The Alkaloids: Chemistry and Biology 68

293 Pages·2010·5.82 MB·English

by  Geoffrey A. Cordell (Eds.)

THE ALKALOIDS
Chemistry and Biology
68
VOLUME
Edited by
Geoffrey A. Cordell
Evanston, Illinois
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Amsterdam Boston Heidelberg London NewYork
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CONTRIBUTORS
Numbers in parentheses indicate the pages on which the authors’ contributions
begin.
Bruce K. Cassels (83), Department of Chemistry, Faculty of Sciences,
University of Chile, Chile; Millennium Institute for Cell Dynamics and
Biotechnology, Santiago, Chile
Juan C. Cedro´n (1), Instituto Universitario de Bio-Orga´nica ‘‘Antonio
Gonza´lez’’, Universidad de La Laguna, La Laguna-Tenerife, Spain;
Instituto Canario de Investigacio´n del Ca´ncer, Spain
M.DelArco-Aguilar(1),DepartamentodeBiolog´ıaVegetal,Universidad
de La Laguna, La Laguna-Tenerife, Spain
AnaEste´vez-Braun(1),InstitutoUniversitariodeBio-Orga´nica‘‘Antonio
Gonza´lez’’, Universidad de La Laguna, La Laguna-Tenerife, Spain;
Instituto Canario de Investigacio´n del Ca´ncer, Spain
Michael Heinrich (157), The School of Pharmacy, Centre for Pharma-
cognosy and Phytotherapy, University of London, London, UK
Emil D. Molle (167), Faculty of Ecology and Landscape Architecture,
University of Forestry, Sofia, Bulgaria
Matthew J. Palframan (39), Department of Chemistry, University of
York, Heslington, York, UK
Andrew F. Parsons (39), Department of Chemistry, University of York,
Heslington, York, UK
EdwinG.Pe´rez(83),DepartmentofChemistry,FacultyofChemistryand
Biology,UniversityofSantiago,Santiago,Chile;MillenniumInstituteforCell
DynamicsandBiotechnology,Santiago,Chile;Presentaddress:Facultadde
Qu´ımica,PontificiaUniversidadCato´licadeChile,Santiago,Chile
A´ngel G. Ravelo (1), Instituto Universitario de Bio-Orga´nica ‘‘Antonio
Gonza´lez’’, Universidad de La Laguna, La Laguna-Tenerife, Spain;
Instituto Canario de Investigacio´n del Ca´ncer, Spain
Marina I. Stanilova (167), Department of Applied Botany, Institute of
Botany-Bulgarian Academy of Sciences, Sofia, Bulgaria
Stanislav G. Yanev (167), Department of Toxicology, Institute of
Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria
vii
PREFACE
This volume of the series presents timely discussions on some of the
important groups of alkaloids derived biosynthetically from phenylala-
nine and tyrosine. These authoritative chapters provide contemporary
commentary on various aspects of alkaloid occurrence, synthesis,
biosynthesis, and in one instance, efforts to enhance production to meet
commercial needs.
Ravelo and coworkers offer a comprehensive overview of the
Amaryllidaceae alkaloids present in the genus Pancratium, with an
emphasisonusingtheirNMRspectroscopicpropertiestodistinguishthe
individualalkaloidtypes.Alsocoveredindetailareimportantaspectsof
their synthesis, and the broad spectrum of biological properties which
the alkaloids represent.
Another small and interesting group of alkaloids with a quite limited
chemotaxonomic distribution is the Erythrina alkaloids. These alkaloids
possess some very interesting structural diversity, which has inspired the
creativity of the synthetic organic chemistry community. Parsons and
PalframanprovideanoverviewofthisareaforthefirsttimesinceVolume48.
The genus Duguetia produces a range of isoquinoline alkaloids,
including those of the benzylisoquinoline type, the aporphinoid type,
and the berberine type. Although only a small number of the species in
the genus have been examined thus far, Pe´rez and Cassals have, for the
first time, summarized these results, and the associated synthetic and
biological efforts, and made chemotaxonomic comparisons with the
botanically close genus Guaterria. Of particular interest is the diverse
pharmacology, some of it potentially useful, which has recently been
disclosed for these alkaloids.
Themostrecentalkaloidadditiontopharmacotherapyistheintroduc-
tion ofgalanthamine,analkaloidfromseveralgenerain theAmaryllida-
ceae.AsummarizingchapterfromHeinrichonthehistoricalaspectsand
backgroundofgalanthamineasadrugisfollowedbyanextensivereview
ofgalanthamineproductionfromthegroupofStanilovabasedinBulgaria.
