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Isolation and Structure Elucidation of Secondary Metabolites from
Endophytic Fungi and the Plant Prismatomeris tetrandra and Synthesis of
(+)-Ochromycinone
Die vom Department Chemie
der Fakultät für Naturwissenschaften
der Universität Paderborn
zur Erlangung des Grades eines
Doktors der Naturwissenschaften
-Dr. rer. nat.-
genehmigte Dissertation
von
Md. Hossain Sohrab
aus Comilla, Bangladesh
Paderborn 2005
Eingereicht am: 29.06.2005
Mündliche Prüfung: 15.07.2005
1. Referent: Prof. Dr. Karsten Krohn
2. Referent: Prof. Dr. Bernhard Westermann
The present study was carried out from August 2001 to March 2005 in the ‘Department
Organische Chemie der Fakultät Naturwissenschaften der Universität Paderborn’ under the
supervision of Prof. Dr. Karsten Krohn.
• I am extremely grateful to Prof. Dr. Karsten Krohn, who gave me the opportunity to work
with this interesting theme and also enriched it with valuable comments and suggestions.
He also very kindly provided the necessary support in all phases of this study.
• I wish to express my gratitude to Prof. Dr. Bernhard Westermann, who gave his kind
consent for being the second referee.
• This study involved many different specific tasks, which were performed in cooperation.
For this, thanks go to Prof. Dr. H.–J. Aust and all members of his group, especially to PD
Dr. B. Schulz for the study related to endophytic fungi; to Prof. Dr. Marsmann, PD Dr. H.
Egold, Dr. D. Gehle, and Ms. K. Stolte for recording NMR spectra; to Mr. Jonk and Ms.
M. Zukowski for mass spectral measurements; to Dr. U. Flörke for performing the single
crystal X-ray analysis; to Ms. C. Neuhaus for help with chiral HPLC; to Dr. T. Kurtán
who recorded and helped to prepare the discussion on CD spectra; and to Mr. J. Vetter
who provided technical assistance.
• I would like to thank Prof. Dr. van Ree who went through the entire dissertation and
helped to minimize the errors.
• I would also like to thank all of my colleagues of the ‘Department Organische Chemie’ for
the many helpful suggestions, especially Dr. K. Steingröver, Dr. B. Elsässer, Dr. M. Riaz,
Ms. A. L. -Risse and Mr. M. Al Sahli. I have no word to express my sincere thanks for
Mr. Ishtiaq Ahmed and Dr. H. Hussain, who helped me as members of my family.
• I am grateful to Dr. J. Vitz who helped me to prepare the dissertation.
• I wish to express my gratitude to Prof. Dr. C. M. Hasan and Prof. Dr. M. A. Rashid for
their many valuable suggestions and constant inspiration.
• I am extremely grateful to all of my family members, to my mother-in-law Prof. Dr.
Nilufar Nahar, and also to my two sisters-in-law for their enthusiasm and prayerful
concerns. Especially, I am much indebted to my parents for their encouragement and
being totally supportive of me throughout my studies. Finally, I wish to express my
heartiest gratitude to my wife Farhana Rob Shampa and my two sons M. M. Farhan
Saleheen Hossain and M. M. Faizan Hossain for their understanding and endurance.
• Leave with pay from BCSIR is highly acknowledged.
