Transcript Slide 1

Marine Biodiversity
What 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 [email protected]
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.
Bryostatin 1 Modulates Protein Kinase C
HO
OAc
H3COOC
O
O
O
OH
O
HO
O
Biosynthetic Source?
O
OH
O
COOCH3
Bryostatin 1 -Complex polyketide natural product
-Not very effective by itself in Phase II trials
-Was in Phase I and Phase II trials with
Pettit,GR Fortschritte der Chemie organischer
Naturstoffe. 1991, 57, 153-195.
other cytotoxic drug therapy (e.g.
Vincristine) to melanoma, kidney
cancer and lymphoma
Bryozoan-Bacterial Symbiosis Produces the
Anticancer Bryostatins (Haygood/Sherman)
• Symbiont is a novel gamma
proteobacterium
(by 16S rRNA)
– named “Candidatus
Endobugula sertula”
Haygood et al, Chem Biol 2005, 12, 397
Sherman et al, J. Nat Prod 2007, 70, 67
•
•
• Pathway
Not yet cultivated
Found in almost all
tested populations,
adults and larvae (by
PCR)
cloned
with Sherman Lab
• Many novel
biosynthetic
aspects
In situ hybridization with symbiont specific probe in larva
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.
Potentially Microbial
HO
O
HO
O
OH
O
O
O
OH
O
O
O
OH
NH2
OH
OH
NH2
DD4
Discodermolide
O
O
CH3 H
H
N
O
Me
Me
Me
N
CH3 H
H
OH
CO2Me
Me
N
Me
N
N CH
3
O
H
Me
Me
OH O
O
OH
AcO
O
H
Sarcodicytin [Sarcodictyon roseum]
N
O
O
O
Me
O
H
CH3 H
H
H3 C
CH3
OH
OCH3
COOCH3
Sarcorobin or Eleutherdyctin
Eleutherobin [Eleutherobia sp.]
Some Microbial Involvement ?
OH
H
HO
O
HO
O
H
H
O
OH
H
H
O
O
O
H
O
O HO
HO
O
O
O
H
H
HO
O
O
H
OH
O
O
Laulimalide
Isolaulimalide
May well be a new binding site
OH
HO
O
OH
OH
Dictyostatin
O
Peloruside A
O
Other Marine-Derived Agents
Tubulin, Proteasome, VDA and VoATPase
HN
H
N
N
N
Cl
OO
HO
HO
O
O
HO
Cl
HN
H
N
N
N
Cl
O
O O
O
O
O
NH
O
Original Diazonamide Structure
N
N
H
NH
OH
O
N
Cl
O
X
E-7974
"OXO"-analogue, X = O
Revised Diazonamide Structure, X = NH
H
N
OH
O
H
O
O
Cl
O
OH
NH
NH
HN
H
O
O
O
N
H
Salicylihalimide A
H
O
OH
H
Salinosporamide A
N
NPI-2358
OH
Kishi Synthesis of Halichondrin B,
1992
HO
H
CH2OH
Me
H
•
•
•
•
1,2,3-butane triol
Asymmetric carbons: 2
Possible stereoisomers: 2n = 22 = 4
OH
“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
114:3162-3164
Professor Yoshito Kishi
Department of Chemistry
Harvard University
Me
Me
H
O
H
O
H
O
H
O
H
HO
HO
H
O
O
H
O
H
H
H
O
O
O
O
H
O
O
Me
Me
HO
H
O
O
O
Halichondrin B
Asymmetric carbons: 32
Possible stereoisomers: 2n = 232 = 4.3 x 109
Total synthesis created an opportunity
to develop halichondrin B-based drugs
from renewable resources
E7389: Synthetic Macrocyclic Ketone
Analog of Halichondrin B’s “Right Half”
Me
Me
H
O
H
O
H
HO
HO
H
O
O
H
HO
H
O
O
H
H
O
H
O
O
O
O
H
H
O
O
Me
H
O
Me
Halichondrin B
O
O
MW = 1110
32 stereocenters
0.2 nM (MDA-MB-435)
~200 analogues
OMe
OH
H
H 2N
O
O
O
O
H
O
E7389
O
Me
O
H
O
O
MW = 730
19 stereocenters
0.1 nM (MDA-MB-435)
Eribulin, E7389 = NSC-707389
previously ER-086526, B1939
Paclitaxel
MW = 854
11 stereocenters
2.5 nM (MDA-MB-435)
“Piece de Resistance”; “Seabed to Sickbed”
O
O
HO
O
H
to be approved for Cancer Treatment.
