OpenLB
Open Library of Bioscience
Advanced Search
The Alkaloids. Chemistry and biology
2017;78 205-352.

Cephalotaxus Alkaloids.

Joëlle Pérard-Viret, Laith Quteishat, Rana Alsalim, Jacques Royer, Françoise Dumas
Author Information
  1. Joëlle Pérard-Viret: Université Paris Descartes, CNRS, Université Sorbonne Paris Cité, Paris, France.
  2. Laith Quteishat: Université Paris Sud, CNRS, Université Paris Saclay, Châtenay-Malabry, France.
  3. Rana Alsalim: Université Paris Sud, CNRS, Université Paris Saclay, Châtenay-Malabry, France.
  4. Jacques Royer: Université Paris Descartes, CNRS, Université Sorbonne Paris Cité, Paris, France.
  5. Françoise Dumas: Université Paris Sud, CNRS, Université Paris Saclay, Châtenay-Malabry, France.
PMID: 28838429 DOI: 10.1016/bs.alkal.2017.07.001

Abstract

Cephalotaxus alkaloids represent a family of plant secondary metabolites known for 60 years. Significant activity against leukemia in mice was demonstrated for extracts of Cephalotaxus. Cephalotaxine (CET) (1), the major alkaloid of this series was isolated from Cephalotaxus drupacea species by Paudler in 1963. The subsequent discovery of promising antitumor activity among new Cephalotaxus derivatives reported by Chinese, Japanese, and American teams triggered extensive structure elucidation and biological studies in this family. The structural feature of this cephalotaxane family relies mainly on its tetracyclic alkaloid backbone, which comprises an azaspiranic 1-azaspiro[4.4]nonane unit (rings C and D) and a benzazepine ring system (rings A and B), which is linked by its C3 alcohol function to a chiral oxygenated side chain by a carboxylic function alpha to a tetrasubstituted carbon center. The botanical distribution of these alkaloids is limited to the Cephalotaxus genus (Cephalotaxaceae). The scope of biological activities of the Cephalotaxus alkaloids is mainly centered on the antileukemic activity of homoharringtonine (HHT) (2), which in particular demonstrated marked benefits in the treatment of orphan myeloid leukemia and was approved as soon as 2009 by European Medicine Agency and by US Food and Drug Administration in 2012. Its exact mechanism of action was partly elucidated and it was early recognized that HHT (2) inhibited protein synthesis at the level of the ribosome machinery. Interestingly, after a latency period of two decades, the topic of Cephalotaxus alkaloids reemerged as a prolific source of new natural structures. To date, more than 70 compounds have been identified and characterized. Synthetic studies also regained attention during the past two decades, and numerous methodologies were developed to access the first semisynthetic HHT (2) of high purity suitable for clinical studies, and then high grade enantiomerically pure CET (1), HHT (2), and analogs.

Keywords

Alkaloid Antiparasitic agent Antiviral Cancer Cephalotaxine Cephalotaxus Harringtonine Homoharringtonine Leukemia Protein synthesis inhibitor

