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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
10.1016/j.bmcl.2010.11.008
Asymmetric synthesis of phenanthroindolizidine alkaloids with hydroxyl group at the C14 position and evaluation of their antitumor activities.
T. Ikeda (2011)
10.1002/EJOC.201000997
One-Pot Conversion of Proline Derivatives into Iodinated Iminosugar-Based Nucleosides, Useful Precursors of Highly Functionalized Nucleoside Analogues
A. Boto (2010)
10.1002/QSAR.200730028
QSAR Studies and Molecular Design of Phenanthrene‐based Tylophorine Derivatives with Anticancer Activity
Siyan Liao (2008)
10.1158/0008-5472.CAN-03-1904
Novel Mode of Action of Tylophorine Analogs as Antitumor Compounds
W. Gao (2004)
10.1016/j.bmc.2008.02.073
Enantiospecific synthesis and cytotoxicity of 7-(4-methoxyphenyl)-6-phenyl-2,3,8,8a-tetrahydroindolizin-5(1H)-one enantiomers.
F. Kimball (2008)
10.1016/J.TETLET.2009.04.082
Enantiopure alkaloid analogues and iminosugars from proline derivatives: stereocontrol in sequential processes
A. Boto (2009)
10.1021/jm9009263
Antitumor agents 268. Design, synthesis, and mechanistic studies of new 9-substituted phenanthrene-based tylophorine analogues as potent cytotoxic agents.
X. Yang (2009)
10.1016/S0960-894X(03)00263-4
Novel 6,7-diphenyl-2,3,8,8a-tetrahydro-1H-indolizin-5-one analogues as cytotoxic agents.
V. M. Sharma (2003)
10.1021/NP0106384
In vitro cytotoxic activity of phenanthroindolizidine alkaloids from Cynanchum vincetoxicum and Tylophora tanakae against drug-sensitive and multidrug-resistant cancer cells.
D. Staerk (2002)
10.1021/jm801344j
Phenanthrene-based tylophorine-1 (PBT-1) inhibits lung cancer cell growth through the Akt and NF-kappaB pathways.
Jau-Chen Lin (2009)
10.1021/OL0161054
Short, highly efficient syntheses of protected 3-azido- and 4-azidoproline and their precursors.
J. A. Gómez-Vidal (2001)
10.1021/jo101051w
Total syntheses of arylindolizidine alkaloids (+)-ipalbidine and (+)-antofine.
M. J. Niphakis (2010)
10.1016/j.bcp.2010.07.026
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)
10.1016/J.BMCL.2005.06.020
Developing microcolin A analogs as biological probes.
Amit K. Mandal (2005)
10.1021/JA993349Z
A Stereoelectronic Model To Explain the Highly Stereoselective Reactions of Nucleophiles with Five-Membered-Ring Oxocarbenium Ions
Catharine H. Larsen (1999)
10.1021/jo902114u
A concise palladium-catalyzed carboamination route to (+/-)-tylophorine.
Lana M Rossiter (2009)
10.1021/AR00156A004
Equilibrium Acidities in Dimethyl Sulfoxide Solution
F. G. Bordwell (1988)
10.1016/J.BMCL.2006.10.070
Synthesis and DNA-binding ability of C2R-fluoro substituted DC-81 and its dimers.
A. Kamal (2007)
10.1021/JA0375176
Nucleophilic additions to fused bicyclic five-membered ring oxocarbenium ions: evidence for preferential attack on the inside face.
D. M. Smith (2003)
10.1021/jm200330s
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)
10.1021/ol1023954
Synthesis of tylocrebrine and related phenanthroindolizidines by VOF3-mediated oxidative aryl-alkene coupling.
M. J. Niphakis (2011)
10.1021/JA0524043
Stereoselective C-glycosylation reactions of ribose derivatives: electronic effects of five-membered ring oxocarbenium ions.
Catharine H. Larsen (2005)
10.1016/J.TET.2010.09.101
m-CPBA/TFA: an efficient nonmetallic reagent for oxidative coupling of 1,2-diarylethylenes
K. Wang (2010)
10.1002/EJOC.200900427
Coupling Radical and Ionic Processes: An Unusual Rearrangement Affords Sugar and C-Glycoside Derivatives
A. Boto (2009)
10.1039/b811068a
A general approach to triphenylenes and azatriphenylenes: total synthesis of dehydrotylophorine and tylophorine.
Andrew L. McIver (2008)
10.1039/B600056H
Electrostatic interactions in cations and their importance in biology and chemistry.
