biologically active indole and bisindole alkaloids from leuconotis and kopsia

452 Pages·2013·19.15 MB·English

BIOLOGICALLY ACTIVE INDOLE AND BISINDOLE
ALKALOIDS FROM
LEUCONOTIS AND KOPSIA

GAN CHEW YAN

A THESIS SUBMITTED IN FULFILMENT OF THE
REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY

FACULTY OF SCIENCE
UNIVERSITY OF MALAYA
KUALA LUMPUR

2013
Abstract

Two Malaysian plants viz., Leuconotis griffithii and Kopsia pauciflora, and one fungi
strain (Penicillium sp. (CDA p48.3)) were investigated for their alkaloidal content and
the results are summarized below (Table). A total of 107 alkaloids were isolated and
characterized from these sources. Of these, 37 are new alkaloids. Leuconotis griffithii
yielded a total of 24 new alkaloids, of which sixteen, viz., the tetracyclic ring-opened
oxindole leucolusine (1), the strychnan alkaloids, leuconicines AG (28), the ring-C
contracted rhazinilam alkaloid, nor-rhazinicine (22), the unprecedented
eburnanequinoline dimer, leucophyllidine (36), the eburnanesarpagine bisindole,
leuconoline (37), the aspidospermatanaspidospermatan bisindole, leucofoline (38), and
the StrychnosStrychnos bisindoles, leucoridines AD (3942), are notable for
incorporating novel or intriguing molecular skeletons. The stem-bark and leaf extracts
of Kopsia pauciflora gave a total of 10 new alkaloids. These new alkaloids are the seco-
leuconoxine alkaloid, compound 62, the eburnane alkaloids, 6364, the corynanthean
oxindole alkaloids, 6971, the corynanthean pseudoindoxyl alkaloid,
tetrahydroalstonine pseudoindoxyl (73), the aspidofractinine alkaloid, 11,12-
dimethoxykopsinaline (77), and the andransinine alkaloids, andransinine (90) and
compound 91. The culture broth extract of a Penicillium sp. (CDA p48.3) gave three
new variotin derivatives, viz., compounds 101103. Among the new alkaloids, 5,21-
dihydrorhazinilam N-oxide (23), leucophyllidine (36), and leucoridine A (39) showed
pronounced cytotoxic effects against human KB cells (IC 0.572.95 g/mL), while
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leuconodine B (10), leuconodine D (12), nor-rhazinicine (22), leuconoline (37),
leucofoline (38), and leucoridines BD (4042) showed only moderate to weak activity
(IC 7.0617.90 g/mL). Leuconicines AB (23), compound 70, and andransinine
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ii
(90) were found to be effective in circumventing MDR in vincristine-resistant KB cells
(IC 1.612.75 g/mL), while leuconicines CE (46), leuconodine E (13), and
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compounds 62, 64, and 91, showed only moderate to weak activity (IC 3.8618.13
50
g/mL).

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Abstrak (Versi Bahasa Malaysia)