References

Antiviral Res. 2015 Feb;114:1-10 [PMID: 25451075]
Antimicrob Agents Chemother. 2014 Aug;58(8):4885-93 [PMID: 24841273]
Cell Biol Int. 2008 Aug;32(8):893-8 [PMID: 18499486]
Trends Mol Med. 2007 Aug;13(8):353-61 [PMID: 17644431]
PLoS One. 2015 Nov 06;10(11):e0142422 [PMID: 26544558]
J Cancer Res Clin Oncol. 2011 Oct;137(10):1563-9 [PMID: 21845438]
Yao Xue Xue Bao. 1985 Apr;20(4):283-7 [PMID: 4072699]
Cancer. 2009 Dec 1;115(23):5382-93 [PMID: 19739234]
Nat Prod Res. 2015;29(12):1161-5 [PMID: 25426576]
J Org Chem. 1974 May 3;39(9):1269-71 [PMID: 4833379]
PLoS One. 2009;4(5):e5428 [PMID: 19412536]
Med Pediatr Oncol. 2001 Aug;37(2):103-7 [PMID: 11496347]
Cancer. 2002 Apr 1;94(7):2024-32 [PMID: 11932905]
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2014 Jun;22(3):712-6 [PMID: 24989282]
Yao Xue Xue Bao. 1992;27(3):178-84 [PMID: 1414382]
Oncotarget. 2015 Oct 20;6(32):33612-22 [PMID: 26384351]
Blood. 2013 Oct 24;122(17):3086-8 [PMID: 24159169]
Zhonghua Xue Ye Xue Za Zhi. 2015 May;36(5):433-5 [PMID: 26031535]
Zhonghua Xue Ye Xue Za Zhi. 2012 Jun;33(6):433-8 [PMID: 22967374]
Cancer Res. 2006 Nov 15;66(22):10959-66 [PMID: 17108134]
J Org Chem. 2005 May 27;70(11):4528-30 [PMID: 15903339]
J Org Chem. 2013 Jan 18;78(2):339-46 [PMID: 23214949]
J Org Chem. 2009 Oct 2;74(19):7592-4 [PMID: 19731926]
Clin Lymphoma Myeloma Leuk. 2010 Oct;10(5):394-9 [PMID: 21030353]
Nature. 2014 Sep 25;513(7519):517-22 [PMID: 25209664]
Cell Commun Signal. 2015 Apr 29;13:25 [PMID: 25925126]
Org Lett. 2015 Sep 18;17(18):4444-7 [PMID: 26332648]
Clin Lymphoma Myeloma Leuk. 2013 Oct;13(5):584-91 [PMID: 23787123]
J Org Chem. 2004 Apr 30;69(9):3087-92 [PMID: 15104447]
Antimicrob Agents Chemother. 2015 Nov;59(11):7011-7 [PMID: 26349826]
Leuk Lymphoma. 2008 Oct;49(10):1954-62 [PMID: 18949618]
J Am Chem Soc. 1975 Apr 30;97(9):2507-16 [PMID: 1133420]
Chin Med J (Engl). 2007 Sep 20;120(18):1643-6 [PMID: 17908488]
Am J Hematol. 2004 Jul;76(3):199-204 [PMID: 15224352]
Antimicrob Agents Chemother. 2013 Apr;57(4):1804-14 [PMID: 23380723]
Cancer Chemother Pharmacol. 2009 Apr;63(5):859-64 [PMID: 18670778]
Int Ophthalmol. 2001;24(4):225-31 [PMID: 12678400]
J Am Chem Soc. 2002 Dec 18;124(50):14824-5 [PMID: 12475305]
Leuk Res. 2014 Oct;38(10):1145-53 [PMID: 24906663]
Int J Hematol. 2011 May;93(5):610-617 [PMID: 21509439]
Cancer. 2015 May 15;121(10):1637-44 [PMID: 25586015]
J Org Chem. 2007 Sep 14;72(19):7352-8 [PMID: 17705540]
Am J Transl Res. 2016 Mar 15;8(3):1355-68 [PMID: 27186264]
Int J Hematol. 2015 Mar;101(3):279-85 [PMID: 25563706]
Leuk Lymphoma. 2013 Oct;54(10):2100-2 [PMID: 23410101]
Org Lett. 2012 Jan 6;14(1):234-7 [PMID: 22176260]
J Org Chem. 2004 Jun 25;69(13):4336-50 [PMID: 15202887]
Leukemia. 2007 Oct;21(10):2204-6 [PMID: 17541396]
J Org Chem. 1973 Jun 1;38(71):2110-2 [PMID: 4710102]
Pharm Res. 2014 Aug;31(8):2178-85 [PMID: 24562810]
J Chromatogr Sci. 2003 Feb;41(2):67-72 [PMID: 12639253]
J Mol Biol. 2009 May 29;389(1):146-56 [PMID: 19362093]
Leuk Lymphoma. 2015 Jan;56(1):120-7 [PMID: 24650054]
Cancer Control. 2009 Apr;16(2):122-31 [PMID: 19337198]