Thechapterbringsfocustotheresearcheffortsovermanyyearstoenhance
theavailabilityofgalanthaminefromnaturalsources.Thisisaclassicissue
for all natural product development, and this intimate and personal
account of the broad diversity of approaches tried, and the sometimes
unexpectedresultsobtained,makesfascinatingreading.
Geoffrey A. Cordell
Evanston, Illinois
ix
1
CHAPTER
Chemistry and Biology of
Pancratium Alkaloids
Juan C. Cedro´n1,2, M. Del Arco-Aguilar3,
Ana Este´vez-Braun1,2,* and A´ngel G. Ravelo1,2,*
Contents I. Introduction 2
A. Classification ofthe Amaryllidaceae Alkaloids 2
B. Biosynthesis 3
II. PancratiumGenus 6
A. General Aspects ofthePancratiumGenus 6
B. Botanical Description 7
C. Alkaloids andOther SecondaryMetabolites Isolated 7
III. NMRStudies 13
A. Lycorenine-Type Alkaloids 14
B. Lycorine-Type Alkaloids 15
C. Montanine-Type Alkaloids 15
D. Narciclasine-Type Alkaloids 16
E. Tazettine-Type Alkaloids 16
F. Galanthamine-Type Alkaloids 17
G. Crinine and Haemanthamine-Type Alkaloids 18
IV. ProductionofPancratium Alkaloids 18
A. RecentSynthetic Studies 18
B. Interconversions betweenSkeletons 28
C. In Vitro CultureSystems 30
V. Biological Activities 31
A. Anticancer Activity 31
1 InstitutoUniversitariodeBio-Orga´nica‘‘AntonioGonza´lez’’,UniversidaddeLaLaguna,LaLaguna-
Tenerife,Spain
2 InstitutoCanariodeInvestigacio´ndelCa´ncer,Spain
3 DepartamentodeBiolog´ıaVegetal,UniversidaddeLaLaguna,LaLaguna-Tenerife,Spain
*Correspondingauthors.
E-mailaddresses:[email protected](A.Este´vez-Braun)[email protected](A´.G.Ravelo)
TheAlkaloids,Volume68 r2010ElsevierInc.
ISSN:1099-4831, DOI10.1016/S1099-4831(10)06801-X Allrightsreserved
1
2 Cedro´netal.
B. Antiplasmodial Activity 33
C. OtherActivities 33
V. Conclusions 33
References 34
I. INTRODUCTION
The Amaryllidaceae is a widely distributed, monocotyledonous family,
represented by 59 genera and over 850 species all over the world
(Figure 1) (1,2). South America (28 genera) and South Africa (19 genera)
aretheregionswithmajordiversity.TheMediterraneanregion,beingthe
source of numerous horticultural introductions, has only eight genera;
whereas Australia has only three genera. Plants in the Amaryllidaceae
occupy many different habitats: seasonally dry places, ephemeral pools,
rainforests understory, and rivers. Currently, molecular evidence places
the most ancient lineages and the origin of the family in Africa (3).
PlantsbelongingtotheAmaryllidaceaefamilyareknownforproducing
an exclusive group of alkaloids, named ‘‘Amaryllidaceae alkaloids,’’
isolated from plants of all genera of this family. Since the isolation of
lycorine(1)fromNarcissuspseudonarcissus in1877,over300alkaloidshave
been isolated from plants of this family (4), including those alkaloids
recentlyisolatedfromPancratiumcanariensis(5).Althoughtheirstructures
appear to be very different, these alkaloids are known to be formed
biogeneticallyfromnorbelladines.
A. Classification of the Amaryllidaceae Alkaloids
According to their structures, the Amaryllidaceae alkaloids are
classified into eight skeleton types (6), for which the representative
Figure1 Distribution ofplants of theAmaryllidaceae family.
ChemistryandBiologyofPancratiumAlkaloids 3
OH OMe
OH
3 3
O 9 10H1O0Ha101b H42a 34 11 MeO9 10O 1201a 10b 441a112 O 9 10 1120a10b4a114OHNH1M2e
N O
O 8 7 6a 6 12 8 7 6a 6 NMe O 8 7 6a 6
1 lycorine 2 galanthamine 3 tazettine
OH
1 2 3 OH 1 2 OMe
H 10 11
O 9 10 10a10b 4a 4OH O 9 10a 10b 4a 3 OH
12 4
O 8 6a 6 NH O 8 6a N H
7 7 6
OH O
4 narciclasine 5 montanine
12 11
MeO 9 10M1e0HNa 1H0b4a14 23 O 9 10 10a110b2 34 OMOeH O 9 1010a 110b 42a11 34 OH
MeO 8 7 6a 6O H O 8 7 6a H6 N4a 1211 O 8 7 6a H6 N 12
OH
6 lycorenine 7 haemanthamine 8 crinine
Figure 2 Amaryllidaceae alkaloid types.
