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Synthesis Of Indolizidinone Analogues Of Cytotoxic Alkaloids: Monocyclic Precursors Are Also Active.
A. Boto, J. Miguélez, Raquel Marín, Mario Díaz
Published 2012 · Chemistry, Medicine
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Readily available proline derivatives can be transformed in just two steps into analogues of cytotoxic phenanthroindolizidine alkaloids. The key step uses a sequential radical scission-oxidation-alkylation process, which yields 2-substituted pyrrolidine amides. A second process effects the cyclization to give the desired alkaloid analogues, which possess an indolizidine core. The major and minor isomers (dr 3:2 to 3:1) can be easily separated, allowing their use to study structure-activity relationships (SAR). The process is versatile and allows the introduction of aryl and heteroaryl groups (including biphenyl, halogenated phenyl, and pyrrole rings). Some of these alkaloid analogues displayed a selective cytotoxic activity against tumorogenic human neuronal and mammary cancer cells, and one derivative caused around 80% cell death in both tumor lines at micromolar doses. The cytotoxicity of some monocyclic precursors was also studied, being comparable or superior to the bicyclic derivatives.
This paper references
Asymmetric synthesis of phenanthroindolizidine alkaloids with hydroxyl group at the C14 position and evaluation of their antitumor activities.
T. Ikeda (2011)
One-Pot Conversion of Proline Derivatives into Iodinated Iminosugar-Based Nucleosides, Useful Precursors of Highly Functionalized Nucleoside Analogues
A. Boto (2010)
QSAR Studies and Molecular Design of Phenanthrene‐based Tylophorine Derivatives with Anticancer Activity
Siyan Liao (2008)
Novel Mode of Action of Tylophorine Analogs as Antitumor Compounds
W. Gao (2004)
Enantiospecific synthesis and cytotoxicity of 7-(4-methoxyphenyl)-6-phenyl-2,3,8,8a-tetrahydroindolizin-5(1H)-one enantiomers.
F. Kimball (2008)
Enantiopure alkaloid analogues and iminosugars from proline derivatives: stereocontrol in sequential processes
A. Boto (2009)
Antitumor agents 268. Design, synthesis, and mechanistic studies of new 9-substituted phenanthrene-based tylophorine analogues as potent cytotoxic agents.
X. Yang (2009)
Novel 6,7-diphenyl-2,3,8,8a-tetrahydro-1H-indolizin-5-one analogues as cytotoxic agents.
V. M. Sharma (2003)
In vitro cytotoxic activity of phenanthroindolizidine alkaloids from Cynanchum vincetoxicum and Tylophora tanakae against drug-sensitive and multidrug-resistant cancer cells.
D. Staerk (2002)
Phenanthrene-based tylophorine-1 (PBT-1) inhibits lung cancer cell growth through the Akt and NF-kappaB pathways.
Jau-Chen Lin (2009)
Short, highly efficient syntheses of protected 3-azido- and 4-azidoproline and their precursors.
J. A. Gómez-Vidal (2001)
Total syntheses of arylindolizidine alkaloids (+)-ipalbidine and (+)-antofine.
M. J. Niphakis (2010)
Inhibition of cell growth and potentiation of tumor necrosis factor-α (TNF-α)-induced apoptosis by a phenanthroindolizidine alkaloid antofine in human colon cancer cells.
Hyeyoung Min (2010)
Developing microcolin A analogs as biological probes.
Amit K. Mandal (2005)
A Stereoelectronic Model To Explain the Highly Stereoselective Reactions of Nucleophiles with Five-Membered-Ring Oxocarbenium Ions
Catharine H. Larsen (1999)
A concise palladium-catalyzed carboamination route to (+/-)-tylophorine.
Lana M Rossiter (2009)
Equilibrium Acidities in Dimethyl Sulfoxide Solution
F. G. Bordwell (1988)
Synthesis and DNA-binding ability of C2R-fluoro substituted DC-81 and its dimers.
A. Kamal (2007)
Nucleophilic additions to fused bicyclic five-membered ring oxocarbenium ions: evidence for preferential attack on the inside face.
D. M. Smith (2003)
Antitumor agents 288: design, synthesis, SAR, and biological studies of novel heteroatom-incorporated antofine and cryptopleurine analogues as potent and selective antitumor agents.
X. Yang (2011)
Synthesis of tylocrebrine and related phenanthroindolizidines by VOF3-mediated oxidative aryl-alkene coupling.
M. J. Niphakis (2011)
Stereoselective C-glycosylation reactions of ribose derivatives: electronic effects of five-membered ring oxocarbenium ions.
Catharine H. Larsen (2005)
m-CPBA/TFA: an efficient nonmetallic reagent for oxidative coupling of 1,2-diarylethylenes
K. Wang (2010)
Coupling Radical and Ionic Processes: An Unusual Rearrangement Affords Sugar and C-Glycoside Derivatives
A. Boto (2009)
A general approach to triphenylenes and azatriphenylenes: total synthesis of dehydrotylophorine and tylophorine.
Andrew L. McIver (2008)
Electrostatic interactions in cations and their importance in biology and chemistry.
D. M. Smith (2006)
Synthesis and biological properties of new constrained CCK-B antagonists: discrimination of two affinity states of the CCK-B receptor on transfected CHO cells.
B. Bellier (1997)
Iron(III) chloride-based mild synthesis of phenanthrene and its application to total synthesis of phenanthroindolizidine alkaloids
K. Wang (2008)
Synthesis and evaluation of heteroaromatic 6,7-diaryl-2,3,8,8a-tetrahydroindolizin-5(1H)-ones for cytotoxicity against the HCT-116 colon cancer cell line.
