Phytoquest Limited

Discovery of Botanical Actives and Extracts

Experts in iminosugars

Phytoquest Limited

PhytoQuest Limited Technology Platform

Isolation Identification Analysis

•  Phytoquest® fingerprint

•  Water soluble and non-polar chemicals

•  extensive database matching (GC-MS, HPLC-MS/PDA)

•  prep. HPLC/ELS/PDA

•  prep. Dionex HPLC

•  Biotage multi flash

•  Automated Flashmaster

•  Cation/anion exchange

•  500 MHz Bruker NMR •  ACD Prediction

Software

Medicines and Foods •  Proven ability to find active components •  Isolation of novel components •  Development of IP (process/activity)

NOH

OHHOH

Purification •  Analysis of components •  Method development •  Identification

AU

0.00

0.20

0.40

0.60

0.80

1.00

1.20

1.40

1.60

1.80

2.00

Minutes1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00

4.768

5.977

6.114

6.235

6.727

7.182

7.478

7.720

7.8788.030

8.299

8.515

8.867

9.129

10.255

G100479_010000fid

5.0 4.5 4.0 3.5 3.0 2.5 2.0Chemical Shift (ppm)

0

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08

0.09

0.10

0.11

0.12

0.13

Nor

mal

ized

Inte

nsity

1.782.002.674.067.152.821.26

M09(d)

M10(d)

M02(m)M01(m)

M07(m)

4.02

4.01

3.83

3.76 3.

75 3.75

3.73

3.41

3.39 3.

373.

363.

30

3.06

2.66

2.64

2.63

2.61

2.60

2.12 2.

102.

092.

092.

08 2.07

2.07

2.06 2.05

12

N+5

3

4

7CH310CH39 O

8

O-11

OH6

Phytoquest Limited

Iminosugars

Iminosugars: •  Stable, small molecules •  Selective glycosylation inhibitors, immune modulators, protein stabilisers •  Orally available, distributed rapidly •  Metabolically inert (excreted in urine unchanged) •  Common in plants and micro-organisms •  Specialised expertise required for discovery and synthesis

NH

OH OH

OH OH

NH

OH

OH

OH

OH

NOH

OH

OH

OHH

OH

N

HOH OH

OH

OH

pyrrolidine � piperidine �

pyrrolizidine �

indolizidine �

Examples:�

O

OHH

HH

OHOH

H OH

H

OH

D-glucose � equivalent iminosugar�

Analogues of sugars, with ring oxygen replaced by nitrogen�

N H O H H H H

O H O H H O H

H O H

HN

HO

OHOH

OH

nortropane �

Phytoquest Limited

Iminosugars Act as Carbohydrate Mimetics •  Plants can produce high levels of carbohydrates

–  And often store them as energy reserves

•  And protect carbohydrates reserves from herbivores

•  The protective agents are often iminosugars

•  Present in aqueous fraction of plant extracts etc.

–  Historically overlooked –  Challenging to isolate, purify, characterise and

synthesise

•  Often present in significant proportion which may explain activity of herbal products/healthy foods

Slide 4

Codonopsis

Lycii Fruit

Chinese Date

Agrimoniae  

Phytoquest Limited

But … more Importantly Iminosugars are part of the Food Chain

•  Stevia

•  Lycium

•  Rice

•  Zizyphus

•  Guarana

•  Cucumber

•  But also Potato, Chickweed, Guarana,

and honey extracts

Slide 5

Phytoquest Limited

PhytoQuest Strategy

PhytoQuest are the leaders in niche area of plant iminosugar discovery

Poorly studied area of plant/microbial chemistry allowing new IP and product differentiation

Key Pharma discovery successes are discovery of novel small molecule immune modulators and anti-diabetic compounds – several licensing options possible

Service work conducted using unique analytical capability and access to proprietary natural product libraries

Now looking to utilise capability and IP for production of bioactive food and cosmetic ingredients and major collaborations

Phytoquest Limited

Carbohydrates: New Therapeutic Targets and Drug Classes

“One of ten emerging technologies that will change the world” MIT Review 2003

Carbohydrates and associated receptors present excellent drug targets and a growing market opportunity