Dedicated to my
Family
Table of Contents
Table of Contents
1 Introduction .................................................................................................................... 1
1.1 Need for new leads from natural products ....................................................................... 1
1.2 The influence of natural products upon drug discovery................................................... 2
1.2.1 Plants: a source of biologically active secondary metabolites ......................................... 4
1.2.2 Fungi: a source of biologically active secondary metabolites.......................................... 5
1.3 Antibiotics ...................................................................................................................... 12
1.3.1 Angucycline antibiotics.................................................................................................. 14
1.4 Peptic ulcers and Helicobacter pylori ............................................................................ 20
1.4.1 Ochromycinone (22) and YM-181741 (25): two selective anti-H. pylori agents .......... 23
1.5 Known syntheses of ochromycinone (22)...................................................................... 24
1.6 Present study: Aim and Scope........................................................................................ 26
2 Results and discussion: metabolites from fungi ........................................................ 28
2.1 Strain 5681 .................................................................................................................... 28
2.1.1 Isolation of secondary metabolites................................................................................. 28
2.1.2 Structure elucidation ...................................................................................................... 30
2.1.3 Biological activity of the secondary metabolites ........................................................... 43
2.2 Strain 6744 .................................................................................................................... 45
2.2.1 Isolation of the secondary metabolites ........................................................................... 46
2.2.2 Structure elucidation ...................................................................................................... 47
2.2.3 Biological activity of the secondary metabolites ........................................................... 61
2.3 Strain 6760 .................................................................................................................... 61
2.3.1 Isolation of secondary metabolites................................................................................. 61
2.3.2 Structure elucidation ...................................................................................................... 62
2.3.3 Biological activity of the secondary metabolites ........................................................... 67
3 Results and discussion: metabolites from the plant Prismatomeris tetrandra......... 69
3.1 Prismatomeris tetrandra (Roxb) K. Schum................................................................... 69
3.1.1 Isolation of secondary metabolites................................................................................. 70
3.1.2 Structure elucidation ...................................................................................................... 70
4 Determination of the Absolute Configuration by the Exciton Chirality Method .. 76
4.1 Introduction .................................................................................................................... 76
4.2 Exciton chirality method: basic principles ..................................................................... 76
4.2.1 Exciton coupling between identical chromophores ....................................................... 77
Table of Contents
4.3 Determination of the absolute configuration of 6744-5 ................................................. 78
4.4 Determination of the absolute configuration of 6744-6 ................................................. 80
5 Results and discussion: synthetic part........................................................................ 82
5.1 Synthesis of (+)-ochromycinone .................................................................................... 82
5.1.1 Retrosynthesis ................................................................................................................ 82
5.1.2 Results and discussion.................................................................................................... 83
6 Summary ....................................................................................................................... 90
7 Experimental part ........................................................................................................ 94
7.1 General methods and Instrumentation ...................................................................... 94
7.2 Microbiological work ................................................................................................... 95
7.3 Experimental part: Isolation of Natural Products .................................................... 96
7.3.1 Metabolites from Strain 5681......................................................................................... 96
7.3.2 Metabolites from Strain 6744....................................................................................... 108
7.3.3 Metabolites from Strain 6760....................................................................................... 118
7.3.4 Metabolites from Prismatomeris tetrandra.................................................................. 121
7.4 Experimental part: Synthesis of (+)-Ochromycinone (22) ..................................... 125
8 Abbreviations.............................................................................................................. 133
9 References ................................................................................................................... 135
1 Introduction 1
1 Introduction
Disease causing microbes that have become resistant to drug therapy are an increasing public
health problem. In spite of the availability of effective drugs and vaccines, the battle against
infectious diseases is far from over. Not only do they continue to cause a large number of
infections and deaths, particularly in developing countries, but the emergence and spread of
antimicrobial resistance is now threatening to undermine our ability to treat infections and save
lives.
Respiratory infections, HIV/AIDS, diarrhoeal diseases, tuberculosis, and malaria are the leading
killers among the infectious diseases. Resistance to first-line drugs has been observed in all these
diseases. In some cases, the level of resistance has forced a change to more expensive second- or
third-line agents. When resistance against these drugs also emerges, the world will run out of
treatment options.
Antibiotic resistance is inevitable, but there are measures we can take to slow it down. Efforts are
under way on several fronts - improving infection control, developing new antibiotics, and using
drugs more appropriately.
1.1 Need for new leads from natural products
There is a general call for new antibiotics, chemotherapeutic agents, and agrochemicals that are
highly effective, possess low toxicity, and will have a minor environmental impact, respectively.
This search is driven by the development of resistance in infectious microorganisms (e.g.,
Staphylococcus, Mycobacterium, Streptococcus) to existing drugs and by the menacing presence
of naturally resistant organisms.[1] The ingress into the human population of new disease-causing
agents such as AIDS, Ebola, and SARS requires the discovery and development of new drugs to
combat them. Not only do diseases such as AIDS require drugs that target them specifically, but
new therapies are needed for treating ancillary infections which are a consequence of a weakened
immune system. Furthermore, patients who are immunocompromised (e.g., cancer and organ
transplant patients) are at risk of infection by opportunistic pathogens, such as Aspergillus,
Cryptococcus, and Candida, that normally are not major problems in the human population.[1] In
addition, more drugs are needed to efficiently treat parasitic protozoan and nematodal infections
1 Introduction 2
such as malaria, leishmaniasis, trypanosomiasis, and filariasis. Malaria, by itself, is more
effective in claiming lives each year than any other single infectious agent with the exception of
AIDS and TB.[2] However, the enteric diseases claim the most lives each year of any other
disease complex, and unfortunately, the victims are mostly children.[2]
Finally, because of safety and environmental problems, many synthetic agricultural agents have
been and currently are being targeted for removal from the market, which creates a need to find
alternative ways to control farm pests and pathogens.[3] Natural products and the organisms that
make them continue to offer opportunities for innovation in drug and agrochemical discovery.
