy; vehicle