F. Kimball (2008)
Modification of Amino Acids, Peptides, and Carbohydrates Through Radical Chemistry
S. Hansen (2006)
Total Syntheses and Cytotoxicity of (R)- and (S)-Boehmeriasin A.
Matthew W. Leighty (2011)
One-Pot Synthesis of Azanucleosides from Proline Derivatives -Stereoselectivity in Sequential Processes
A. Boto (2010)
Phenanthroindolizidines and Phenanthroquinolizidines: Promising Alkaloids for Anti-Cancer Therapy.
S. Chemler (2009)
Highly diastereoselective approach to novel phenylindolizidinols via benzothieno analogues of tylophorine based on reductive desulfurization of benzo[b]thiophene
P. Šafár̆ (2009)
Identification of phenanthroindolizines and phenanthroquinolizidines as novel potent anti-coronaviral agents for porcine enteropathogenic coronavirus transmissible gastroenteritis virus and human severe acute respiratory syndrome coronavirus
C. Yang (2010)
One-pot stereoselective synthesis of 1,2-amino alcohol derivatives.
A. Boto (2011)
First total synthesis of (-)- and (+)-6-O-desmethylantofine.
M. Wu (2011)
The Effect of Lewis Acids on the Stereochemistry in the Ugi Three-Component Reaction with D-lyxo-Pyrroline†
K. M. Bonger (2008)
Structural analogs of tylophora alkaloids may not be functional analogs.
W. Gao (2008)
Simple and efficient syntheses of Boc- and Fmoc-protected 4( R )- and 4( S )-fluoroproline solely from 4( R )-hydroxyproline
M. Doi (2002)
Total Synthesis of Phenanthro-Quinolizidine Alkaloids: (±)-Cryptopleurine, (±)-Boehmeriasin A, (±)-Boehmeriasin B and (±)-Hydroxycryptopleurine
M. Cui (2009)
Total synthesis of phenanthroindolizidine alkaloids (+/-)-antofine, (+/-)-deoxypergularinine, and their dehydro congeners and evaluation of their cytotoxic activity.
Chung-Ren Su (2008)
Synthesis and reductive desulfurization of chiral non-racemic benzothienoindolizines. An efficient approach to a novel bioactive tylophorine alkaloid analogue and 6-phenylindolizidine
P. Šafár̆ (2009)
Synthesis, in vitro and in vivo cytotoxicity of 6,7-diaryl-2,3,8,8a-tetrahydroindolizin-5(1H)-ones.
F. Kimball (2007)
Isolation, Total Synthesis and Biological Activity of Phenanthroindolizidine and Phenanthroquinolizidine Alkaloids
Z. Li (2004)
Synthesis of alkaloids from amino acids via N-acyliminium ions generated by one-pot radical decarboxylation–oxidation
A. Boto (2000)
Asymmetric synthesis of (R)-antofine and (R)-cryptopleurine via proline-catalyzed sequential α-aminoxylation and Horner-Wadsworth-Emmons olefination of aldehyde.
M. Cui (2010)
Racemization-free synthesis of (S)-(+)-tylophorine from L-proline by radical cyclization.
Alexander Stoye (2010)
Total synthesis of the tylophora alkaloids rusplinone, 13aα-secoantofine, and antofine using a multicatalytic oxidative aminochlorocarbonylation/Friedel–Crafts reaction
Lisa M. Ambrosini (2010)
Antitumor agents. 274. A new synthetic strategy for E-ring SAR study of antofine and cryptopleurine analogues.
X. Yang (2010)
One-pot synthesis of azanucleosides from proline derivatives
A. Boto (2008)
Catalytic, one-pot synthesis of beta-amino acids from alpha-amino acids. Preparation of alpha,beta-peptide derivatives.
Carlos J Saavedra (2009)
Asymmetric palladium-catalyzed carboamination reactions for the synthesis of enantiomerically enriched 2-(arylmethyl)- and 2-(alkenylmethyl)pyrrolidines.
D. N. Mai (2010)
Synthesis of Phenanthro[9,10‐b]indolizidin‐9‐ones, Phenanthro[9,10‐b]quinolizidin‐9‐one, and Related Benzolactams by Pd(OAc)2‐Catalyzed Direct Aromatic Carbonylation
S. Yamashita (2009)
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Falko Abels (2014)
Metal-free [3 + 2 + 1]/[2 + 2 + 1] biscyclization: stereospecific construction with concomitant functionalization of indolizin-5(1H)-one.
Tuanjie Li (2013)
Synthesis of multi-functionalized 1-azabicycles through MAOS acid catalyzed formal aza-[3+3] cycloaddition of heterocyclic enaminones with oxazolones
S. Cunha (2013)
Enantioselective approach to 13a-methylphenanthroindolizidine alkaloids.
Bo Su (2012)
Simplification of antitumoral phenanthroindolizidine alkaloids: short synthesis of cytotoxic indolizidinone and pyrrolidine analogs.
J. Miguélez (2013)
Synthesis of Indolizidinone Analogues of Cytotoxic Alkaloids: Monocyclic Precursors Are also Active.
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Synthesis of alkaloids: recent advances in the synthesis of phenanthroindolizidine alkaloids.
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The First Enantioselective Approach to 13a‐Methyl‐14‐hydroxyphenanthroindolizidine Alkaloids – Synthetic Studies towards Hypoestestatin 2
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