Alkaloids: Chemical and Biological Perspectives

387 Pages·1998·6.521 MB·1-388\387

by  S. William Pelletier (Eds.)

Contributors
Detlev Belder, Johannes Gutenberg-Universitat, Institut fiir Pharmazie, Lehrstuhl fiir
Pharmazeutische Biologic, Staudinger Weg 5, D-55099 Mainz, GERMANY
Michael F. Clothier, Animal Health Discovery Research, Pharmacia and Upjohn Inc.,
Kalamazoo, Michigan 49001, U.S.A.
Gabe I. Kornis, Animal Health Discovery Research, Pharmacia and Upjohn Inc.,
Kalamazoo, Michigan 49001, U.S.A.
Byung H. Lee, Animal Health Discovery Research, Pharmacia and Upjohn Inc.,
Kalamazoo, Michigan 49001, U.S.A.
Sylvie Michel, Universite Rene Descartes-Paris V, Faculte de Pharmacie, Laboratoire de
Pharmacognosie, 75270 Paris Cedex 06, FRANCE
Helmut Ripperger, Institute of Plant Biochemistry, D-06120 Halle (Saale), GERMANY
Alexios-L6andros Skaltsounis, Universite Rene Descartes-Paris V, Faculte de Pharmacie,
Laboratoire de Pharmacognosie, 75270 Paris Cedex 06, FRANCE
Michael B. Smith, Department of Chemistry, The University of Connecticut, Storrs,
Connecticut 06269-4060, U.S.A.
Detlef Stockigt, Institute fiir Pharmazie, Lehrstuhl fur Pharmazeutische Biologic, Johannes
Gutenberg-Univcrsat Mainz, Staudinger Weg 5, 55099 Mainz, GERMANY
Joachim Stockigt, Institute fiir Pharmazie, Lehrstuhl fur Pharmazeutische Biologic,
Johannes Gutenberg-Univcrsat Mainz, Staudinger Weg 5, 55099 Mainz,
GERMANY
Fran9ois Tillcquin, Universite Rene Descartes-Paris V, Faculte de Pharmacie, Laboratoire
de Pharmacognosie, 75270 Paris Cedex 06, FRANCE
Matthias Unger, Institute fiir Pharmazie, Lehrstuhl fur Pharmazeutische Biologic, Johannes
Gutenberg-Univcrsat Mainz, Staudinger Weg 5,55099 Mainz, GERMANY
Peter Wipf, Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania
15260, U.S.A.
vii
Preface
Acronycine, a potent antitumor agent with a broad spectrum of activity, was discovered in
1948 in the bark of the small Australian Rutaceous tree, Acronychia baueri Schott. Since then,
many derivatives and structural analogues have been isolated from various Rutaceae species and
prepared by synthesis. Chapter 1 by Fran9ois Tillequin, Sylvie Michel, and Alexios-Leandros
Skaltsounis presents a comprehensive survey of the isolation, structure determination, methods of
synthesis, and the biological properties of acronycine, as well as an account of natural and syn
thetic analogs of acronycine, and their biological properties.
Since the last review on the Solanum alkaloids in 1990, there has been substantial progress in
the field concerning isolation procedures and structure elucidation methods. Chapter 2 by Helmut
Ripperger, provides a brief survey of new developments and critically updates earlier reviews.
Chapter 3 by Peter Wipf reviews the interesting chemistry and synthesis of cyclopeptide alka
loids characterized by an alternating sequence of five-membered heterocycles and hydrophobic
amino acid residues. These cyclopeptide alkaloids have been isolated from ascidians, sea hares,
and cyanobacteria.
A common synthetic strategy for constructing natural products is to use a chiral, nonracemic
starting material. The availability of amino acids have made them popular starting materials for
such applications. Chapter 4 by Michael B. Smith summarizes the use of the functionalized lac
tam, pyroglutamic acid, as a chiral templete for the synthesis of alkaloids. The chapter focuses
exclusively on compounds derived from L-, D-, or D, L- glutamic acid.
Chapter 5 by Joachim Stockigt, Matthias Unger, Detlef Stockigt, and Detlev Belder presents
a brief review on the on-line coupling of capillary electrophoresis (CE) and mass spectrometry
(MS) for the analysis of alkaloid mixtures. Because of particular physical and chemical properties
of alkaloids, their analytical separation and identification are frequently not easily carried out. This
chapter demonstrates that the CE-MS technique provides a rapid and efficient screening procedure
for alkaloid mixtures.
