FLUORINE IN MEDICINAL CHEMISTRY...of Phylosophy) in Barcelona in the field of medicinal chemistry (2011-2015) • Since last November, I am doing a postdoctoral stay at RIKEN thanks

Dr. Elena Valverde MurilloFujishima High School, Fukui

9th June 2016

FLUORINE IN MEDICINAL CHEMISTRY

Personally....• I am Elena Valverde Murillo

Who am I?

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Who am I?

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Personally....• I am Elena Valverde Murillo• I was born in Barcelona (Spain) on the 30th

September 1987 (28 years ago)

Who am I?

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Banyeres del Penedès (Spain)


September 1987 (28 years ago)• In my village (Banyeres del Penedès) I have 3 dogs! Bolo

Miel

Joy

Who am I?

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September 1987 (28 years ago)• In my village (Banyeres del Penedès) I have 3 dogs!• I love to hike, travel, climb, meet new people and

learn new languages!

日本語を勉強しましょう!!




Professionally...• I studied Pharmacy in University of Barcelona (2005-

2010)

Who am I?

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2010)• Then, I did an internship at GlaxoSmithKline as

undergraduate student in Stevenage (United Kingdom) (2010-2011)

Who am I?

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• I did an M.S. (Master in Science) and a Ph.D. (Doctor of Phylosophy) in Barcelona in the field of medicinal chemistry (2011-2015)

Who am I?

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• I did an M.S. (Master in Science) and a Ph.D. (Doctor of Phylosophy) in Barcelona in the field of medicinal chemistry (2011-2015)

• Since last November, I am doing a postdoctoral stay at RIKEN thanks to the JSPS Fellowship program (2015-to date, Prof. Sodeoka’s research group)

Who am I?

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Wakō-shi campus (Saitama)

Where do I come from?

Barcelona is the capital of Catalonia, a region located in the north-eastern end of

Spain 10

10,413 km

Current catalan scenario: a little bit of insight

• Catalonia is fighting for its independence since long time ago, now more than ever before• Spain opposes Catalan independence, and appoints any type of referendum as ilegal

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Catalan pro-independence flag

Cultural features

SARDANA

CORREFOCS

CASTELLS

PA AMB TOMÀQUET

Let’s compare Japan versus Spain…

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JAPAN SPAIN

Area 377,972 km2 < 505,990 km2

Population 126,919,659 people > 46,423,064 people

Density 336 per km2 > 92 per km2

Official languages 1 (Japanese) 5 (Spanish, Catalan, Basque, Galician, Occitan)

Drives on the Left Right

Life expectancy 83.7 (1st overall rank) ~ 82.3 (9nd overall rank)

Biggest city Tokyo (8,949,447 people) > Madrid (3,165,235 people)

Highest mountain Fuji-san (3,775 m) ~ Teide (3,718 m)

Why did I become a scientist?

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TV influence Science museum influence

School influence

Why did I become a scientist?

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• Science can explain everything!• Science can solve everyday problems • Science can promote a better world to

live in• Science is about to write and share ideas

with others

Science as an engine of progress

“Equipped with his 5

senses, man explores the

universe around him and

calls the aventure

Science”

-Edwin Powell Hubble,

1929-Personally...

• Science helps you to build up your brain (knowlegde, logic and critical mind)• Science satisfies curiosity

• Science helps you to develop creativity, imagination and new skills

• Science can be really fun!

Why did I come to Japan?

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1. RESEARCH: Japan is one of the best ranked countries for conducting research in the world.

2. PEOPLE: Japanese people are very friendly and helpful. Also, Japan is the safest country in the whole world!

And the people make the place!3. COUNTRYSIDE: Japan possesses an incredible landscape with many

different nature (from Hokkaido to Okinawa!)4. FOOD: I love Japanese food in all its kinds!

Let’s talk about Science…

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How are drugs made?

