This is a repository copy of Achieving High 1H Nuclear Hyperpolarization Levels with LongLifetimes in a Range of Tuberculosis Drug Scaffolds.

White Rose Research Online URL for this paper:https://eprints.whiterose.ac.uk/123750/

Version: Accepted Version

Article:

Norcott, Philip orcid.org/0000-0003-4082-2079, Rayner, Peter J. orcid.org/0000-0002-6577-4117, Green, Gary G.R. orcid.org/0000-0003-1977-7509 et al. (1 more author) (2017) Achieving High 1H Nuclear Hyperpolarization Levels with Long Lifetimes in a Range of Tuberculosis Drug Scaffolds. Chemistry : A European Journal. pp. 16990-16997. ISSN 1521-3765

https://doi.org/10.1002/chem.201703278

eprints@whiterose.ac.ukhttps://eprints.whiterose.ac.uk/

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laxa

en r

in co

nativ

agne

ove

ave

pola

ir p

y to

bercu

uctu

the r

SABR

the

moun

ewer

further

MR

(1)

stud

de (

he la

been

ercu

to ex

s 3-H

was

R sa

ut ch

sed in

D)(IM

-2-yl

hyper

sible

ling n

into

driv

ments

prog

nucl

ated

at

mally

teronuc

nucl

establ

d for

search

xation

reporte

conju

tively

etiza

er 4

alr

lariza

poten

to in

culosi

tural

relax

RE

e fact

unt of

er 1H

er bene

R re

) a

dy w

(1)

latter

rec

culosi

exhib

H, 5

fou

sampl

chan

n the

IMes)]

yliden

erpo

po

netw

to th

ven

ts in

ogress

clei

wi

wh

y dis

nucle

clei m

ablish

rm,

ch g

n tim

ported

junctio

ly, 1H

zation

min

read

ation

tential

increa

sis

ana

xatio

cou

ct th

of und

H site

enefit

espon

and

with

and

r, a

cogn

sis.[24

ibit T

5-H

und to

ples

nging

e SAB

s)] (w

ene,

olariz

olariz

work

he t

by

in SA

ess in

amo

with

hich

istrib

lei bu

mak

hme

refle

goal

imes

rted in

ion

H sin

ion in

nutes

dy

ion,[22]

ial in

rease

re

nalog

ion t

uld

hat

nderly

ites

efit to

onse

me

h the

d m

along

nize4]

T1 va

and

to ex

of t

g th

ABR

(whe

an

rization

izatio

rk[15]

targ

rad

SABR

in th

ongs

a

th

ribute

ut th

ke it

ent o

lect

l tha

of 1

in a

wit

inglet

in

s.[21]

bee] bu

viv

e th

relate

gues

time

als

eac

rlyin

on

o this

e tha

ethy

e tw

methy

gside

ed a

alue

d 6-

xhib

thes

he

BRE

ere

nd

ion

ion

of

rget

dio

BRE

he

st

all

he

ed

he

its

of

a

at

H

an

ith

let

a]

en

ut

ivo

he

ed

s,

es

lso

ch

ing

a

his

at

yl

wo

hyl

ide

as

es

H

bit

se

tw

ra

sa

p

sh

a

im

a

m

le

w

h

Tab

deuter

Com

1

3

4

5

6

7

8

9

3

4

5

6

two ag

atio

samp

polar

shaki

asso

imme

avera

measu

levels

were

highly

able

deuter

ompound

agen

with

ples

rizati

king

ociate

edia

age

sure

ls of

e 2.4

ly su

1.

deuterated

pound

ents w

th th

s we

ation

the

ated

ate1H

emen

f 1.7

4%,

suitab

T1 v

d methy

pound

wer

the

ere p

tra

e sam

wit

tran

H NM

ents,

7%,

4.3

ble f

value

thyl p

re pr

pre

place

ansfe

mple

h a

nsfe

MR

, un

, 2.6

3% a

for SA

es an

pyraz

repared

ecata

ced u

er ex

le for

a 9

r in

sign

nder

.6% a

and

SAB

and hy

razinec

Si

356

356

56

36

35

5

6

35

356

56

36

35

pared

alyst

under

expe

for 10

9.4

into

gnal i

er SA

and

3.9%

BRE.

hyper

necarbo

ite

-H:-H:-H:

-H:-H:-H:

-H:-H:

-H:-H:

-H:-H:

-H:

-H:

-H:-H:

-H:-H:-H:

-H:-H:

-H:-H:

-H:-H:

pared at

st [I

er 3

erim

0 se

T N

the

inten

ABRE,

nd 2.7%

%. H

. As

perpolari

arboxylat

T

Methanol

Ethanol

a co

IrCl(

bar

iments

secon

NMR

ma

tensitie

RE,

.7%

Hen

s exp

arizat

ate deri

T1(no ca

ethanol

80.620.921.2

64.123.423.5

24.924.0

91.184.0

99.7144.5

39.5

98.1

53.053.1

thanol

55.417.217.2

11.011.7

18.320.9

21.423.8

conce

l(COD

r of p

ts u

nds

R sp

agne

ties

corr

resp

ence,

xpect

ation

derivati

cat.) (s)

ethanol-d4

80.620.921.2

64.123.423.5

24.924.0

91.184.0

99.7144.5

39.5

98.1

53.053.1

thanol-d6

55.417.217.2

11.011.7

18.320.9

21.423.8

centra

OD)(I

p-H2

unde

in t

spec

net

see

rresp

pect

bot

ted,

leve

atives

)

4

ration

IMe

2 an

ertak

he 6

ctro

for

en fo

pond

tively

th of

, the

els o

s.