1.2 The influence of natural products upon drug discovery
Throughout the ages humans have relied on nature for their basic needs for the production of
foodstuffs, shelter, clothing, means of transportation, fertilizers, flavours and fragrances, and,
not least, medicines. Nature has been a source of several medicines for treating various types of
diseases in humans and animals for many years.[4]
Natural products are naturally derived metabolites and/or byproducts from microorganisms,
plants, or animals.[5] These products still play a major role in drug treatment either as the drug, or
as a ‘forebear’ in the synthesis or design of the agent.[6] The world’s best known and most
universally used medicinal agent is aspirin, which is related to salicin, having its origins in the
plant genera Salix sp. and Populus sp.[1] Examples abound of natural product use, especially in
small native populations in a myriad of remote locations on Earth. For instance, certain tribal
groups in the Amazon basin, the highland peoples of Papua New Guinea, and the Aborigines of
Australia each have identified certain plants to provide relief of symptoms varying from head
colds to massive wounds and intestinal ailments.[7]
Even with untold centuries of human experience behind us, and a movement into a modern era of
chemistry and automation, it is still evident that natural product-based compounds have had an
immense impact on modern medicine. For instance, about 40% of prescription drugs are based
on them. Furthermore, well over 50% of the new chemical products registered by the FDA as
anticancer agents, antimigraine agents, and antihypertensive agents were natural products or
derivatives thereof in the time-frame of 1981-2002.[8] Excluding biologics, between 1989 and
1995, 60% of approved drugs and pre-new drug application candidates were of natural origin.[9]
1 Introduction 3
From 1983 to 1994, over 60% of all approved and pre-NDA stage cancer drugs were of natural
origin, as were 78% of all newly approved antibacterial agents.[10] At least 21 natural product and
natural product-derived drugs have been launched onto the market in the United States, Europe
or Japan since 1998 and there are many natural product-derived compounds in Phase III or
registration that may be launched in 2005 and 2006.[11] Many other examples abound that
illustrate the value and importance of natural products from plants and microorganisms in
modern civilization, and paclitaxel (1, Taxol) is the most recent example of an important natural
product that has made an enormous impact on medicine (Figure 1).[12,13] It interacts with tubulin
during the mitotic phase of the cell cycle, and thus prevents the disassembly of the microtubules
and thereby interrupts the cell division.[14] The original target diseases for this compound were
ovarian and breast cancers, but now it is used to treat a number of other human tissue-
proliferating diseases as well.[1]
O
O O OH
O
NH O
O
O H
HO O O
OH
O
O
1
Figure 1: Paclitaxel (1)
In recent years a renewed interest in obtaining biologically active compounds from natural
sources has been observed, notwithstanding the impressive progress of new competing
methodologies, as for example, combinatorial chemistry and high throughput screening or
genetic engineering. Contributing to this world-wide attention towards formulations based on
natural products, are their low or absent toxicity, their complete biodegradability, their
availability from renewable sources, and, in most cases, their low cost when compared with those
of compounds obtained by total chemical synthesis.[15]
1 Introduction 4
1.2.1 Plants: a source of biologically active secondary metabolites
Plants have formed the basis for traditional medicine systems which have been used for
thousands of years in countries such as China[16] and India.[17,18] The use of plants in the
traditional medicine of many other cultures has been extensively documented.[19] These plant-
based systems continue to play an essential role in health care, and it has been estimated by the
World Health Organization that approximately 80% of the world’s inhabitants rely mainly on
traditional medicines for their primary health care.[20,21] Plant products also play an important
role in the health care systems of the remaining 20% of the population, mainly residing in
developed countries. In a study it has been shown that at least 119 chemical substances, derived
from 90 plant species, can be considered as important drugs that are in use in one or more
countries.[20] Of these 119 drugs, 74% were discovered as a result of chemical studies directed at
the isolation of the active substances from plants used in traditional medicine.