Carbohydrate complexity and diversity greatly exceeds that of proteins and genes

D N A

R N A

P r o t e i n

C a r b o h y d r a t e s

T r a d i t i o n a l D r u g D i s c o v e r y

PQ D r u g D i s c o v e r y

G e n o m e

R i b o m e

P r o t e o m e

G l y c o m e

M o l e c u l a r I n f o r m a t i o n

Phytoquest Limited

Iminosugar Therapeutic Target Space is Vast

•  For enzyme targets: –  Iminosugars can inhibit aberrant enzyme

activity

–  Iminosugars can act as molecular chaperones to restore function for mutated gene products

Non-functionalFunctional

HN

HOOH

OHHO

HN

HOOH

OHHO

Non-functional mutant

(protein misfolded & degraded)Functional

HN

HOOH

OHHO

HN

HOOH

OHHO

Glycoside hydrolases

Glycoside transferases

Carbohydrate receptors

Carbohydrate transporters

Inositol utilising/met. enzymes

Phytoquest Limited

Importance of Carbohydrates

•  Growing understanding of how nature uses carbohydrates

–  Protein/Cell recognition •  Immunology

–  Cell adhesion, migration •  Inflammation, Metastasis

–  Protein folding •  Neurodegeneration

–  Receptor binding

•  Opportunities for therapeutic intervention

–  Mimic the carbohydrate directly –  Alter the carbohydrate coating of proteins or cells

–  Iminosugars provide a mechanism for either of these

Phytoquest Limited

Natural Active Components Identified

Market Exclusivity Enrich Activity

Standardise Products

Unlock New Activities

Basis for Substantiation

Market Challenges for foods, cosmetic ingredients providing opportunities for new Pharma products

Phytoquest Limited

•  Gymnema sylvestre – diabetes

•  Proven to work in Man but wrong components studied

•  One iminosugar isolated and appears to have all the in vivo activity of the plant

, 11-Aug-2006 + 08:02:59Gynema from Anita

3.50 5.50 7.50 9.50 11.50 13.50 15.50 17.50 19.50 21.50 23.50 25.50 27.50Time0

100

%

mnl154103 Scan EI+ TIC

5.30e89.22

2.68

3.243.62

7.689.48

Diabetes

Phytoquest Limited

Iminosugar Suppresses Hyperglycaemia in Fasted Male ddy Mice

Blo

od g

luco

se le

vel (

mg/

dl)

Maltose challenge of 2.5g/kg administered at time 0 Compound given at time of challenge (PO or IP) or 30mins prior to challenge (Predose-PO)

Phytoquest Limited

Casuarine Boosts Type-1 Immune Responses

NOH

OHH

CH2OH

HO

OH

MNLP462a

NOH

OHH

CH2OH

HO

O

O

CH2OH

HO

OHHO

MNLP462b

Natural Occurrence

Present in at least three distinct medicinal plants but very rare in nature. Guacatonga – Casearia which has casuarine as a major alkaloid) claimed to treat AIDS, cancer, TB, leprosy, flu, herpes, wounds and diabetes; all used orally in water.

NOH

H OHHO

HO

CH2OH

3-epi-462a

Phytoquest Limited

Casuarine B16 Tumour In Vivo Efficacy: Significant anti-cancer activity

80% tumour reduction

Phytoquest Limited

Cucumber Extract

•  A single anti-inflammatory iminosugar present in certain varieties

•  Compound reduces TNF-alpha directly

•  Orally available and stable

•  Reduces inflammatory responses like a steroid but is not steroidal

, 01-Oct-2010 + 18:46:27cucumber 108/3

4.93 6.93 8.93 10.93 12.93 14.93 16.93Time0

100

%

PHQ015308 Scan EI+ TIC

5.67e75.45

4.57

4.02

10.636.73

6.34

Phytoquest Limited

What Do We Offer? •  Phytoquest have world-leading expertise in natural product phytochemistry and plant iminosugar

discovery

•  We have a dominant and extensive IP portfolio built around iminosugars for bioactive food and cosmetic ingredients

•  We are creating unique series of products with:

–  High value –  Performance USPs

•  Biologically active •  Guaranteed presence of key components (=USP) •  Performance claims linked to key components

•  We can control this high value new segment with myriad of product opportunities

Slide 16