Marine Biodiversity What Is It Good For ?

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Marine BiodiversityWhat Is It Good For ?
David J. Newman, D.Phil. Chief, Natural Products
Branch Developmental Therapeutics Program
Division of Cancer Treatment
Diagnosis NCI-Frederick, Frederick, MD, 21702,
USA 1.301.846.5397 Voice 1.301.846.6178
Facsimile Email dn22a_at_nih.gov
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Why Look There ?
A question that is very frequently asked is the
title of this short talk, and what I intend to
try to do in the next 15 or so minutes is to
show you what is going on from the perspective of
drug discovery in utilization of the marine
resources, meaning coral reefs, marine muds and
sessile invertebrates, but the emphasis as will
become apparent is on the organisms we cannot
see. Because of my background, the focus is on
cancer, but any of the materials may (will ?)
have utility in other diseases.
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Bryostatin 1 Modulates Protein Kinase C
Biosynthetic Source?

• Complex polyketide natural product
• Not very effective by itself in Phase II trials
• Was in Phase I and Phase II trials with
• other cytotoxic drug therapy (e.g.
• Vincristine) to melanoma, kidney
• cancer and lymphoma

Pettit,GR Fortschritte der Chemie organischer
Naturstoffe. 1991, 57, 153-195.
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Bryozoan-Bacterial Symbiosis Produces the
Anticancer Bryostatins (Haygood/Sherman)

• Pathway cloned
• with Sherman Lab
• Many novel
• biosynthetic
• aspects

• Symbiont is a novel gamma
• proteobacterium
• (by 16S rRNA)
• named Candidatus Endobugula sertula

• Not yet cultivated
• Found in almost all tested populations, adults
  and larvae (by PCR)

Haygood et al, Chem Biol 2005, 12, 397 Sherman et
al, J. Nat Prod 2007, 70, 67
In situ hybridization with symbiont specific
probe in larva
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Microbes and Tubulin Interactive Agents
Tubulin as a target has a relatively long
history, though not with agents from microbes
(though just wait until a little later). With
the discovery of the mechanism of action of
Taxol by Susan Horwitz in 1979, a new target
came into play for antitumor agents. The marine
environment in particular has yielded some
extremely interesting molecules that interact
with tubulin in a variety of ways and that
probably also involve microbes in their
biosynthesis.
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Potentially Microbial
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Some Microbial Involvement ?
May well be a new binding site
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Other Marine-Derived AgentsTubulin, Proteasome,
VDA and VoATPase
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Kishi Synthesis of Halichondrin B, 1992
1,2,3-butane triol Asymmetric carbons 2 Possible
stereoisomers 2n 22 4
Professor Yoshito Kishi Department of
Chemistry Harvard University

• Acyclic Stereochemistry Control
• Synthetic access to highly complex natural
  products
• New Ni/Cr-mediated coupling reaction to form C-C
  bonds
• Nozaki-Hiyama-Kishi reaction
• Why halichondrin B?
• Showcase Ni/Cr-mediated coupling
• Highly potent anticancer activity (Hirata
  Uemura, 1986) was added value
• Halichondrin B total synthesis
• Aicher TD, Buszek KR, Fang FG, Forsyth CJ, Jung
  SH, Kishi Y, Matelich MC, Scola PM, Spero DM,
  Yoon SK (1992) JACS 1143162-3164

• Total synthesis created an opportunity to develop
  halichondrin B-based drugs from renewable
  resources

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E7389 Synthetic Macrocyclic Ketone Analog of
Halichondrin Bs Right Half
Paclitaxel MW 854 11 stereocenters 2.5 nM
(MDA-MB-435)
Eribulin, E7389 NSC-707389 previously
ER-086526, B1939
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Piece de Resistance Seabed to Sickbed
The first Direct from the Sea drug to be
approved for Cancer Treatment. EMEA 20SEP07
Just about every technique used
large-scale harvesting, aquaculture and
semisynthesis from Cyanosafracin B
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You are what you eat
Dolabella auricularia Dolastatins come from a
Symploca species that they graze on
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Dolastatin 10 and a Synthetic Analogue
Dolastatin 10
Auristatin PE Phase I (II)
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Marine Sediments Nereus Pharmaceuticals
Marine Microbe Culture Collection Over
15,000 Strains50 Actinomycetes 10 New genera
discovered 50 Fungi
Sediment sampler
Fenical et al., Angew. Chem. Int. Ed., 42,
355-357 (2003)
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Salinosporamide Development Time Line
Preclinical Development (30 months)
Dec 2005 NPI-0052 IND Filed
2Q 2006 Phase I Solid Tumors and Lymphoma
2Q 2007 Phase I Multiple Myeloma
Preclinical models (in vitro/in vivo) API
manufacturing (saline fermentation) Formulation
development Drug product manufacturing Toxicology
DISCOVERY AND DEVELOPMENT OF NPI-0052, A NOVEL
PROTEASOME INHIBITOR FOR THE TREATEMENT OF CANCER
May 2003 FDA approves Velcade for treatment of
multiple myeloma, validating the proteasome as a
target for cancer treatment
June 2007 Total synthesis (Ling et al)
June 2005 Total synthesis (Danishefsky)
Oct 2002 Novel Marine actinomycete
Salinispora discovered (Mincer et al)
Mar 2006 X-Ray Crystal Structure in complex with
20S proteasome
May 2004 Total synthesis (EJ Corey)
Dec 2005 NPI-0052 efficacy in mouse multiple
myeloma xenograft models (Chauhan et al)
Nov 2006 NPI-0052 efficacy in mouse colon
cancer xenograft models (Cusack et al)
Feb 2003 NPI-0052 (Salinosporamide A)
structure, cytotoxicity and proteasome inhibitory
activity established (Feling et al)
Ray Lam, Nereus Pharma

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Imperial Purple and The Cell Cycle
Hexaplex trunculus (A) was extracted for Tyrian
purple (B), various brominated indirubins (14)
(C), and indigos. Oxime derivatives (58) and
N1-methylated analogs (911) of these indirubins
were synthesized, as well as the methoxime and
acetoxime of 6-bromoindirubin (12, 13).
6-bromoindirubin-3-oxime (BIO) (7) and its
control analog 1-methyl-6-bromoindirubin-3-oxime
(MeBIO) (11) were used in the biological models.
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Isolation of Indirubin-Binding ProteinsPotential
Anti-Alzheimers Treatment
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Cell Cycle and Natural Products
Modified from Meijer, 2003