Dua jenis tumbuhan dari Malaysia iaitu Leuconotis griffithii, dan Kopsia pauciflora, dan
sejenis kulat (Penicillium sp. (CDA p48.3)) telah dikaji dari segi kandungan
alkaloidnya, keputusan yang diperoleh telah dirumuskan di dalam jadual seperti di
bawah. Sebanyak 107 alkaloid telah diasingkan dan dicirikan dari sumber yang
dinyatakan di atas. Dari jumlah tersebut, 37 alkaloid merupakan alkaloid baru.
Sebanyak 24 alkaloid baru telah diasingkan dari Leuconotis griffithii, antaranya, enam
belas memiliki rangka karbon yang menarik, iaitu leucolusine (1), leuconicines AG
(28), nor-rhazinicine (22), leucophyllidine (36), leuconoline (37), leucofoline (38) dan
leucoridines AD (3942). Ekstrak-ekstrak dari kulit-batang dan daun Kopsia
pauciflora memberikan sejumlah 10 alkaloid baru. Alkaloid baru ini termasuklah
sebatian 6264, 6971, tetrahydroalstonine pseudoindoxyl (73), 11,12-
dimethoxykopsinaline (77), andransinine (90) dan sebatian 91. Ekstrak dari supernatan
Penicillium sp. (CDA p48.3) telah menghasilkan tiga terbitan baru variotin, iaitu
sebatian 101103. Antara alkaloid baru ini, 5,21-dihydrorhazinilam N-oxide (23),
leucophyllidine (36), dan leucoridine A (39), menunjukkan kesan sitotoksik yang kuat
terhadap sel-sel KB (IC 0.572.95 g/mL), manakala leuconodine B (10),
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leuconodine D (12), nor-rhazinicine (22), leuconoline (37), leucofoline (38), dan
leucoridines BD (4042) menunjukkan kesan sitotoksik yang sederhana sahaja (IC
50
7.0617.90 g/mL). Leuconicines AB (23), sebatian 70, dan andransinine (90)
memberikan kesan yang sangat kuat dalam memintasi ketahanan multidrug dalam sel-
sel KB vincristine-resistant (IC 1.612.75 g/mL), manakala leuconicines CE (46),
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leuconodine E (13), dan sebatian 62, 64, dan 91, hanya menunjukkan aktiviti yang
sederhana sahaja (IC 3.8618.13 g/mL).
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Table: Alkaloid Composition of L. griffithii, K. pauciflora, and Penicillium sp. (CDA
p48.3)
Plant Plant part Alkaloid
L. griffithii (Plant) Stem-bark Leucolusine (1) [New]
Leuconicine A (2) [New]
Leuconicine B (3) [New]
Leuconicine C (4) [New]
Leuconicine D (5) [New]
Leuconicine E (6) [New]
Leuconicine F (7) [New]
Leuconicine G (8) [New]
Leuconodine A (9) [New]
Leuconodine B (scholarisine G) (10) [New]
Leuconodine C (11) [New]
Leuconodine D (12) [New]
Leuconodine E (13) [New]
Leuconoxine (14)
Leuconodine F (6-oxoleuconoxine) (15)
Mersicarpine (16)
Arboloscine (17)
3,14-Dehydroleuconolam (18) [New]
Leuconolam (19)
O-Methylleuconolam (20)
Epi-leuconolam (21) or 6,7-dehydroleuconoxine (21a)
Nor-rhazinicine (22) [New]
5,21-Dihydrorhazinilam N-oxide (23) [New]
5,21-Dihydrorhazinilam (24)
Rhazinilam (25)
Rhazinal (26)
Rhazinicine (27)
()-Eburnamaline (28) [New]
()-Eburnamonine (29)
()-Eburnamenine (30)
O-Methylisoeburnamine (31)
O-Methyleburnamine (32)
()-Isoeburnamine (33)
()-Eburnamine (34)
(±)-Vincamine (35)
Leucophyllidine (36) [New]
Leuconoline (37) [New]
Leucofoline (38) [New]
Leucoridine A (39) [New]
Leucoridine B (40) [New]
Leucoridine C (41) [New]
Leucoridine D (42) [New]
Tetrahydroalstonine (43)
17(S)-Ajmalicinial (44) and 17(R)-Ajmalicinial (45)
Akuammidine (46)
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Table, continued
Plant Plant part Alkaloid
16(R)-19,20-E-Isositsirikine (47)
16(S)-19,20-E-Isositsirikine (48)
Z-Geissoschizol (49)
Fluorocarpamine (50)
Pleiocarpamine (51)
16-Hydroxymethylpleiocarpamine (52)
()-Isovallesiachotamine (53)
()-Isovallesiachotamine (53) and ()-Vallesiachotamine (54)
Norfluorocurarine (55)
12-Hydroxynorfluorocurarine (56)
Tubotaiwine (57)
Tubotaiwine N-oxide (58)
N(4)-Chloromethyltubotaiwine chloride (59)
Venoterpine (60)
Syringaresinol (61)

