Download The Relationship Between Diversity and Natural Product Chemistry

Dr Ed Anderson Chemistry Research Laboratory, University of Oxford
The Relationship Between Diversity
and Natural Product Chemistry
or... How Biodiversity Leads to Innovation
and Value in Organic Chemistry
Biosymposium 2015, University of Oxford
7th January 2015
Natural Product Biodiversity: Natureʼs Medicine Cabinet
Nature is an unparalleled source of novel (bioactive) organic molecules
Biodiversity = Chemical Diversity = Bioactivity Diversity = New Medicines?
Chemical Diversity leads to Chemical Innovation
All small molecule drugs, 1981-2010
Anticancer drugs, 1981-2010
“...Despite the intensive investigation of terrestrial flora, it is estimated that only 5–15 % of the approximately
250,000 species of higher plants have been systematically investigated, chemically and pharmacologically.”
(from Cragg, “Biodiversity and the continued generation of molecular diversity”)
Figures taken from D. J. Newmann, G. M. Cragg, J. Nat. Prod. 2012, 75, 311
Quotation from: G. M. Cragg, D. J. Newmann, Biochimica et Biophysica Acta 2013, 1830, 3670
Natural Products (or Derivatives) in Clinical Use
Influenza
Cancer
Ph
O
NH
Ph
AcO
O
O
HO
O
OH
O
OEt
OH
O
HO
HO
Taxol
O O
O
Ph
OH
NH2
O
NHAc
OH
O
Shikimic acid
Ac
Tamiflu
Malaria
H
O O
O O
HO
O
H
O
O
N
Aterolane
N
Cl
Quinine
H
H
H
HO
H
O
O
Cancer
H
O
H
H
Halichondrin B
IC50 (DLD-1) 0.74 nM
H
H
Chloroquine
MeO
O
O
O
O
HO
NH2
N
HN
O
O
Artemisinin
HO
NH
H
N
O
O
H
O
O
H
O
O
O
O
left half
deletion
H2N
macrolactone ! ketone
O
H
O
O
H
O
O
H
OH
O
O
O
O
O
H
Eribulin
IC50 (DLD-1) 13.0 nM
Taxol: Biodiversity comes to the rescue
Ph
• First isolated from the bark of the Pacific
Yew Tree (1964)
O
NH
Ph
AcO
HO
Taxol
OH
• Potent anticancer activity against ovarian,
breast and lung cancer
O
HO
Taxus brevifolia
(Pacific yew tree)
O
O
O O
O
Ph
• An initial harvest of 1200kg of bark gave
only 10g of pure Taxol: SUPPLY PROBLEM!
O
Ac
semisynthesis
40-61 steps
Solution 2: Semisynthesis
HO
e.g.
O
Solution 1: Total Synthesis
Chemical synthesis of Taxol is
NOT VIABLE! (Despite SEVEN
complete syntheses)
OH
HO
HO
verbenone
O
O O
O
Ph
O
Ac
10-Deacetylbaccatin III
Taxus baccata
(European yew tree)
Isolation of 10-Deacetylbaccatin III from the needles of the
European Yew tree solved these environmental problems
4
Taxol: Biodiversity comes to the rescue
Ph
• First isolated from the bark of the Pacific
Yew Tree (1964)
O
NH
AcO
Ph
O
HO
O
OH
O
Taxol synthesis:
44-60
HO O
O
Taxol
Taxus brevifolia
(Pacific yew tree)
O
O
50 steps
40-61 steps
Ac
Ph
at 80%
• Potent anticancer activity against ovarian,
breast and lung cancer
• An initial harvest of 1200kg of bark gave
chemical
only 10gsteps!
of pure Taxol: SUPPLY PROBLEM!
per step = 0.850 %
semisynthesis
= 0.0014%
over 50 steps
Solution 2: Semisynthesis
= 1 g from 71
HO kg of sm
O
e.g.
