Bioactives from Nature - Hanze University of Applied Sciences€¦ · • Potential source of...
Transcript of Bioactives from Nature - Hanze University of Applied Sciences€¦ · • Potential source of...
Bioactives from NatureAndré Heeres, August 2018
Introduction
• André Heeres, Groningen, The Netherlands
• Syncom, Hanze University of Applied Sciences
• CRO in organic/medicinal chemistry
• 135 FTE (65% PhD)
• Pharmaceutical Industry
• Biobased activities (5-7 FTE)
• > 29.000 students
Content
• Natural Products in drug discovery
• Optimization/medicinal chemistry
• Lutein/Tagetes
Part I: Natural Products in Drug Disovery
Natural Products in Drug Discovery
• Natural Products Have an Outstanding Track Record
New chemical entities 1981-2014:
• Total: 1562
• 1/4 are natural products or natural product derived
Examples
General features of natural products
• Structural diversity and complexity
• More sp3 carbons and less nitrogen/halogens
• Chiral centers
Semi-synthesis
• Sometimes good is not good enough!
Optimization
The drug discovery process
• Total costs > 1.000.000.000 USD!!!! (billion)
Drug administration
• Preference for oral
administration
Requirements of drugs
• Question: What is required to become a successful
drug?
• Groups, 5-10 minutes
Requirements of drugs
“Farmaco-dynamics” (interaction)
• Activity for target receptor (“on-target”)
• Selectivity against other receptor (sub-)types
“Farmaco-kinetics” (ADME)
• (Administration, Distribution, Metabolism, Excretion)
• Bioavailability (transport, metabolic stability)
• Good duration of action (t 1/2)
Requirements of drugs (II)
“Farmaco-kinetics”
Good farmacokinetics require favourable physico-chemical properties….
• Water solubility > 20 mg/L
• “Compliance” to Lipinski and Veber “rules” (drug likeness)
MW HA/ HD clogP PSA RotB
Lipinski/Veber < 500 < 10/5 < 5 < 120 < 11
For CNS < 400 < 7/3 2 - 4 < 70 < 9
Present drugs 380 6/2 2.5 21 6
Requirements of drugs (III)
“Safety”
• No acute toxicity (e.g. cardiac [Herg], liver…)
• No long-term risks (DNA)
“Other”
• Chemical stability (heat, moisture…)
• Synthetic accessibility
• Patentability
- = Novelty (New Chemical Entity)
- + Inventivity (against existing patent claims)
- + Industrial application (therapeutic)
Requirements of drugs (IV)
Multi-factorial problem:
1. Improve all weak properties…..
2. …without destroying any strong properties
try to improve in cycles till the full
combination of properties is in
the acceptable range (or
fantastic)….
Modification of natural products (strategies)
• Simplifying structures
• Diminishing chiral centers
• Increasing activity or selectivity
• Increasing metabolic stability
• Improving physico-chemical
properties
Simplifying structures
• Decrease molecular size
• Eliminate unnecessary functional groups
• Halichondrin B (marine sponge, Halichondria okadai)
Erubilin
Breast cancer
FDA 2010
Diminish chiral centers
• Lovastatin (fungi; Pleurotus ostreatus)
Increase activity/selectivity
• Himbacine, Magnoleacea, Galbulimima baccata
Increase metabolic stability• Phlorizin (SGLT inhibitor) (bark of apple, strawberries, etc.)
• Aim: To increase metabolic stability and preferably increase activity
Improving physico-chemical properties
• Lavendustin A (potent in cell-free extracts (tyrosine kinase (epidermal growth factor
receptor))
• Aim: To decrease the solubility while balancing the (in vitro) activity
Inactive in cells Activity in cells
(mM range)
Activity in cells
(nM range)
in the clinic
Part II: Lutein from Tagetes
Tagetes in Northern Netherland
Bulb farming (tulips, lilies etc.)