Examples of traditional medicine providing leads to bioactive natural products abound. Suffice it
to point to some recent confirmations of the wealth of this resource. Artemisinine (qinghaosu) (2,
Figure 2) is the antimalarial sesquiterpene from a Chinese medicinal herb Artemisia annua
(Wormwood) used in herbal remedies since ancient times.[22,23] Forskolin (3, Figure 2) is the
antihypertensive agent from Coleus forskohlii Briq. (Labiatae), a plant whose use was described
in ancient Hindu Ayurvedic texts.[24,25]
H O
OH
O O
O
O OH
H
O OCOCH3
H
OH
O
2 3
Figure 2: Artemisinin (2) and forskolin (3)
The ginkgo tree, mentioned in Chinese medicinal books from 2800 B.C. and used in
antiasthmatic and antitussive preparations, produces the ginkgolides (e.g. 4, Figure 3), unusual
diterpenes containing a tertiary butyl group. Their involvement in the clinical efficacy of ginkgo
tree extracts was reported in 1985.[26] Castanospermine (5, Figure 3), a tetrahydroxyindolizidine
alkaloid isolated from the Australian plant Castanospermum australe, inhibits replication of the
human immunodeficiency virus (HIV).[27]
1 Introduction 5
O
OH
HO O
H HO OH
H
O O
OH O H H
t-Bu
H3C H N OH
H OH H
O O
4 5
Figure 3: A ginkgolide (4) and castanospermine (5)
A case of serendipity is the discovery of the so-called vinca alkaloids, vincristine (6) and
vinblastine (7), in Catharanthus roseus. A random screening programme (conducted at Eli Lilly
and Company) of plants with antineoplastic activity found these anticancer agents in the 40th of
200 plants examined. Ethnomedicinal information attributed an anorexigenic effect (i.e. causing
anorexia) to an infusion from the plant.[26,28]
HO
N
N
H
N
H CO2CH3 OH
H3CO N OAc
H
R CO2CH3
6 R = CHO
7 R = CH3
Figure 4: Vincristine (6) and vinblastine (7)
Taxol (1, Figure 1), the world’s first billion-dollar anticancer drug, is found in each of the
world’s yew (Taxus) species, but was originally isolated from Taxus brevifolia.[1,12,29]
1.2.2 Fungi: a source of biologically active secondary metabolites
Fungi are a diverse and valuable resource for the discovery of novel beneficial natural products.
The chemical potential of fungi is enormous and new approaches need to be devised to
efficiently access this genetic and chemical diversity for the development of new medicines.
Fungi have been studied for more than 70 years due to the pharmaceutical potential of their
secondary metabolites. The search for new drugs from fungi started with the discovery of
penicillin, a potent antibiotic active against Gram-positive bacteria, by Fleming from Penicillium
1 Introduction 6
notatum in 1928 and reported in the British medical literature in 1929.[30] An excellent reprint has
also been issued on ‘History of Penicillin Production’[31] and that publication goes into the story
in detail from the aspect of large scale production of penicillin G (8) and penicillin V (9) (Figure
5).
O H H O H H
S S
CH3 O CH3
N N
H N CH3 H N CH3
O O
COOH COOH
8 9
Figure 5: Penicillin G (8) and penicillin V (9)
A screen designed to find metabolites from microorganisms active against parasitic infections
resulted in the detection and isolation of the avermectins, (e.g., avermectin1a 10, Figure 6). The
producer organism Streptomyces avermitilis MA-4680 is a soil isolate.[32,33]
OCH3
HO OCH3
O CH3
H
H3C O O O
H
H3C O H
H H
H3C CH3
O O
OH H
O
CH3
H
OCH3
10
Figure 6: Avermectin1a (10)
Cyclosporin A, a nonpolar cyclic undecapeptide, was isolated from the extract of a soilborne
fungus Tolyplocladium inflatum (formerly Trichoderma polysporum). It was isolated in 1973 and
has since become the prototype of a new generation of immunosuppressants that is used in organ
transplantation surgery.[34-36] The antifungal agent ‘griseofulvin’ from Penicillium
griseofulvum[37] and the cholesterol biosynthesis inhibitor ‘lovastatin’ from Aspergillus terreus[38]
are two further examples of important fungal metabolites.
Considering that 6 out of 20 of the most commonly prescribed medications are of fungal
origin[39] and only ~ 5% of the fungi have been described,[40,41] fungi offer an enormous potential
1 Introduction 7
for new products. Most fungi studied to date have been isolated from soil and were proven to
have a high creative index, i.e. new and interesting secondary metabolites could be isolated.