O
verbenone
Solution 1: Total Synthesis
Chemical synthesis of Taxol is
NOT VIABLE! (Despite SEVEN
complete syntheses)
+ HO
COST!!!,
Environment,
HO
TimeO O
Ph
O
OH
O
Ac
10-Deacetylbaccatin III
Taxus baccata
(European yew tree)
Isolation of 10-Deacetylbaccatin III from the needles of the
European Yew tree solved these environmental problems
5
The Taxol challenge: Whatʼs the problem?
HO
O
OH
Phil Baran
O
H
HO
HO
O
O
O
O
C29H36O10
10-Deacetylbaccatin III
A. Mendoza, Y. Ishihara, P. S. Baran, Nat. Chem. 2012, 4, 21
N. C. Wilde, M. Isomura, A. Mendoza, P. S. Baran, J. Am. Chem. Soc. 2014, 136, 4909
The Taxol challenge: Whatʼs the problem?
H H
H
H
Phil Baran
H
H
H
H
O
H
Computationally-predicted site selectivity of oxidation
C20H32
Taxadiene
A. Mendoza, Y. Ishihara, P. S. Baran, Nat. Chem. 2012, 4, 21
N. C. Wilde, M. Isomura, A. Mendoza, P. S. Baran, J. Am. Chem. Soc. 2014, 136, 4909
The Taxol challenge: Whatʼs the problem?
Taxadiene is a natural product, but this
route has prepared more pure material
than has ever been isolated from Nature
(1 mg from 750 kg bark!)
Biomimetic synthesis
'CYCLASE PHASE'
H H
H
H
Phil Baran
10 steps
10% overall yield
>1 g prepared
H
H
H
H
O
H
3 further steps
O
'OXIDASE PHASE'
Et3SiO
OAc
H
O
H
A. Mendoza, Y. Ishihara, P. S. Baran, Nat. Chem. 2012, 4, 21
N. C. Wilde, M. Isomura, A. Mendoza, P. S. Baran, J. Am. Chem. Soc. 2014, 136, 4909
This work advances the
state-of-the-art in the
chemical diversification
of complex molecules!
Terpenoid natural products from the genera Kadsura and Schisandra
• Climbing plants, located widely through East Asia; ‘...most have been used in
Chinese traditional medicine’ (and by Russian swimmers).
• >400 triterpenoid and nortriterpenoid natural products isolated since the discovery
of micrandilactone A in 2003 by Han-Dong Sun.
• Bioactivity: HIV, HSV, HBV, possible anticancer
Schisandra chinensis
O
H
O
O
O
H
O
H
HO
O
O
O
O
O
OH
H
O
H
H
O
OH
H
H
H
HO
O
O
OH
H
H
O
H
O
Micrandilactone A
O
O
H
O
O
O
H
O
H
H
O
Lancifodilactone I
O
H
O
O
H
H
H
H
Rubriflordilactone A
H
Rubriflordilactone B
Y.-M. Shi, W.-L. Xiao, J.-X. Pu, H.-D. Sun, Nat. Prod. Rep. 2015, DOI: 10.1039/c4np00117f
A. Panossian, G. Wikman, J. Ethnopharmacology 2008, 118, 183
O
O
H
O
Han-Dong Sun
(Kunming Institute of Botany,
Yunnan province)
Terpenoid natural products from the genera Kadsura and Schisandra
Natural product distribution: Core structures split into three types: Lanostane, Cycloartane, Schinortriterpenoids (Schiartanes).
Schisanartane
Lanostane
Cycloartane
NP distribution varies with:
• Genus (Kadsura mainly L, C; Schisandra mainly C, S);
• Species (several NPs are found in two or more species);
• Location (suggesting an environmental pressure on the
production of these metabolites?).
e.g. Schisandra chinensis:
Shanxi province: only Cycloartanes
Jiangxi or Heilongijang provinces: only Schinortriterpenoids
Is this a case for preserving biodiversity??
Y.-M. Shi, W.-L. Xiao, J.-X. Pu, H.-D. Sun, Nat. Prod. Rep. 2015, DOI: 10.1039/c4np00117f
A. Panossian, G. Wikman, J. Ethnopharmacology 2008, 118, 183
Schiartane
Schinortriterpenoids
Biosynthetic / synthetic relationships?