K. pauciflora Stem-bark Leuconoxine (14)
(Plant) Rhazinilam (25)
Compound 63 [New]
Compound 64 [New]
(+)-Eburnamonine (29)
(+)-Eburnamenine (30)
(+)-Isoeburnamine (33)
()-Eburnamine (34)
19-Oxoeburnamine (66)
()-19(R)-Hydroxyisoeburnamine (67)
()-19(R)-Hydroxyeburnamine (68)
Tetrahydroalstonine (43)
11,12-Dimethoxykopsinaline (77) [New]
Pseudokopsinine (78)
Kopsinine (79)
Kopsamine (80)
N(1)-Decarbomethoxykopsamine (81)
Kopsilongine (82)
Paucifinine (83)
Kopsanone (84)
11,12-Methylenedioxykopsine (85)
Kopsifine (87)
N(1)-Decarbomethoxykopsifine (88)
Methyl 11,12-methylenedioxy-N(1)-decarbomethoxy-
chanofruticosinate (95)
Methyl 11,12-methylenedioxychanofruticosinate (96)
()-Norpleiomutine (100)

Leaves Compound 62 [New]
Leuconoxine (14)
Leuconodine F (6-oxoleuconoxine) (15)
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Table, continued
Plant Plant part Alkaloid
Mersicarpine (16)
Leuconolam (19)
Rhazinilam (25)
Compound 63 [New]
Larutenine (65)
Compound 69 [New]
Compound 70 [New]
Compound 71 [New]
()-Catharinensine (72)
Tetrahydroalstonine pseudoindoxyl (73) [New]
Tetrahydroalstonine (43)
16(R)-19,20-E-Isositsirikine (47)
()-Aspidospermidine (74)
()-1,2-Dehydroaspidospermidine (75)
()-Quebrachamine (76)
Pseudokopsinine (78)
Kopsinine (79)
N(1)-Decarbomethoxykopsamine (81)
Paucifinine (83)
11,12-Methylenedioxykopsine (85)
12-Methoxykopsine (86)
Akuammicine (89)
Andransinine (90) [New]
Compound 91 [New]
Condylocarpine (92)
Precondylocarpine (93)
Stemmadenine (94)
Methyl 11,12-methylenedioxy-N(1)-decarbomethoxy-
chanofruticosinate (95)
Methyl 11,12-methylenedioxychanofruticosinate (96)
Methyl chanofruticosinate (97)
Methyl N(1)-decarbomethoxychanofruticosinate (98)
Methyl 12-methoxychanofruticosinate (99)

Penicillium sp. Culture broth Compound 101 [New]
(CDA p48.3) Compound 102 [New]
(Fungi) Compound 103 [New]
Variotin (104)
Viriditin (105)
cyclo (L-Phenylalanine-trans-4-hydroxy-L-proline) (106)
cyclo (L-Leucine-trans-4-hydroxy-L-proline) (107)

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Acknowledgements

First and foremost, I would like to express my deepest gratitude to my supervisor,
Professor Dr. Kam Toh Seok, for his invaluable guidance and support throughout my
study in the University of Malaya. I would also like to thank my co-supervisor,
Associate Professor Dr. Geok Yuan Annie Tan from the Institute of Biological
Sciences, University of Malaya, for her help and advice. I would also like to extend my
sincere thanks to our collaborator, Professor Dr. Noorlidah binti Abdullah, from the
Institute of Biological Sciences, University of Malaya.

I also wish to convey my appreciation to all my colleagues in the laboratory. I am
particularly thankful to Ms. Lim Siew Huah for her continuous support and
encouragement, and Mr. Low Yun Yee for performing the X-ray diffraction analysis. I
would also like to thank my former colleagues, Dr. Lim Kuan Hon and Dr. Tan Shin
Jowl, for their support and advice during the first year of my graduate studies. The staff
of the Department of Chemistry, University of Malaya are also greatly appreciated for
their assistance.

Last but not least, warmest thanks to my family and dear ones whose patience, support,
and understanding allowed me to complete this thesis.

Financial support from the University of Malaya is gratefully acknowledged.

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Contents

Abstract ii
Abstrak (Versi Bahasa Malaysia) iv
Acknowledgements ix
List of Figures xviii
List of Tables xxvii
List of Schemes xxxiv
Chapter One 1
1 Introduction 1
1.1 General 1
1.2 The Alkaloids 3
1.3 Indole Alkaloids of the Apocynaceae 6
1.3.1 General 6
1.3.2 Classification of the Indole Alkaloids 7
1.4 The Genus Leuconotis 11
1.4.1 General 11
1.4.2 Alkaloids of the Genus Leuconotis 12
1.4.3 Occurrence and Distribution of Alkaloids in the Genus Leuconotis 12

x