Part F | 32.2
760 Part F Marine Derived Metabolites
to have the potential for the development of drugs
or drug leads from various marine invertebrates including sponges, ascidians, and soft corals. However,
the sustainable and sufficient supply of these substances to meet the demands of clinical trials and
the future market needs has been problematic and
opposed the development of further marine-inspired
pharmaceuticals.
Alternative production procedures and strategies,
such as total and/or partial chemical synthesis, or the
production of these natural compounds through microbial fermentation of endosymbionts associated with
the marine host organism have been developed and in
some cases they have successfully overcome the supply
problems [32.5]. Due to the aforementioned conditions,
relatively few marine secondary metabolites have entered preclinical or clinical trials compared to the huge
number of natural products reported from marine organisms with potential bioactivities [32.3, 4].
In this chapter, we will briefly survey the history
of marine-inspired pharmaceuticals and discuss marine-derived fungal metabolites according to chemical
classes. In addition, a future overview of marine-derived fungi is presented as an alternative to provide
a sustainable supply of lead compounds replacing other
production methods, such as aquafarming which mostly
failed to yield significant results contrary to earlier
expectations.
32.2 Drug Screening from Marine Organisms
In this section, we will provide in brief a historical background of marine-inspired pharmaceuticals and those
marine natural products that have successfully reached
preclinical or clinical trial phases.
32.2.1 US FDA-Approved Marine-Inspired
Pharmaceuticals
Bergman and Feeney succeeded in the early 1950s to
identify hitherto unprecedented nucleosides from the
marine sponge Tethya crypta [32.6, 7], which inspired
the first marine-derived pharmaceuticals Ara-C (cytarabine, Cytosar, Fig. 32.1) and Ara-A (vidarabine,
Vira-A). Both were approved by the FDA as anticancer
and antiviral drugs, respectively [32.8]. However, the
latter has been recently withdrawn from US market by
an executive FDA decision in 2001, probably due to
its diminished therapeutic window compared to other
antivirals [32.3].
In 1987, zidovudine was the first reverse transcriptase (RT) antagonist approved by the FDA
for the treatment of human immunodeficiency virus
(HIV)/aquired immuno deficiency syndrom (AIDS) under the trade name Retrovir (Fig. 32.1) [32.9]. Zidovudine is structurally a 3
0 -azido, 3
0 -deoxy derivative of
2
0 -deoxythymidine, which was first reported from the
starfish Acanthaster planci in 1980 [32.10, 11]. In the
mid-1990s, other derivatives were also developed and
approved by the FDA, such as lamivudine (Epivir)
and stavudine (Zerit), which were approved as RT
antagonists for HIV/AIDS and the hepatitis B virus
(HBV) [32.12, 13].
Afterwards, it took about a decade to introduce the
next marine-based pharmaceutical, ziconotide, which
received FDA approval in December 2004. Ziconotide
is the synthetic form of the naturally-occurring peptide
!-conotoxin MVIIA, which was first isolated from the
Pacific piscivorous marine cone snail Conus magus by
Olivera and co-workers in 1979 [32.14]. It took more
than two decades of research and development to get ziconotide launched, under the brand name Prialt, as the
first marine-inspired pharmaceutical for the specific indication of severe chronic pain (Fig. 32.1) [32.15].
Later, in July 2007, trabectedin, the synthetic form
of ecteinascidin-743 isolated from the marine tunicate
Ecteinascidia turbinata, was approved by the Committee for the Evaluation of Medicinal Products from
the European Medicines Agency (EMEA) for the treatment of refractory soft tissue sarcoma and ovarian
cancer [32.16]. To fulfill the supply needs during the
clinical trial phases and the market needs thereafter,
different strategies were evaluated, such as aquaculture and chemical synthesis [32.17, 18]. However, no
promising outcomes have been achieved from either of
them, but a breakthrough took place when PharmaMar,
the license holder of trabectedin (ET-743), managed
to develop a large-scale semisynthetic protocol starting
with cyanosafracin B, an antibiotic produced on multikilogram scale by Pseudomonas fluorescens [32.19].