O
H
O
O
H
O
O
O
H
H
H
H
O
Lancifodilactone G
O
O
O
O
O
H
O
H
O
O
Micrandilactone F
O
H
H
O
H
H
H
H
O
O
O
O
H
O
H
O
H
H
O
H
O
Henridilactone A
O
O OH
O
H
H
H
H
O
H
H
Lancifodilactone A
O
H
O
H
HO
O
O
O
Micrandilactone G H
O
HO
O
H
O
H
O
Schindilactone B
O
O
O
O
O
O
H
H
H
pre-Schisanartanin
O
Rubriflordilactone B
H
H
H
H
O
O
H
O
O
O
O
O
H
O
H
OH
H
OAc
O
H
H
H
HO
O
H
H
O
OH
O
Schindilactone C
O
O
O
H
Rubriflordilactone A
O
O
O
H
O
OH
H
O
O
Micrandilactone A
HO
O
H
H
HO
O
H
H
H
Schindilactone A
O
O
O
H
O
H
H
H
H
O
H
O
H
H
O
H
O
OH
O
H
O OH
O
O
O
O
H
O
O
O
OH
H
O
Henridilactone B
O
O
O
H
O
O
HO
O
O
H
O
H
O
H
H
O
O
OH
O
H
O
Lancifodilactone M
O
O
H
H
O
O
O
H
Lancifodilactone K
O
OAc
OH
H
H
H
HO
O
H
O
O
O
H
O
H
O
O
O
O
H
H
OH
OH
H
O
O
O
O
H
H
O
O
OH
H
O
O
Lancifodilactone B
O
O
H
O
H
O
O
O
O
O
H
O
O
OH
H
O
H
H
O
O
O
O
H
O
Micrandilactone E
O
H
H
H
HO
H
O
H
H
Lancifodilactone N H
O
O
H
O
O
O
O
O
H
Lancifodilactone D
OH
H
H
O
OH
O
H
H
O
R = Ac: Lancifodilactone J
O
O
H
Henridilactone C
O
H
O
H
O
H
O
H
R = H: Lancifodilactone I
H
O
H
H
H
O
Lancifodilactone E
O
O
O
O
OH
H
O
H
H
H
HO
O
H
RO
O
O
O
O
O
OH
O
H
H
O
H
Lancifodilactone L
O
O
H
H
O
H
O
O
O
H
O
Rubriflorin A
O
O
H
H
O
H
O
O
H
O
O
O
O
H
H
H
HO
H
O
O
O
H
O
O
H
O
OH
O
Lancifodilactone C
MeO2C
H
O
O
H
O
H
O
O
O
O
H
H
H
HO
O
O
H
H
O
H
Henridilactone D
H
O
H
O
O
O
O
H
H
H
HO
O
HO
H
O
O
H
O
O
O
O
HO
O
H
O
O
Rubriflordilactones A and B
O
H
EC50 >40 µg mL-1
O
O
C
H
O
O
O
H
D
H
O
O
C
H
E
Rubriflordilactone B
O
H
H
D
E
H
Rubriflordilactone A
EC50 9.75 µg mL-1
H
H
O
O
O
(Inhibition of HIV-1
syncytium formation)
H
Isolated from / produced by Schisandra rubriflora (Yunnan province).....
....and in the Oxford Botanic Garden???
Schisandra rubriflora
– in Oxford!
...does this specimen produce any rubriflordilactones?
Our synthetic strategy:
Pd(II)Ln
Pd(0)
Br
SiR3
base
Pd(II)Ln
SiR3
SiR3
Isolation: W.-L. Xiao, L.-M. Yang, N.-B. Gong, L. Wu, R.-R. Wang, J.-X. Pu, X.-L. Li, S.-X. Huang,
Y.-T. Zheng, R.-T. Li, Y. Lu, Q.-T. Zheng, H.-D. Sun, Org. Lett. 2006, 8, 991.