H
N
EMEA 20SEP07
S
N
O
The first “Direct from the Sea” drug
H
O
OH
O
Just about every technique used; large-scale
O
O
NH
HO
Et743; Trabectedin; Yondelis(R)
harvesting, aquaculture and semisynthesis from
Cyanosafracin B
“You are what you eat”
Dolabella auricularia
Dolastatins come from a Symploca species that they graze on
Dolastatin 10 and a Synthetic Analogue
H
N
N
O
N
N
O
NH
CH3 OCH3 O
OCH3 O
N
Dolastatin 10
H
N
N
O
O
N
CH3
H
N
N
OH
O
OCH3 O
Auristatin PE
Phase I (II)
S
Marine Sediments: Nereus Pharmaceuticals
Marine Microbe Culture Collection
Over 15,000 Strains
~50 % Actinomycetes; 10 New genera discovered
~50 % Fungi
Sediment sampler
H
H
H
N
OH
O
O
Cl
Salinosporamide A
Fenical et al., Angew. Chem. Int. Ed., 42, 355-357 (2003)
Salinosporamide Development Time Line
Dec 2005:
NPI-0052
IND Filed
Preclinical Development (30 months)
Preclinical models (in vitro/in vivo)
API manufacturing (saline fermentation)
Formulation development
Drug product manufacturing
Toxicology
2Q 2006:
2Q 2007:
Phase I
Phase I
Solid Tumors
Multiple Myeloma
and Lymphoma
DISCOVERY AND DEVELOPMENT OF NPI-0052, A NOVEL
PROTEASOME INHIBITOR FOR THE TREATEMENT OF CANCER
Oct 2002:
Novel Marine
actinomycete
Salinispora
discovered
(Mincer et al)
May 2003:
FDA approves Velcade™
for treatment of multiple
myeloma, validating the
proteasome as a target
for cancer treatment
Feb 2003:
NPI-0052 (Salinosporamide A)
structure, cytotoxicity and
proteasome inhibitory activity
established (Feling et al)
June 2005:
Total synthesis
(Danishefsky)
May 2004:
Total synthesis
(EJ Corey)
Mar 2006:
X-Ray Crystal
Structure in
complex with
20S proteasome
Dec 2005:
NPI-0052 efficacy in
mouse multiple
myeloma xenograft
models (Chauhan et al)
Ray Lam, Nereus Pharma
June 2007:
Total synthesis
(Ling et al)
Nov 2006:
NPI-0052 efficacy in
mouse colon cancer
xenograft models
(Cusack et al)
Imperial Purple and The Cell Cycle
Hexaplex trunculus (A) was extracted for Tyrian purple (B), various brominated indirubins (1–4) (C), and
indigos. Oxime derivatives (5–8) and N1-methylated analogs (9–11) 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.
Isolation of Indirubin-Binding Proteins
Potential Anti-Alzheimer’s Treatment
Cell Cycle and Natural Products
trabectedin
wortmannin
caffeine
fumagillin,TNP-470
PRIMA-1, pifithrin a
UCN-01, SB-218078
debromohymenialdisine
isogranulatimide
nitrogen mustards
nitrosoureas
mitomycin C
menadione (K3)
p53/MDM2
hydroxyurea
(R)-roscovitine (CYC202)
ATM/ATR
cytarabine
paullones, indirubins
Chk1
nucleotide excision
antifolates
Chk2
repair
Vinca alkaloids
Plk1
5-fluorouracil
DNA synthesis
PD0166285 taxol/taxotere
G2
6-mercaptopurine
halichondrin
CDC25
HMGA
FK317
spongistatin
S
CDK1 Wee1
rhizoxin
camptothecin
topoisomerase I
Aurora
cryptophycin
Pin1
tubulin
podophyllotoxin,doxorubicin topoisomerase II
M polymerisation/
sarcodictyin
etoposide, mitoxantrone
CDK2
eleutherobin
depolymerisation
Cdc7
(R)-roscovitine (CYC202)
epothilones
CDK4
kinesin Eg5
paullones, indirubins
discodermolide
ODC/SAMD
indibulin
actin
G1
C GSK-3
flavopiridol
dolastatin
Pin1
AhR
monastrol combretastatin
polyamine analogues
MEK1/Erk-1/2
G0
cytochalasins eribulin
Raf
paullones, indirubins
ROCK
latrunculin A
farnesyl transferase
DF203
scytophycins
tyrosine kinases
PD98059, U0126
dolastatin 11
proteasome
PS-341
jaspamide
sorafenib*
choline kinase
CT-2584
Y27632
mTOR/FRAP
rapamycin
tipifarnib gleevec
bryostatin, PKC412
PKC
lonafarnib iressa
HSP90
geldanamycin, 17-AAG
erlotinib
cytosolic phospholipase A2
ATK, MAFP
histone deacetylase
trichostatin, FK228
phospholipase D
hexadecylphosphocholine
Modified from Meijer, 2003
phosphatases
okadaic acid, fostreicin, calyculin A