Genera such as Aspergillus, Penicillium, Acremonium, Fusarium, all typical soil isolates, are
known for their ability to synthesize diverse chemical structures. Dreyfuss, however, described a
problem which is often encountered during microbiological screening of fungal isolates for their
content of secondary metabolites.[42] Increasingly, known metabolites are rediscovered making
screening programmes less efficient. This may be due to the use of the same well-established
isolation methods for fungi. Thus, often the same fungal strains are reisolated and this could also
result in the rediscovery of known compounds as the same taxa produce the same metabolites
with high coincidence.[43]
According to Schulz et al.,[44] in optimizing the search for new bioactive secondary metabolites,
it is relevant to consider that: (1) the secondary metabolites a fungus synthesizes may correspond
with its respective ecological niche, e.g. the mycotoxins of plant pathogens;[39] and (2) that
metabolic interactions may enhance the synthesis of secondary metabolites. Thus, the fungi
screened should originate from biotopes from which fungi have not been previously isolated for
biochemical purposes and they should have metabolic interactions with their environment. This
is an example of intelligent screening and is a strategy for exploiting the untapped potential for
secondary metabolites that fungi offer. Endophytic fungi are one source for intelligent screening
and fulfil both criteria.
1.2.2.1 Endophytic fungi: a source of biologically active secondary metabolites
Endophytic microorganisms are to be found in virtually every plant on earth. These organisms
reside in the living tissues of the host plant and do so in a variety of relationships ranging from
symbiotic to pathogenic. Since the discovery of endophytes in Darnel, Germany, in 1904, various
investigators have defined endophytes in different ways, usually dependent on the perspective
from which the endophytes were being isolated and subsequently examined.[45] Bacon et al. give
an inclusive and widely accepted definition of endophytes: “microbes that colonize living,
internal tissues of plants without causing any immediate, overt negative effects”.[46] While the
symptomless nature of endophyte occupation in plant tissue has prompted focus on symbiotic or
mutualistic relationships between endophytes and their hosts, the observed biodiversity of
endophytes suggests they can also be aggressive saprophytes or opportunistic pathogens.[1]
1 Introduction 8
The most frequently isolated endophytes are the fungi. Dreyfuss and Chapela estimate there may
be at least 1 million species of endophytic fungi alone.[47] They grow within their plant hosts
without causing apparent disease symptoms[48,49] and growth in this habitat involves continual
metabolic interaction between fungus and host and consequently should produce more secondary
metabolites.[50] Tan and Zou pointed out that, in comparison to fungal plant pathogens and fungal
soil isolates, relatively few secondary metabolites have been isolated from endophytic fungi.[45]
Currently, endophytic fungi are viewed as an outstanding source of bioactive natural products
because there are so many of them occupying literally millions of unique biological niches
(higher plants) growing in so many unusual environments. Of the approximately 300 000 higher
plant species that exist on the earth, each individual plant, of the millions that exist here, is host
to one or more endophytes.[1] It seems obvious that they are a rich and reliable source of genetic
diversity and may represent previously undescribed species. Finally, novel microbes (as defined
at the morphological and/or molecular levels) often have associated with them novel natural
products. This fact alone helps eliminate the problems of dereplication in compound discovery.
In addition, it is worthy of note that some plants generating bioactive natural products have
associated endophytes that produce the same natural products. This is the case with paclitaxel (1,
Figure 1), a highly functionalized diterpenoid and famed anticancer agent that is found in each of
the world’s yew tree species (Taxus spp.).[29] In 1993, a novel paclitaxel-producing fungus,
Taxomyces andreanae, from the yew Taxus brevifolia was isolated and characterized.[51] The
concept, that was proposed as a mechanism to explain why T. andreanae may be producing
paclitaxel, is that some endophytes produce certain phytochemicals, originally characteristic of
the host, might be related to a genetic recombination of the endophyte with the host that occurred
in evolutionary time.[45,52] Thus, if endophytes can produce the same rare and important bioactive
compounds as their host plants, this would not only reduce the need to harvest slow-growing and
possibly rare plants but also help to preserve the world’s ever-diminishing biodiversity.
Furthermore, it is recognized that a microbial source of a high value product may be easier and
more economical to produce effectively, thereby reducing its market price.
