SmallMolecules

Biolink Group AS 1998

Natural Small Molecules

Prophylactic Health Care

Medpalett AS Polyphenols AS

Synthetic Small Molecules

Therapeutic Health Care

Biosynth AS

Professional DietarySupplement

Natural Polyphenolsstandards

Drug Discovery R&D

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Natural, Small molecules since 1998 www.polyphenols.com

We deliver natural small molecules to research institutions world wide

SmallMolecules

BSC3G – 484,838g/mol BSD3G – 500,837g/mol

BSPn3G – 498,864g/mol

Synthetic: For our own drug discovery R&D use onlySmall Molecules: Copies of orto-dihydroxyphenyl Anthocyanins (P*) Small Molecules: Other Anthocyanin related special structures (P*)

These small moleculesmodulates a wide range ofenzymes and cell receptors

* Patents

SmallMolecules

11.03.200868

Developing an advanced membrane technology and applying chromathography, made us able to make MP865®(Medox®) for early human clinicalstudies. A compound that contains a calculated amount

of about 90% C-3G & D-3G

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Biolink Group ASRevenue 2001-2007 (Medox®)

SmallMolecules

Stavanger University HospitalNorway

Karolinska University Hospital, Sweden

Summa Health Systems, USA

Sun Yat-senUniversity, China

Ullevål University Hospital, Norway

University of OsloNorway

University ofBergen, Norway

Dr. Med. M. NylanderSweden

SmallMolecules

Main areas of pre-clinical and clinical studies

Name Study Study Phases

Possible effects Pre Cl. Phase 0 Phase I Phase II Phase III Phase IV

CIF-C/D-3G Chronic Inflammation

CAN-C/D-3G Cancer impeding

HPT-C/D-3G Cardiov./Hypertension

Absorption and metabolization

Cell lines Natural & Synthetic Small Molecules

Animals Natural & Synthetic Small Molecules, oral

Human/MP865® Natural Small Molecules MP865®/Medox®, oral

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COX-2, playing a key role in tumorgenesis, is a rate limiting factor in synthesis of prostaglandin

E2(PGE2). Anthocyanins(especially orto-dihydroxyphenyl structures) inhibit Cox-2 interfering with the

signaling mechanisms that regulate the Cox-2 gene. Anthocyanins downregulate iNOS, being

responsible for up to an amount of 50-75% of COX-2 PGE2 expression. These small molecules also

block LPS-induced IĸB degradation supressing NF-ĸB activation and COX-2 geneexpression.

Clinical human study on anthocyanins (MP865®/Medox®) and their influence on Chronic Inflammation.

Randomized, double blind, placebo controled, n=118. University Hospital of Ullevål and The University

of Oslo, Norway. Funded by:The Norwegian Cancer Society, The Norwegian Research Foundation,

Trone Holst Foundation. Randomized, double blind, placebo controled. Published in “Journal of

Nutrition”, August 2007, USA.

In vitro study, single molecules from Biolink Group(Standards), SunYat-sen, University, Guangzhou,

P RC. Funded by a foundation in NY, USA and by PRC. Published in “Arteriosclerosis, Thrombosis

and Vascular Biology” April, 2007, USA.

NF-kB, TNFα, T-cells/RANTES (-15%), CD-40, IL-8 (-45%), IL-4 (-60%), IL-13 (-38%), IFNα-NF-kB initiator (-40%), TRAF-2, IL-2,…

SmallMolecules

MS*

Alzheimers

Parkinson

CHD/Atheroscl.

Cancer

Ulcerus Colitis*

Asthma*

Cols*

Allergy*

Arthritis/Rheumatism*

Psoriasis*

Cataract**

Lupus

Fibromyalgia

Surgical complications

Migraine** Hypertension

Diabetes*

Kidney failureUrologic Diseases*

Crohn`s Disease*

Our Small Molecules; A Drug Development Platform

ChronicInflammation

The MetabolicSyndrome

OxidativeStress

* Mapped anecdotic effects on oral consumption of MP865®/Medox® ( Since 2001 )

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• Anthocyanins Induce Cholesterol Efflux from Mouse PeritonealMacrophages, ”Journal of Biologic Chemistry,”vol 280, issue44, 36792-36801, Nov. 4,2005; Wenhua Ling et al, Sun Yat-sen University, PRC

• Metabolic syndrome; Human, randomized, double blind, placebo controlled study on MP865® (HDL, LDL, CETP, T-AOC), n=40. Dose 320mg, To be published in USA 2008.