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1 APPROVED

DRUG

Synthesis and

structural modification

Biological evaluation

Design

DRUG DISCOVERY

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Medicinal chemistry is a stimulating field that tightstogether several scientific

disciplines for the research and development of new drugs

How are drugs made?

An example to illustrate

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OBJECTIVE: Inhibition of protein X, which has an important role in the development of cancer

Design of compound based on literature, computational studies, ...

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Design and synthesis of new compounds based on data from compound A

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Optimization: design and synthesis of compound F

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Compound: 化合物Synthesis: 合成

Another example to illustrateSITAGLIPTIN: a marketed drug that targets DDP-IV, a

protein involved in Diabetes Mellitus

(抗糖尿病薬）

Why is Fluorine so special?

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FLUORINE as a substituent is:

• SMALL• Low MOLECULAR WEIGHT (19)• HIGHLY ELECTRONEGATIVE

The C-F bond is:

• VERY STRONG• HIGHLY POLARIZED

C Fδ+ δ-

H C N O F Cl

Van der Waals radius

1.2 1.7 1.55 1.52 1.47 1.75

Electronegativity 2.1 2.5 3 3.5 4 3.2

Bond strength to C

98 83 70 84 105 77

Effects of Fluorine in Drugs

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pKa

Lipophilicity(脂溶性)

Influence to structure

(配座効果)

Changes in physicochemical

properties

Molecular recognition

Stability

Solubility Potency

Selectivity

ADME*

process

*ADME: Absorption, Distribution, Metabolism (代謝), Elimination

Modulation ofdrug profile

Some fluorine-containing drugs

SITAGLIPTIN: a marketed drug that targets DDP-IV, a protein involved in Diabetes Mellitus

Potency

Potency &

CV safety

PotencyPotency &

ADME

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(抗糖尿病薬）

EZETIMIBE: a marketed drug that lowers cholesterol plasma levels

Metabolism

Metabolism


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APREPITANT: a marketed drug, which targets NK1 receptor, approved for the prevention of nausea and vomiting associated with cancer

treatment

Elimination

Potency


FLUOXETINE: a marketed anti-depressant drug that controls the

levels of serotonin

Potency

18(抗嘔吐薬）

(抗鬱薬）


CELECOXIB: a marketed drug that inhibits COX2 enzyme for the treatment of inflammation

Extremely high stability

Potency

Metabolism Potency

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(抗炎症薬）

How can we synthesize fluorine-containing drugs?

Because of the unique and particular properties of fluorine atom, the introduction of a fluorine atom or a trifluoromethyl group (CF3) needs of sophisticated synthetic methods that differ from conventional organic reactions

F or CF3“F or CF3” source

Examples of fluorinating reagents (F source)

Examples of trifluoromethylating reagents (CF3 source)

LIMITATION 1: Hazarous and/or expensive reagents!!

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A few examples of trifluoromethylation reaction (introduction of a CF3 group)

LIMITATION 2: Only a limited number of reactions can be done!!

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Research on alkene difunctionalization

However, there is a need to find new methods for the trifluomethylation reaction that will fulfil the following requirements:

CF3“CF3” source

EASY, CHEAP and EFFICIENT

LIMITATION 2: Only a limited number of reactions can be done!!

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My research at RIKEN


Previous findings from Sodeoka’s research group as starting points: a new CF3 source

My objective is to develop new methods for the

difunctionalization reaction involing trifluoromethylation

EASYCHEAP

EFFICIENT

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Research concept



Application on an specific trifluoromethylation reaction

EASYCHEAP

EFFICIENT24


Final objective of the research: use of this new methodology in the synthesis of new drugs

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Thank you for your attention. Any questions?

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“The best preparation of

tomorrow is doing your best

today”

- H. Jackson Brown, Jr. -

Documents

FLUORINE IN MEDICINAL CHEMISTRY...of Phylosophy) in Barcelona in the field of medicinal chemistry (2011-2015) • Since last November, I am doing a postdoctoral stay at RIKEN thanks