SiR3
Rubriflordilactones A and B
O
O
H
EC50 >40 µg mL-1
O
O
O
H
D
C
H
O
Rubriflordilactone B
O
O
C
H
E
O
H
H
H
D
EC50 9.75 µg mL-1
H
E
H
(Inhibition of HIV-1
syncytium formation)
H
O
Rubriflordilactone A
O
O
H
Reality:
O
O
H
A O
O B
Br
O B
H
O
2 steps
H
SiMe2Bn
H
A O
H
O
10 mol% Pd(PPh3)4,
Et3N, MeCN, 80 °C
Br
H
SiR3
TBSO
H
O
O
SiMe2Bn
73%
H
H
H
TBSO
F–, H2O2
46% unopt.
O
Strategy to access diverse natural products
Potential for analogue synthesis
H
O
O
A O
A
O
OH
B
B
C
C
H
D
D
O
H
E
E
TBSO
H
H
NP-inspired chemistry: “Biodiversity Added Value”?
These natural product synthesis ideas have led us in new research directions, adding chemodiversity value:
• Original
chemistry:
+N
R'
Pd(0)
Br
R'
Pd(0)
Br
base
R
Met
R'
R
Ph
R
R'
Pd(0)
N
Ts
Br
N
Ph
R
Met
N
R'
P
P
N
N
R
Ts
Ts
Hex
N
OBn
Ts
– Met
70%
88%
81%
Pd(0)
Br
N
R
EtOH
R
N
P
P
R'
R'
R
– Br
N
P
Pd(II)
N
play!
TsN
R''
N
Ts
R
N
R
P
P
Pd(II)
n-Hex
80%
R
H
H
N
N
N
R
P
P
R
P
R
N
P
N
P
N
N
H
Peduncularine
Structural diversity: An exploration of new ‘chemical space’
P. R. Walker, C. D. Campbell, A. Suleman, G. Carr, E. A. Anderson,
Angew. Chem. Int. Ed. 2013, 52, 9139
Pet Frogs are not Poisonous
Environmental pressures and seasonality strongly affect natural product production: NP biodiversity depends
crucially on the originating habitat
• >800 alkaloid toxins with potential uses as analgesics have
been isolated from poison dart frogs
• Frogs reared in ‘captivity’ do not produce toxins: natural
product biodiversity is habitat-dependent.
eat
Cl
H
N
N
H
OH
Histrionicotoxin 235A
eat
eat
N
Epibatidine
myrmicine ant
orbatid mite
dead plants
• Temporal and regional changes in the production of natural products from marine invertebrates could depend on many
factors (growth / latency periods, temperature, predation, concentration of nutrients, getting on with your neighbours...)
HO
OH
H
Peloruside A
Mycale hentschelli
Avarol
Dysidea avara
Frogs: J. W. Daly, T. F. Spande, H. M. Garraffo, J. Nat. Prod. 2005, 68, 1556. Dysidea: S. De Caralt, D. Bry, N. Bontemps, X. Turon, M.-J. Uriz,
B. Banaigs, Mar. Drugs 2013, 11, 489; Mycale: M. Page, L. West, P. Northcote, C. Battershill, M. Kelly, J. Chem. Ecol. 2005, 31, 1161
Conclusions
How does biodiversity add value to human society?
Biodiversity = Chemical Diversity = Bioactivity Diversity = New Medicine Leads
Chemical Diversity leads to Chemical Innovation:
Natural product biodiversity inspires new organic synthesis methods
Chemical Innovation improves the diversity and availability of useful molecules
such as pharmaceuticals, at lower cost, and with lower environmental impact
Natural product distribution and seasonality show that Biodiversity is strongly
influenced by environment...
...So how do we value and conserve it?!
Acknowledgements
Current co-workers:
Dr Glenn Archibald
Dr Guilhem Chaubet
Dr Venkaiah Chintalapudi
Ross Walker
Shermin Goh
Bryony Elbert
Bobby Brooks
Haraldur Gudmundsson
Marius Haugland
Rob Straker
Aroonroj Mekayeera
Christian Kuper
Mohammad Mujahid
Andrew North
Dizzy Roe
Rachel Porter
Dan Mercea
Former co-workers:
Dr Birgit Gockel
Dr Craig Campbell
Becky Greenaway
Jenny Kan