• Human, randomized, double blind, placebo controlled clinical studyon MP865® and its influence on inflammation and cardiovasculareffects. n=120. Dose 300mg; Leiv Sandvik et al, Norway

Resting Pulse, Blood Pressure (16-20mm), eNOS, iNOS,LDL, HDL, LCAT, CETP, PGL -F2α, T-AOC( ), CRP, T-SOD,Carotide IMT, Insulin secretion, Glucose, EndothelinBlood Pressure, Resting Pulse, . . .

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Small Molecules; Lipid Profile

To what extent will MP865® modulate CETP, LDL, HDL & T-AOC ?

MP865®

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• Resting Pulse • Blood Pressure*• iNOS, eNOS• LDL-HDL• CETP mass • CETP activity• T-AOC• Endothelin-1• NF-kB

In vivo animal studies has shown thatAnthocyanins significant reduce (30%) theamount of cardiac tissue that was damagedfollowed by ischemic conditions. Both total and reduced GSH concentrations were greaterin animals consuming anthocyanins.”Journal of Nutrition”, April 2008, Vol 139; ”Chronic dietary intake of plant derived Antho-cyanins protects the rat heart against ischemia-reperfusion injury”. Nagy N et al.

Multiple BloodPressure studieson rats

* Patent filed

Some samples of cardiovascular related effects:

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• A human, randomized, cross over, dobbel blind, placebo controled Cardiovascular, clinicalstudy, on MP865®/Medox®. Oral consumtion.

• The purpose is to study multiple parameters relatedto development of Cardiovascular Diseases. Bloodpressure, Fibrogen, Glucose, CETP, LDL, HDL, HbA1c, insulin, CRP, . . . .) n=30-40

Ullevål University Hospital, Oslo, Norway 2008-2010

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Human, randomized, double blind, placebo controledCoronary Artery Disease study applying MP865® in atherosclerosis on atherosclerotic patients (Medicationnot started). Oral consumption.

(HDL, LDL, CETP, T-AOC, Carotid IMT, Fasting serum lipid profile, glucose, insuline, F2α, IL-6, CRP, . . . ), n ˃ 120.

Sun Yat-sen University, Guangzhou, China 2008-2010

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AGS (Stomach), HCT116 (Colon), MCF-7(Breast),

SF-268 (Central Nervous System), HL60 (Leuchemia),

NCI-H460 (Lung) TVM-A12 (Melanoma Skin) and

U-87 (Glioblastoma)

Small molecules C3G & D3G posess chemopreventiveeffects impeding growth and spread of cancer cells:

Masuko Kobori, National Food Research Institute, (JARQ, Jpn. Agric. Res. Q.)2003, Vol 37

Molecular Mechanism Behind the Chemopreventive Effects of Anthocyanidins,De-xing Hou et al. Dep. Of Biochemical Sciense and Tecnology, Japan, Journal of Biomed Biotechnology, 2004

SmallMolecules

University of Bergen 2001Small molecules MP865®

GlioblastomaU-87

Read: cancer cellsGreen: healthy cells

48 hoursno MP865®

48 hoursMP865®

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• These small molecules (anthocyanins) can suppress growth and spread of cancer:

– Delphinidin (83% - 23%)

– Cyanidin (48% - 14%)

– Petunidin (43%)

– Peonidin (15%)

– Malvidin ( 9%)

Our small molecules suppress Glioblastoma U-87

Anthocyanidins inhibit migration of glioblastoma cells: Structure-activity relationship and involvment of thePlasminolytic system; Lamy S, Lafleur R, Bedard V, Moghrabi A, Barrette S, Gingras D, Beliveau R. Laberatoirede Medicine Molecularire, Hospital Ste-Justine-Universite du Quebeca Montreal, Quebec, Canada H3T 1C5Pmid: 16823770. Nutr Cancer. 2006;54(1): 8493