Parasitic nematodes cause substantial health problems in humans and in domestic animals.
None of the drugs currently used for control of gastrointestinal nematodes is ideally suited for all
therapeutic situations. Thus expansion of the anthelmentic arsenal is an urgent goal. Chapter 6 by
Byung H. Lee, Michael F. Clothier, and Gabe I. Kornis treats oxygenated analogs of Marcfortine
A, an alkaloid with potent antiparasitic activity. These analogs were prepared by chemical synthe
sis and by microbiological hydroxylation.
Each chapter in this volume has been reviewed by at least one expert in the field. The editor
thanks these reviewers for the very significant contributions they have made to this volume.
Indexes for both subjects and organisms are provided.
ix
X Preface
The editor invites prospective contributions to write him about topics fc»^ review in future vol
umes in this series.
S. William Pelletier
Athens, Georgia
September 3,1997
Chapter One
Acronycine-Type Alkaloids :
Chemistry and Biology
Fran9ois Tillequin, Sylvie Michel, and Alexios-Leandros Skaltsounis
University Rene Descartes - Paris V
Faculty de Pharmacie
Laboratoire de Pharmacognosie
75270 Paris Cedex 06, France
CONTENTS
1. INTRODUCTION 2
2. ACRONYCINE 3
2.1. Isolation, Chemical Properties and Structural Elucidation 3
2.2. Spectral Data 9
2.3. Synthesis 11
2.3.1. Syntheses by alkylation of a preformed 1,3-dioxygenated acridone 11
2.3.2. Syntheses including the construction of the acridone skeleton 21
2.3.2.1. Syntheses involving a carboxylic diphenylamine intermediate 21
2.3.2.2. Syntheses involving an aminobenzophenone intermediate 28
2.3.2.3. Syntheses involving a quinoHne or quinolone intermediate 31
2.4. Biological properties 38
2.4.1. Antitumor activity 38
2.4.2. Other biological activities 42
2.4.3. Pharmacokinetics and metaboHsm 42
3. NATURALLY OCCURING ACRONYCINE ANALOGS 49
3.1. Acronycine analogs modified at C(6), N(12), and their derivatives
substituted on C ring 49
3.2. Alkaloids modified on the A aromatic ring 50
3.2.1. Alkaloids monosubstituted at C(ll) 50
3.2.2. Alkaloids disubstituted at C(10) and C(l 1) 54
3.2.3. Other alkaloids with modified A aromatic ring 57
3.3. Alkaloids with oxidized pyran D ring 58
3.3.1. Acronycine derivatives with oxidized pyran D ring 58
3.3.2. 12-Demethylacronycine derivatives with oxidized pyran D ring 60
2 F.Tilieqiiiii, S. Mkhel and A-L. Skaltsoimis
3.3.3. Citracridone I derivative with oxidized pyran D ring 61
3.4. Dimeric alkaloids 62
3.4.1. Dtmeric acridone alkaloid containing an ether linkage 62
3.4.2. Dimeric acridone alkaloids containing a carbon-carbon linkage 63
4. SYNTHETIC ACRONYCINE ANALOGS 66
4.1. Acronycine analogs modified at C(6) and/or N(12) 67
4.2. 3,12-Dihydro-7//-pyrano[2,3-c]acridin-7-thiones 72
4.3. Acronycine analogs modified at the A ring 73
4.3.1. Acronycine analogs substituted at the A ring 73
4.3.2. 11-Azaacronycine 85
4.4. Acronycine analogs modified at the D ring 87
5. CONCLUSION 94
Acknowledgements 95
References 95
1. INTRODUCTION
Acronycine (3,12-dihydro-6-methoxy-3,3,12-trimcthyl-7//-pyrano[2,3-c]acridin-7-one)
(1) is a natural alkaloid which was first isolated in 1948 by the group of Hughes and Lahey [l]
from the baiic of the small Australian Rutaceous tree Acronychia baueri Schott
The structure of acronycine has long been discussed, mainly to ascertain whether the
pyran ring was fused lineaiiy or angularly on the acridone skeleton. It was only in 1966 that the
angular structure 1 could be unambiguously assigned to acronycine on the basis of oxidative
degradation evidence [2] and of ^H nmr data [3]. Final proof of the structure was obtained in
1970 from X-ray crystallographic data of 5-bromo-l,2-dihydn>acronycine (2) [4].