Quite commonly, endophytes do produce secondary metabolites when placed in culture.
However, the temperature, the composition of the medium, and the degree of aeration will affect
the amount and kinds of compounds that are produced by an endophytic fungus.[1] Sometimes
endophytic fungi produce antibiotics. Natural products from endophytic fungi have been
observed to inhibit or kill a wide variety of harmful microorganisms including, but not limited to,
1 Introduction 9
phytopathogens, as well as bacteria, fungi, viruses, and protozoans that affect humans and
animals.[1]
Tan and Zou recently reviewed the diversity of metabolites that have been isolated from
endophytic fungi emphasizing their potential ecological role.[45] These secondary metabolites of
endophytes are synthesized via various metabolic pathways,[45] e.g. polyketide, isoprenoid, or
amino acid derivation, and belong to diverse structural groups, i.e. steroids, xanthones, phenols,
isocoumarins, perylene derivatives, quinines, furandiones, terpenoids, depsipeptides, and
cytochalasines.[53-67] Some of them represent novel structural groups, for example the
palmarumycins[62,63] and benzopyranone.[68] Endophytes may contribute to their host plant by
producing this plethora of substances to provide protection and ultimately survival value to the
plant. Ultimately, these compounds, once isolated and characterized, may also have potential for
use in modern medicine, agriculture, and industry. Described below are some examples of
bioactive products from endophytic fungi and their potential in the pharmaceutical and
agrochemical arenas.
Cryptocandin A (11), an antifungal lipopeptide, was isolated and characterized from the
endophytic fungus Cryptosporiopsis quercina.[69] This compound contains a number of unusual
hydroxylated amino acids and a novel amino acid, 3-hydroxy-4-hydroxymethylproline (Figure
7). Cryptocandin A is active against some important human fungal pathogens including Candida
albicans and Trichophyton sp. and also against a number of plant pathogenic fungi including
Sclerotinia sclerotiorum and Botrytis cinerea.[1] Cryptocin (12), a tetramic acid antifungal
compound was also obtained from C. quercina (Figure 7).[70] This unusual compound possesses
potent activity against Pyricularia oryzae, the casual organism of one of the worst plant diseases
in the world, as well as a number of other plant pathogenic fungi.[70]
1 Introduction 10
OH
HO
CH3
O O O
H N H OH
N
H2N N OH O
H
HO O N CH3
H CH3
N O O O
O CH3
HO O
OH
N H3C
HN H OH H
OH NH
O
(CH2)14
11 12
Figure 7: Cryptocandin A (11) and cryptocin (12)
Ambuic acid (13), a highly functionalized cyclohexenone possessing antifungal activity,
produced by a number of isolates of the endophytic fungus Pestalotiopsis microspora found in
rainforests around the world (Figure 8).[71] A strain of P. microspora, isolated from the tree
Torreya taxifolia, produces several compounds having antifungal activity including the
glucosylated aromatic compound pestaloside (14) (Figure 8).[72]
HO
CH3
O H H O
HO
H3C COOH HO O
O OH
H
H3C OH
H HH
OH OH
OH
13 14
Figure 8: Ambuic acid (13) and pestaloside (14)
Pestalotiopsis jesteri is a newly described endophytic fungal species from the Septik river area of
Papua New Guinea, and it produces the highly functionalized cyclohexenone epoxides jesterone
(15, Figure 9) and hydroxyjesterone, which exhibit antifungal activity against a variety of plant
pathogenic fungi.[73] Torreyanic acid (16), a selectively cytotoxic quinone dimmer and potential
anticancer agent, was isolated from a P. microspora strain (Figure 9).[74]
1 Introduction 11
HO2C
O
CH3
CH3 O O
O H H O CH3
HO2C H
O O
O H
H O O
HO H H
H
15 H3C
16
Figure 9: Jesterone (15) and torreyanic acid (16)
The distribution of the endophytic fungi making paclitaxel (1) is worldwide and is not confined
to endophytes of yew (Taxus) species. The ecological and physiological explanation for the wide
distribution of fungi making paclitaxel seems to be related to the fact that paclitaxel is a
fungicide, and the most sensitive organisms to it are plant pathogens such as Pythium sp. and
Phytophthora sp.[75] These pythiaceous organisms are among the world’s most important plant
pathogens and are strong competitors with endophytic fungi for niches within plants.
Pestacin (17) and isopestacin (18) (F


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