SmallMolecules

• 10 out of 12 prostate cancer patients seems to get a relative rapid and efficient response on their PSA-values.(Early stage=long term effect(figure); Late stage=shorter term effect)

• Applied doses = 480-640mg MP865®

Several cancer patients, of whom, 40 prostate cancer patients*

* (Non scientific, 480-640mg MP865® combo with ordinary treatment)

Normal treatment Added MP865®

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Small molecules BSC3G & BSD3G and apoptosis studies at

Summa Health Center, Ohio, US

Apoptosis

Autocchises

Necrosis

P53 Gene

P27 Gene

VEGF

bFGF

GSH

Interleuc

p38, JNK,

MAPK

Bcl-2BIM,

AP-1

MMP 2+9

COX-2

iNOS

SOD

NF-κB

Apoptosis play a key role eliminating tumor cells. The small orto-dihydroxyphenyl molecules trigger an apoptotic death program through an oxidative stress-mediated JNK-signaling cascade in tumor cells. The effect of this mechanism is closely associated with thenumber of hydroxyl groups at the B-ring. These smallmolecules produce ROS and show pro-oxidantactivities in cancer cells, but show antioxidantactivities in healthy cells.

SmallMolecules

NF-κB, iNOS-COX-2/PGL-E2, TNFα, VEGF/bFGF(blocking p38 & JNK-MAPK`s). MAPK and NF-κB induct MMP-9 by IL-1ß, MMP-2, Apoptosis…

Delphinidin and cyanidin inhibit PDGFAB-induced VEGF release in vascular smooth muscle cells by preventing activation of p38 MAPK and JNK. M-H Oak,1,2 J E Bedoui,1 S V F Madeira,1 K Chalupsky,1 and V B Schini-Kerth1*

1Dépt. Pharmacologie et Physicochimie, Faculté de Pharmacie, Institut Gilbert-Laustriat, UMR 7175, Université Louis Pasteur (Strasbourg I), Strasbourg, France

In vitro cell line studies of BSC3G/BSD3G on 5 different cancer tumor cell lines; Breast Cancer, Lung Cancer, Owary Cancer, Prostate Cancer and Colon Cancer at Summa Health Center,USA

SmallMolecules

Matrix MetalloproteasisMMP 2 and 9

Growth FactorsVEGF, bFGF

Apoptosis (Autoscises, Necrosis), COX-2...

These Small Molecules (SM), C3G & D3G,suppress MMP 2 and 9significant blocking MAPK`s and NF-κB that Induce MMP-9

These Small Molecules(SM), C3G & D3G, suppress growth factorssignificant by blocking p38-, MAPK`s and JNK

C3G/D3G lower iNOS(Can suppress COX-2 50-75% ). Cox-2 in cancer cells protect against Apoptosis and promotesAngiogenesis.

High CETP forms FoamCells that could induce Matrix Metalloproteasis2&9. SM induce Foam Cell Apoptosis via p38 & p53 pathway.

High CETP forms Foam Cells that could induceGrowth Factors, VEGF, bFGF,… SM Induce Foam Cell Apoptosis via p38 & p53 pathway.

SM induced ROS activate p38 MAPK and JNK con-tribution to Apoptosis, activating the Mitochon-dria pathway mediated bylowering Bcl-2 and eleva-tingBim. This is not the case in healthy cells

Suppression of Chronic Inflammation

Lipid profile influence through Foam Cells

SmallMolecules

• The BSC3G and BSD3G and other small anthocyanin relatedmolecules and their metabolites are synthezised

• The small molecules are in a patent filed, scale up process

• The modulating effects on enzymes and cell-receptors arestrong, numerous & non toxic

• The modulating effects are somewhat documented in clinical human studies on single molecules and MP865®

• The small molecules has shown no side effects after 7 years ofhuman oral consumption (MP865®/Medox®; 80-640mg dosis)

• The synthetic small molecules might be modified/optimized to a significant higher effect level compared to the natural ones

• Absorption & Metabolic clinical studies have been performedsince 2006

How can our synthtic small molecules save time in the drug discovery & development process?

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Laboratories and processing facilities in Sandnes, Norway, since 1998