Chemistry. 2013 Sep 23;19(39):13075-86 [PMID: 23956001]
J Chromatogr B Analyt Technol Biomed Life Sci. 2015 Oct 1;1002:152-9 [PMID: 26319804]
J Org Chem. 2002 Apr 5;67(7):2283-6 [PMID: 11925242]
Chem Asian J. 2012 May;7(5):894-8 [PMID: 22383373]
J Nat Prod. 2003 Jan;66(1):152-4 [PMID: 12542368]
Arch Pharm Res. 2000 Apr;23(2):163-6 [PMID: 10836744]
Acta Pharmacol Sin. 2007 Jun;28(6):859-68 [PMID: 17506945]
Yao Xue Xue Bao. 1981 Oct;16(10):752-6 [PMID: 7336935]
Med Oncol. 2014 Feb;31(2):836 [PMID: 24415355]
Org Lett. 2003 Aug 7;5(16):2931-4 [PMID: 12889911]
J Org Chem. 1996 Oct 18;61(21):7335-7347 [PMID: 11667659]
Chin Med J (Engl). 2009 Jun 20;122(12):1413-7 [PMID: 19567163]
J Am Pharm Assoc Am Pharm Assoc. 1954 Aug;43(8):503-5 [PMID: 13192002]
J Zhejiang Univ Sci. 2004 Feb;5(2):230-4 [PMID: 14674038]
J Pharm Biomed Anal. 2000 Apr;22(3):541-54 [PMID: 10766371]
J Med Chem. 1977 Mar;20(3):328-32 [PMID: 845863]
Pak J Med Sci. 2014 Nov-Dec;30(6):1270-2 [PMID: 25674121]
J Org Chem. 2005 Mar 4;70(5):1922-5 [PMID: 15730324]
Chem Commun (Camb). 2006 Aug 14;(30):3243-5 [PMID: 17028757]
Org Lett. 2017 Jun 2;19(11):2965-2968 [PMID: 28514154]
J Nat Prod. 2004 Jul;67(7):1182-5 [PMID: 15270578]
J Org Chem. 1972 Nov 17;37(23):3691-5 [PMID: 4639032]
J Am Chem Soc. 1972 Oct 4;94(20):7172-3 [PMID: 5072334]
Leukemia. 2006 Aug;20(8):1361-7 [PMID: 16791270]
J Org Chem. 2009 Apr 17;74(8):3211-3 [PMID: 19320459]
Enzyme Microb Technol. 2014 Dec;67:77-81 [PMID: 25442952]
Oncotarget. 2015 Jul 10;6(19):16951-62 [PMID: 26219258]
J Org Chem. 1975 Mar 5;41(5):875-78 [PMID: 1214184]
BMC Complement Altern Med. 2014 Aug 18;14:305 [PMID: 25135691]
Leukemia. 2009 Aug;23(8):1446-54 [PMID: 19322212]
Tumori. 2015 May-Jun;101(3):323-7 [PMID: 26045111]
Leuk Lymphoma. 2009 Nov;50(11):1889-91 [PMID: 19860613]
Onco Targets Ther. 2014 Jan 31;7:177-86 [PMID: 24516334]
Org Lett. 2002 Mar 21;4(6):885-8 [PMID: 11893177]
Cancer. 2001 Sep 15;92(6):1591-605 [PMID: 11745238]
Nat Prod Rep. 2012 Aug;29(8):845-69 [PMID: 22714632]
Angew Chem Int Ed Engl. 2009;48(40):7428-31 [PMID: 19739165]
Ann Hematol. 2010 Nov;89(11):1099-105 [PMID: 20499235]
Cancer Chemother Pharmacol. 2013 Jan;71(1):35-41 [PMID: 23053254]
Antimicrob Agents Chemother. 2013 Jan;57(1):155-67 [PMID: 23275491]
Yakugaku Zasshi. 1976 Nov;96(11):1373-7 [PMID: 1034698]
J Hematol Oncol. 2014 Jan 03;7:2 [PMID: 24387717]
Biomed Chromatogr. 2014 Dec;28(12):1607-14 [PMID: 24827904]
Sci Rep. 2015 Jul 13;5:8477 [PMID: 26166037]
Chem Pharm Bull (Tokyo). 1999 Jul;47(7):983-7 [PMID: 10434399]
Chin Med J (Engl). 2005 Apr 5;118(7):548-54 [PMID: 15820085]
Mol Cancer Ther. 2010 Jan;9(1):211-23 [PMID: 20053766]
J Chromatogr A. 2009 May 29;1216(22):4663-7 [PMID: 19393155]
Acta Haematol. 2014;132(2):172-6 [PMID: 24603361]
Naunyn Schmiedebergs Arch Pharmacol. 2003 Jan;367(1):56-67 [PMID: 12616342]
J Org Chem. 2005 Apr 15;70(8):3277-80 [PMID: 15822994]
Phytochemistry. 1997 Feb;44(4):735-8 [PMID: 9041720]
Leuk Lymphoma. 2007 May;48(5):964-77 [PMID: 17487741]
Org Lett. 2008 Jul 17;10(14):3045-8 [PMID: 18549234]
Mol Pharmacol. 2011 Jun;79(6):1072-83 [PMID: 21415308]