• Use of marigolds (Tagetes spp.) for nematode suppression
(biological herbicide)
• 400 hectare (2017, growing at the 7 collaborating farms)
• Soil improvement (organics, etc.)
• “Beneficial for bees population”
Tagetes• Potential source of lutein, a high-value carotenoid
• Pharmaceutical, cosmetic (and nutraceutical) applications
• Ocular health
• Skin care (UV protection)
• Reduction of cancer
• Strengthening the immune system
• In 2010, lutein occupied a $233 million share of the worldwide carotenoid market (BCC
Research 2011).
• Lutein will be worth $309 million in 2018, a CAGR of 3.6%.
Lutein from Tagetes
Proces:
• Tagetes selection (herbicide + lutein)
• Harvesting flowers
• Drying and milling
• Extraction towards lutein esters
• Hydrolysis and purification
• Stabilization
• Conversion to other carotenes
Achievements
Tons/flowers tagetes per ha (2017, 6 x harvested)
Achievements
• Hybrid Tagetes
• 2016
- Planted middle May
- 6 x harvested
- Sunny conditions
• 2017
- Planted middle June (extremely wet)
- 3 x harvested
- Wet, cloudy weather
Lutein from tagetes in kg Drenthe 2016 Drenthe 2017
30-60 ton per hectare Bioresource Technol. 2015, 421-428 30000 33000 8400
drying Bioresource Technol. 2015, 421-428 4500 4950 1260
hexane extraction Sep. Sci. Tech. 2001, 265-271 450 495 126
hydrolysis and crystallisation Sep. Sci. Tech. 2001, 265-271 67,5 74,25 15,12
Achievements
• > 100 kg dried and milled flowers available
• 2017 > 5000 kg (wet) flowers (0.5 hectare)
• Extraction with heptane/supercritical CO2
(analysis in progress)
• Saponification and purification towards lutein >
50 g scale
• Increased lutein levels detected in eggs
chickens feeded with milled flowers of Tagetes
Optimization (aiming for)
• Alteration of lutein content – Increasing the dry weight lutein content of
marigold flowers.
• Alteration of visible properties of marigold – This includes aspects of
the flowers (more and/or larger flowers, flowers that all grow at the
same height) and of the stalk (flowers that are higher above the leaves
allowing for easier separation, a thicker stalk).
• Mechanical harvesting: e.g., Spanish Journal of Agricultural Research
2014 12(2): 329-337.
Towards higher value carotenes
Markets Zeaxanthin/Astaxanthin
Zeaxanthin
• Food/feed, cosmetics, pharma
• Anti-oxidant, macular degeneration
• Synthetic, extraction (marigold, paprika)
• Market 2020: USD 50 Million
Astaxanthin
• Food/feed, cosmetics, supplement
• Anti-oxidant, coloring properties
• Synthetic, extraction (plant, marine, yeast/microbes)
• Market 2020: USD 800 Million
Current synthesis
Zeaxanthin from Lutein (extracts)
Zeaxanthin:
• Extraction, chemical synthesis (3R, 3R’)
• From lutein
• Stereochemistry (3R, 3S’(meso))
• Epimerization needed in order to achieve market interest (3R, 3R’)
(3R,3R’)-Zeaxanthin from Lutein
(3R,3R’)-Zeaxanthin from epi-Lutein
Conclusions
• Natural products remain of interest for drug discovery, owing to their unique
structures
• Medicinal Chemistry is sometimes needed to transfer bioactive compounds
into real drugs.
• Tagetes is interesting source of carotenes!
Acknowledgements
Hanze University
• Dr. Patrick Uiterweerd
• Nanne Brattinga
• Jan Weever
• Dr. Doede Binnema
Syncom
• Dr. Jochem van Erpt
• Gerard Metselaar
• Sarah van Dijk
• Dr. Bernard van Vliet
• Dr. Jack den Hartog
• Dr. Ton Vries