D. M. Smith (2006)
10.1021/JM970439A
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)
10.1016/J.TET.2008.06.003
Iron(III) chloride-based mild synthesis of phenanthrene and its application to total synthesis of phenanthroindolizidine alkaloids
K. Wang (2008)
10.1016/j.bmcl.2008.04.051
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)
10.1002/CHIN.200730227
Modification of Amino Acids, Peptides, and Carbohydrates Through Radical Chemistry
S. Hansen (2006)
10.1021/ML1003074
Total Syntheses and Cytotoxicity of (R)- and (S)-Boehmeriasin A.
Matthew W. Leighty (2011)
10.1002/EJOC.201000360
One-Pot Synthesis of Azanucleosides from Proline Derivatives -Stereoselectivity in Sequential Processes
A. Boto (2010)
10.2174/157340709787580928
Phenanthroindolizidines and Phenanthroquinolizidines: Promising Alkaloids for Anti-Cancer Therapy.
S. Chemler (2009)
10.1016/J.TETASY.2009.02.042
Highly diastereoselective approach to novel phenylindolizidinols via benzothieno analogues of tylophorine based on reductive desulfurization of benzo[b]thiophene
P. Šafár̆ (2009)
10.1016/j.antiviral.2010.08.009
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)
10.1021/ol201173a
One-pot stereoselective synthesis of 1,2-amino alcohol derivatives.
A. Boto (2011)
10.1039/c0ob00287a
First total synthesis of (-)- and (+)-6-O-desmethylantofine.
M. Wu (2011)
10.1002/EJOC.200800340
The Effect of Lewis Acids on the Stereochemistry in the Ugi Three-Component Reaction with D-lyxo-Pyrroline†
K. M. Bonger (2008)
10.1016/J.BMCL.2007.11.054
Structural analogs of tylophora alkaloids may not be functional analogs.
W. Gao (2008)
10.1016/S0040-4020(02)01020-7
Simple and efficient syntheses of Boc- and Fmoc-protected 4( R )- and 4( S )-fluoroproline solely from 4( R )-hydroxyproline
M. Doi (2002)
10.1002/EJOC.200900834
Total Synthesis of Phenanthro-Quinolizidine Alkaloids: (±)-Cryptopleurine, (±)-Boehmeriasin A, (±)-Boehmeriasin B and (±)-Hydroxycryptopleurine
M. Cui (2009)
10.1016/j.bmc.2008.04.032
Total synthesis of phenanthroindolizidine alkaloids (+/-)-antofine, (+/-)-deoxypergularinine, and their dehydro congeners and evaluation of their cytotoxic activity.
Chung-Ren Su (2008)
10.1016/J.TETASY.2009.08.010
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)
10.1016/J.BMCL.2007.05.103
Synthesis, in vitro and in vivo cytotoxicity of 6,7-diaryl-2,3,8,8a-tetrahydroindolizin-5(1H)-ones.
F. Kimball (2007)
10.1055/S-2001-18703
Isolation, Total Synthesis and Biological Activity of Phenanthroindolizidine and Phenanthroquinolizidine Alkaloids
Z. Li (2004)
10.1016/S0040-4039(00)00306-3
Synthesis of alkaloids from amino acids via N-acyliminium ions generated by one-pot radical decarboxylation–oxidation
A. Boto (2000)
10.1021/jo101510x
Asymmetric synthesis of (R)-antofine and (R)-cryptopleurine via proline-catalyzed sequential α-aminoxylation and Horner-Wadsworth-Emmons olefination of aldehyde.
M. Cui (2010)
10.1021/ol100652b
Racemization-free synthesis of (S)-(+)-tylophorine from L-proline by radical cyclization.
Alexander Stoye (2010)
10.1016/J.TET.2010.03.021
Total synthesis of the tylophora alkaloids rusplinone, 13aα-secoantofine, and antofine using a multicatalytic oxidative aminochlorocarbonylation/Friedel–Crafts reaction
Lisa M. Ambrosini (2010)
10.1021/ol902819j
Antitumor agents. 274. A new synthetic strategy for E-ring SAR study of antofine and cryptopleurine analogues.
X. Yang (2010)
10.1016/J.TETLET.2007.11.113
One-pot synthesis of azanucleosides from proline derivatives
A. Boto (2008)
10.1021/jo9004487
Catalytic, one-pot synthesis of beta-amino acids from alpha-amino acids. Preparation of alpha,beta-peptide derivatives.
Carlos J Saavedra (2009)
10.1021/ja106989h
Asymmetric palladium-catalyzed carboamination reactions for the synthesis of enantiomerically enriched 2-(arylmethyl)- and 2-(alkenylmethyl)pyrrolidines.
D. N. Mai (2010)
10.1002/EJOC.200801047
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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