Recently, on November 15th, 2010, eribulin mesylate (E7389), a fully synthetic ketone analog
of the polyether marine macrolide halichondrin B
first isolated from the marine sponge Halichondria
okadai [32.20, 21], was approved by the FDA for use
760 Part F Marine Derived Metabolites
to have the potential for the development of drugs
or drug leads from various marine invertebrates including sponges, ascidians, and soft corals. However,
the sustainable and sufficient supply of these substances to meet the demands of clinical trials and
the future market needs has been problematic and
opposed the development of further marine-inspired
pharmaceuticals.
Alternative production procedures and strategies,
such as total and/or partial chemical synthesis, or the
production of these natural compounds through microbial fermentation of endosymbionts associated with
the marine host organism have been developed and in
some cases they have successfully overcome the supply
problems [32.5]. Due to the aforementioned conditions,
relatively few marine secondary metabolites have entered preclinical or clinical trials compared to the huge
number of natural products reported from marine organisms with potential bioactivities [32.3, 4].
In this chapter, we will briefly survey the history
of marine-inspired pharmaceuticals and discuss marine-derived fungal metabolites according to chemical
classes. In addition, a future overview of marine-derived fungi is presented as an alternative to provide
a sustainable supply of lead compounds replacing other
production methods, such as aquafarming which mostly
failed to yield significant results contrary to earlier
expectations.
32.2 Drug Screening from Marine Organisms
In this section, we will provide in brief a historical background of marine-inspired pharmaceuticals and those
marine natural products that have successfully reached
preclinical or clinical trial phases.
32.2.1 US FDA-Approved Marine-Inspired
Pharmaceuticals
Bergman and Feeney succeeded in the early 1950s to
identify hitherto unprecedented nucleosides from the
marine sponge Tethya crypta [32.6, 7], which inspired
the first marine-derived pharmaceuticals Ara-C (cytarabine, Cytosar, Fig. 32.1) and Ara-A (vidarabine,
Vira-A). Both were approved by the FDA as anticancer
and antiviral drugs, respectively [32.8]. However, the
latter has been recently withdrawn from US market by
an executive FDA decision in 2001, probably due to
its diminished therapeutic window compared to other
antivirals [32.3].
In 1987, zidovudine was the first reverse transcriptase (RT) antagonist approved by the FDA
for the treatment of human immunodeficiency virus
(HIV)/aquired immuno deficiency syndrom (AIDS) under the trade name Retrovir (Fig. 32.1) [32.9]. Zidovudine is structurally a 3
0 -azido, 3
0 -deoxy derivative of
2
0 -deoxythymidine, which was first reported from the
starfish Acanthaster planci in 1980 [32.10, 11]. In the
mid-1990s, other derivatives were also developed and
approved by the FDA, such as lamivudine (Epivir)
and stavudine (Zerit), which were approved as RT
antagonists for HIV/AIDS and the hepatitis B virus
(HBV) [32.12, 13].
Afterwards, it took about a decade to introduce the
next marine-based pharmaceutical, ziconotide, which
received FDA approval in December 2004. Ziconotide
is the synthetic form of the naturally-occurring peptide
!-conotoxin MVIIA, which was first isolated from the
Pacific piscivorous marine cone snail Conus magus by
Olivera and co-workers in 1979 [32.14]. It took more
than two decades of research and development to get ziconotide launched, under the brand name Prialt, as the
first marine-inspired pharmaceutical for the specific indication of severe chronic pain (Fig. 32.1) [32.15].
Later, in July 2007, trabectedin, the synthetic form
of ecteinascidin-743 isolated from the marine tunicate
Ecteinascidia turbinata, was approved by the Committee for the Evaluation of Medicinal Products from
the European Medicines Agency (EMEA) for the treatment of refractory soft tissue sarcoma and ovarian
cancer [32.16]. To fulfill the supply needs during the
clinical trial phases and the market needs thereafter,
different strategies were evaluated, such as aquaculture and chemical synthesis [32.17, 18]. However, no
promising outcomes have been achieved from either of
them, but a breakthrough took place when PharmaMar,
the license holder of trabectedin (ET-743), managed
to develop a large-scale semisynthetic protocol starting
with cyanosafracin B, an antibiotic produced on multikilogram scale by Pseudomonas fluorescens [32.19].
Recently, on November 15th, 2010, eribulin mesylate (E7389), a fully synthetic ketone analog
of the polyether marine macrolide halichondrin B
first isolated from the marine sponge Halichondria
okadai [32.20, 21], was approved by the FDA for use