O OCH3
Acronycine-Type Alkaloids: Chemistry and Biology 3
The biological interest of acronycine was revealed in 1966 by Svoboda and co-workers
in the Eli Lilly Laboratories [5,6]. Acronycine is a potent antitumor agent whose main interest
lies in its broad spectrum of activity, including numerous solid tumors resistant to other
chemotherapeutic agents [5-8]. In contrast, acronycine exhibits only marginal activity against
leukemias [5-8].
Since the discovery of the antitumor properties of acronycine, numerous derivatives and
structural analogues have been both isolated from various Rutaceae species and prepared by total
synthesis. A survey of natural alkaloids and synthetic analogues derivating from the pyrano[2,3-
c]acridin-7-one skeleton is presented below.
2. ACRONYCINE
2.1 Isolation, Chemical Properties and Structural Elucidation
Isolation,Tht first isolation of acronycine from a methanolic extract of Acronychia baueri
bark relied only on solubility differences between the various alkaloids contained in the plant
material [9]. Further isolations from the same source involved both crystallizations and
chromatography on alumina and/or silica gel [5.6.10]. A chemical study of the leaves of the
same plant resulted in the isolation of various acridone and furo[2,3-b]quinoline alkaloids but no
acronycine could be detected [11].
Since the first isolation of acronycine, the status of Acronychia baueri Schott within the
Rutaceae family has been revised several times by Hartley at the Herbarium Australiense, in the
course of successive taxonomic studies of genera Acronychia [12], Bauerella [13] and
Sarcomelicope [14.15]. Hartley now considers this taxon belongs to the genus Sarcomelicope
and should be named Sarcomelicope simplicifolia (Endl.) Hartley subsp. simplicifolia [14].
Apart from Sarcomelicope simplicifolia, all the other species belonging to that genus are
endemic in New Caledonia [14,15], and most of them have been studied for their alkaloid
contents [16-27]. Acronycine was obtained from the bark of Sarcomelicope simplicifolia (Endl.)
Hartiey subsp. neo-scotica (P.S. Green) Hartley [16, 18], from the bark of Sarcomelicope
argyrophylla Guill. [20], from the bark of Sarcomelicope glauca Hartley [21], and from the
leaves and bark of Sarcomelicope dogniensis Hartiey [22,25] and Sarcomelicope pembaiensis
Hartley [23]. In addition, acronycine has also been isolated from the aerial parts o fMelicope
leptococca (Baill.) Guill. [28].
Chemical properties and structural elucidation, Acronycine crystallizes from alcohol as
yellow needles, m.p. 175-176°C [9]. It also readily crystallizes from methanol and acetone [5]. A
dilute alcoholic solution of the base is yellow with a bright green fluorescence [9]. Acronycine
forms an orange picrate, m.p. 150-154**C, a red hydrochloride which easily separates from 10
4 F.Tillequin, S. Michel and A-L. Skaltsovids
per cent hydrochloric acid in red needles, m.p. 125-130^0 (dec.)* and a sulfate which
crystallizes as red needles from alcoholic sulfuric acid, m.p. 158-159°C [9].
Treatment of acronycine (1) with hot alcoholic hydrochloric acid yields polymeric
amorphous products. In contrast, heating acronycine hydrochloride in the dry state brings
demethylation with the fcMtnation of noracronycine (3) [29] (Scheme 1). The hydroxy group of
this latter compound is chelated by the neighbouring carbonyl group at C(7), as shown by uv
spectroscc^y [30] and therefcxre cannot be methylated upon treatment with diazomethane [29].
However, treatment with dimethylsulfate and potassium carbonate in acetone converts it back to
acronycine, whereas hot acetic anhydride in the presence of pyridine gives a monoacetate (4)
[29].
Acronycine contains a reactive double-bond since catalytic reduction in the presence of
Raney nickel yields dihydroacronycine (5) [29].
Hydrochloric or hydrobromic acid converts dihydroacronycine (5) to
nordihydioacronycine (6) without polymerization [29].
Oxygenation patterns on A and C rings of acronycine, as well as fusion of a
dimethylpyran unit with the latter ring, were early deduced from degradative experiments [29.
31].