N Engl J Med. 2003 Mar 13;348(11):994-1004 [PMID: 12637609]
Oncotarget. 2015 Jun 20;6(17):15111-21 [PMID: 25915158]
Org Lett. 2006 Oct 26;8(22):5145-8 [PMID: 17048864]
Cancer. 2005 May 15;103(10):2099-108 [PMID: 15830345]
Hematology. 2004 Aug;9(4):259-70 [PMID: 15621733]
Acta Pharmacol Sin. 2004 Mar;25(3):319-26 [PMID: 15000885]
Cancer. 2003 Sep 1;98(5):888-93 [PMID: 12942553]
J Int Med Res. 2009 Jul-Aug;37(4):1191-201 [PMID: 19761704]
Front Genet. 2015 Jan 13;5:465 [PMID: 25628645]
Chin Med J (Engl). 2010 Jan 5;123(1):108-10 [PMID: 20137586]
Xenobiotica. 2016 Dec;46(12):1122-1132 [PMID: 26998885]
J Org Chem. 2005 Oct 14;70(21):8508-12 [PMID: 16209600]
Int J Clin Exp Med. 2015 Nov 15;8(11):19891-4 [PMID: 26884901]
J Org Chem. 2013 Jan 18;78(2):786-90 [PMID: 23214930]
Am J Hematol. 2009 Jul;84(7):422-7 [PMID: 19484734]
Angew Chem Int Ed Engl. 2012 May 14;51(20):4802-36 [PMID: 22555867]
J Hematol Oncol. 2011 Nov 10;4:45 [PMID: 22075327]
Br J Cancer. 2006 Aug 7;95(3):253-9 [PMID: 16847470]
Drugs Today (Barc). 2013 Jul;49(7):447-56 [PMID: 23914353]
Chemistry. 2000 Feb 4;6(3):510-8 [PMID: 10747418]
J Org Chem. 2009 Mar 6;74(5):2213-6 [PMID: 19170601]
Leuk Lymphoma. 2007 Jul;48(7):1400-6 [PMID: 17613769]
FEBS Lett. 2007 Aug 7;581(20):3826-32 [PMID: 17659279]
Nat Prod Bioprospect. 2016 Jun;6(3):149-54 [PMID: 27016921]
Apoptosis. 2013 Jun;18(6):739-50 [PMID: 23456623]
Mol Cancer Ther. 2006 Mar;5(3):723-31 [PMID: 16546987]
Oncologist. 2014 Jan;19(1):94-9 [PMID: 24309980]
Acta Biochim Biophys Sin (Shanghai). 2007 Dec;39(12):982-91 [PMID: 18064391]
Org Lett. 2017 May 5;19(9):2250-2253 [PMID: 28409934]
Leuk Res. 2008 Aug;32(8):1288-91 [PMID: 18035413]
Leuk Lymphoma. 2015 Jul;56(7):2162-9 [PMID: 25330443]
J Cancer Res Clin Oncol. 2011 Jun;137(6):997-1003 [PMID: 21152934]
Med Pediatr Oncol. 2003 Jul;41(1):70-2 [PMID: 12764750]
Org Lett. 2011 Jul 1;13(13):3538-41 [PMID: 21650169]
Leukemia. 2011 Jun;25(6):985-94 [PMID: 21468038]
Planta Med. 2007 Jun;73(6):552-8 [PMID: 17458779]
Chemistry. 2008;14(14):4293-306 [PMID: 18366032]
Chem Biodivers. 2013 Apr;10(4):584-95 [PMID: 23576344]
Org Lett. 2008 Sep 18;10(18):4129-31 [PMID: 18720987]
Clin Lymphoma Myeloma Leuk. 2013 Oct;13(5):530-3 [PMID: 23790799]
Ann Hematol. 2013 Aug;92(8):1091-100 [PMID: 23595277]
Blood. 2007 Oct 1;110(7):2779-80 [PMID: 17881650]
Int J Hematol. 2008 Jun;87(5):507-515 [PMID: 18415656]
Nat Prod Res. 2014;28(18):1503-6 [PMID: 24787645]
J Org Chem. 1974 Mar 8;39(5):676-80 [PMID: 4833503]
Leuk Lymphoma. 2016;57(6):1367-74 [PMID: 26397697]
Org Lett. 2007 Mar 29;9(7):1211-4 [PMID: 17348663]
J Org Chem. 2008 Oct 17;73(20):8045-8 [PMID: 18785776]
Org Lett. 2016 May 6;18(9):2044-6 [PMID: 27070197]
J Am Chem Soc. 2006 Aug 16;128(32):10370-1 [PMID: 16895394]
Leuk Lymphoma. 2015 Jan;56(1):141-6 [PMID: 24724783]
J Org Chem. 1997 Nov 14;62(23):8251-8254 [PMID: 11671947]

MeSH Term

Animals
Antineoplastic Agents, Phytogenic
Harringtonines
Humans

Chemicals

Antineoplastic Agents, Phytogenic
Harringtonines
Journal Article Review

Word Cloud

Similar Articles

Cited By