alkaloidsare:lycorine(1),galanthamine(2),tazettine(3),narciclasine(4),
montanine (5), lycorenine (6), haemanthamine (7), and crinine (8)
(Figure 2). Ghosal’s model has been used for numbering each skeleton
(7).Recently,UnverandJinhaveproposedsubgroupsfor someskeleton
types, according to the structures of new alkaloids isolated from
Galanthus species (8,9).
B. Biosynthesis
Except for galanthamine, most of the biosynthetic research on the
Amaryllidaceae alkaloids was developed in the 1960s and 1970s.
Biosynthesis of this class of alkaloids is the result of several intramole-
cular oxidative couplings of precursors related to norbelladine (12) (10).
Norbelladine (12) is formed through the combination of 3,4-dihydrox-
ybenzaldehyde(10)withtyramine(9);thesetwoprecursorsarisingfrom
phenylalanine and tyrosine, respectively (Figure 3). After reduction of
4 Cedro´netal.
OH
H
HO
O
HO
+
NH
HO 2 HO
N
9 10 HO 11
OH OH
HO MeO 4(cid:2)
H H
N N
HO HO
12 norbelladine 13 4(cid:2)-O-methylnorbelladine
Figure3 Biosynthesis of norbelladine (12) and4u-O-methylnorbelladine (13) from
tyramine(9) and 3,4-dihydroxybenzaldehyde (10).
the resulting Schiff’s base 11 and methylation of norbelladine, 4u-O-
methylnorbelladine (13) is obtained. Alkaloid 13 is considered the key
intermediate in the elaboration of most of the alkaloids (11). 4u-O-
Methylnorbelladine (13)canundergothreetypes ofoxidative couplings:
ortho(cid:1)parau, para(cid:1)parau, and para(cid:1)orthou (Figure 4).
Lycorine (1) is formed through an ortho(cid:1)parau coupling, while the
crinine(8)andhaemanthamine(7)skeletonsareformedfromapara(cid:1)parau
coupling. The galanthamine skeleton (2) is biosynthesized from a
para(cid:1)orthoucoupling(Figure4).
Aprecursoroflycorine(5),norpluviine(14)isalsoanintermediatein
theformationofthelycorenineskeleton(6).Inthiscase,norpluviine(14)
is oxidized at the benzylic position to yield a cyclic hemiaminal group,
which is in equilibrium with the corresponding open form. The rotation
of the C-10a(cid:1)C-10b bond of the amino aldehyde intermediate, followed
byhemiacetalformationandmethylation,providethelycoreninecore(6)
(Figure 5) (12).
The alkaloid haemanthamine (7) is the precursor of the tazettine (3),
montanine (5), and narciclasine (4) skeletons. Haemanthamine (7) is
formed through a para(cid:1)parau coupling as the enantiomeric skeleton of
crinine (8). The biosynthesis of tazettine (3) has been studied and
described(Figure6)(13).Itinvolvestheoxidationofhaemanthamine(7)
to haemanthidine (15) followed by ring opening to form the amino
aldehyde equilibrium system, which, after hemiacetal formation and
methylation, yields pretazettine (16) (14). Although pretazettine (16)
has been identified in plants, it is unstable either in basic or acid
solutions,anditconvertsslowlyintotazettine(3)(15).Biosynthesisofthe
ChemistryandBiologyofPancratiumAlkaloids 5
OH
HO HO
H H
MeO O
H ortho-para'
N N
HO O
1 lycorine
OH OH
MeO O
para-para' H
NH N
HO O
8 crinine
OH O O
OH OH OH
MeO MeO MeO
para-ortho'
HN NH NH
OH
OH OH
O O
O
MeO MeO
= MeO
NH N
Me
NMe
2 galanthamine
Figure 4 Phenoloxidative couplings of4u-O-methylnorbelladine (13) toyield the
lycorine, crinine, andgalanthamine skeletons.
HO HO HO
H H H H H H
MeO MeO MeO 10b
oxidation 10a
N N HN
HO HO HO CHO
OH
14 norpluviine
HN H HN H HN H
H H H H H
rotation MeO MeO MeO
OH O O
HO CHO HO MeO
OH OH
6 lycorenine
Figure 5 Biosynthesis of lycorenine(6)from norpluviine(14).