Concentrated nitric acid in alcohol yields a mononitroacronycine whose structure was
tentatively described as l-nitroacronycine [31]. The same reaction was then claimed to yield
2-nitroacronycine (7) [S] and this latter structure could finally be assigned to the mononitration
product of acronycine on the basis of nOe experiments in ^H nmr spectroscopy [32]. With hot
concentrated nitric acid, acronycine is converted to an orange trinitroacronycine, to which the
structure of 2,5,9-trinitroacronycine (8) should reasonably be assigned.
7 R = H
8 R = N02
By prolonged heating with concentrated nitric acid, trinitroacronycine dissolves and gives
rise to 6-nitro-l-methyl-4-quinolone-3-carboxylic acid (9) identical with a synthetic sample.
Similarly, both noracronycine (3) and nordihydioacronycine (6) lead, upon treatment with nitric
acid, to l-methyl-4-quinolone-3-carboxylic acid (10) whose structure was identical with that of
the methylation product of 4-hydroxyquinoline-3-carboxylic acid synthetized by the Gould-
Jacobs method [31].
Acronyciiie>Type Alkaloids: Chemistry and Biology
O OH
O OCHj
HCl, heating
Me2S04/K2C03
H2/RaneyNi AC2O
O OCH3
O OCOCHa
HClorHBr
Scheme 1
CXX)H
9 R =N02
10 R=H
6 F.Tilieqtiin, S. Michel and A-L. Skaltsow^
Oxidation of acronycine with potassium permanganate in acetone gave rise to the
dicarfooxylic add 11, easily decarboxylated to acronycinic acid (12) upon crystallizatkm frcrni 10
per cent hydn)chloric acid [29].
OCH,
11 R = CXX)H
12 R = H
COOH
Pyrolysis of 12 yields three products : a-hydroxyisobutyric acid (13), 1,3-dihydroxy-
10-methyl-9(10//)-acridinone (14) and l-hydroxy-3-methoxy-10-methy]-9(10//)-acridinone
(15). Treatment of 14 with diazomethane gives 15, which in turn can be converted by use of
dimethylsulfate into-l,3-dimethoxy-10-methyl-9(10//)-acridinone (16). Compounds 14,15
and 16 were identified by comparison with authentic synthetic samples [29,31].
HO^-J^
CXX>H
13
Similarly, noracronycine yields, upon permanganate oxidation followed by
decarboxylation, noracionycinic acid (17). Pyrolysis of this latter only gives a-hydroxybutyric
acid (13) and l,3-dihydroxy-10-metiiyl-9(10//)*acridinone (14) [29,31].
0 ORi
8 9U ll
M li
II ju
5 4
CH3
COOH
14 R, = R2= H
15 Ri = H R2 = CH3
16 Ri = R2 — Cfl3
19 R, = CH3 R2 = H
Acronycine-Type Alkaloids: Chemistry and Biology 7
The results of these experiments can be explained only if acronycine contains a
dimethylpyran ring fused with an acridone system. They permit assignment of either the angular
structure 1 or the linear structure 18 (= isoacronycine) to acronycine.
18
The only apparent inconsistency in these reactions is found in the obtention of methyl
ether 15, which is presumably formed during the degradation reaction of 12 by remethylation
of the 1,3-dihydroxy derivative 14, or by intermolecular transmethylation of the 3-hydroxy-l-
methoxy-10-methyl-9(10//)-acridinone (19) initially formed.
Ozonolysis of acronycine gives a phenolic aldehyde, which can be methylated on its free
phenolic group, oxidized to the corresponding carboxylic acid, and finally esterifled using
diazomethane [2,31]. If acronycine had a linear structure, this product would be 1,3-dimethoxy-
2-methoxycarbonyM0-methyl-9(10//)-acridinone (20), whereas if it had an angular structure,
the product would be l,3-dimethoxy-4-methoxycarbonyl-10-methyl-9(10f/j-acridinone (21).
Unambiguous structure determination of the degradation product would therefore define the
structure of acronycine.
20 RI = COCX:H3 R2 = H
21 Ri=H R2 = COOCH3
OCHa
The chemical proof of acronycine structure was finally obtained in 1966 by Macdonald
and Robertson who achieved the regioselective synthesis of 20 according to Scheme 2 [2]. The
synthetic compound was not identical with the degradation product of acronycine, which was
therefore l,3-dimethoxy-4-methoxycarbonyl-10-methyl-9(10//)-acridinone (21), indicating the
angular structure of acronycine.
Subsequently, Govindachari isolated noracronycine (3) from Glycosmis pentaphylla in
1966 and provided independendy a proof of the angular structure of the latter compound [3].