T1(w

tion of

s)]

nd a

ken

65 g

mete

me

for 1

onded

ly, w

f the

e me

of 1,

with cat.

32.712.112.3

20.69.3

12.0

10.314.1

26.039.2

32.926.2

22.6

43.1

25.621.8

8.34.67.4

5.47.6

5.913.6

10.811.5

f 20

(5

serie

wh

gauss

ter,

easu

1 in

to

while

ese

easu

3 a

t.) (s)

32.712.112.3

20.69.3

12.0

10.314.1

26.039.2

32.926.2

22.6

43.1

25.621.8

8.34.67.4

5.47.6

5.913.6

10.811.5

0 mM

mM

ies o

which

ss fr

foll

surem

the

po

e th

mate

ured

and

) P

Lev

M in

M). T

of S

h invo

fringe

llowed

ment.

e resu

olariz

those

teria

d T1 v

a ser

Polari

Level

2.72.81.6

4.33.92.4

3.52.8

6.76.2

11.99.2

7.8

2.5

8.87.5

3.161.960.95

2.350.99

4.43.9

4.72.9

in a 4

The

SABR

volve

e fie

ed

t. T

sulti

izatio

se for

als a

valu

eries

arizati

el (%)

2.7 ± 0.2.8 ± 0.1.6 ± 0.

4.3 ± 0.3.9 ± 0.2.4 ± 0.

3.5 ± 0.2.8 ± 0.

6.7 ± 0.6.2 ± 0.

11.9 ± 09.2 ± 0.

7.8 ± 0.

2.5 ± 0.

8.8 ± 0.7.5 ± 0.

16 ± 0.1.96 ± 0.0.95 ± 0.

35 ± 0.0.99 ± 0.

4.4 ± 0.3.9 ± 0.

4.7 ± 0.2.9 ± 0.

4:1

These

RE

ved

ield

by

The

ing

ion

r 3

are

ues

s of

tion

%)

.3

.3

.1

.3

.2

.2

.3

.2

.3

.3

0.6.5

.2

.2

.3

.2

.08

.05

.04

.05

.02

.2

.3

.3

.2

F

of

in

fro

fa

th

be

st

Sy

m

hyp

and

co

tra

sy

th

Sch

isotopcM

Na

S

py

po

a

deu

re

wh

In

exh

leve

su

25

its

ca

co

st

po

~3

va

hen

FULL

f 3 u

in acc

om th

fall in

that fo

etter

ronger

ynth

methy

yper

nd 3

corresp

anse

synth

the su

chem

otopol

Methy

a2CO

SABR

yrazi

olariz

sing

eute

elaxa

hilst

In con

xhib

levels

subst

5 an

its ab

cataly

conse

rikin

ositio

3700

value

ence

LL

under

ccord

the

in T1 fo

for 3

tter po

ger

hesis

hyl p

erpola

3 we

spond

seste

thetic

supple

eme 2

ologues

ethyl 3,6

O3 us

BRE

zine

izati

ngle

teratio

ation

st de

ntra

ibits si

ls (6

rate

and 3

bsen

lyst

sequen

ing re

tion

00-fo

es of

ce we

ULL PAP

er SA

danc

free

for t

3 wa

olariz

inte

is of

pyra

lariza

ere p

ndin

erific

pro

lemen

2. S

ues

6-dib

sed in

studi

e-2-c

ion d2H-

ion

ion tim

eliveri

ast,

sign

6.2‒6.7%). In this case the effective e in

39 se

nce.

is t

ently

resu

as

old s

f the

e ha

PAPER

SAB

ce w

e an

the s

as 6

rization

eract

of de

razine

ation

prep

ing h

ication

roced

enta

Synth

3-12

bromo

n plac

tudie

carboxy

data

-labe

at t

imes

ring

com

ignifica

‒6.7%). In this case the effective the

econ

The

there

ly high

ult th

com

signa

e 1H

ave

PER

RE

with the

and bo

sites

60%

tion tr

tion

eute

ne-2-

n le

epared

heter

tion o

dure

ary in

nthetic

2.aC

opyra

ce of

ies

boxy

a for

el a

the

es of

com

mpou

cantly

‒6.7%). In this case the effective pre

nds,

hese

erefor

igher

though

mpou

gnal ga

H nucl

ach

R

con

the fa

bound

s in

% wh

trans

with

erat

-carb

level,

ed by

teroaryl

or a

es an

infor

c route

Comm

razine

of K2C

on

ylate

r the

are

3-p

the

mpa

ound

tly im

‒6.7%). In this case the effective esenc

s, and

num

fore r

r hy

ugh w

ound

gain)

uclei

chieve

ndition

fact

d fo

1 und

which

ansfer

th the

ted a

arboxy

, a se

by the

oaryl ch

amid

and ch

formatio

oute

merc

ne-2-c

CO3.

n d

e

he me

deta

positio

e re

parab

5,

improve

‒6.7%). In this case the effective nce

nd th

umber

redu

perpo

was

6

) and

in 6

ed ou

ons

ct tha

forms.

under

is co

r in

e ca

ana

xylat

serie

e pal

chlo

idatio

char

tion.

to

ercially

carbox

deut

(3)

ethyl

ailed

tion

emai

ble le

whe

ved

‒6.7%). In this case the effective of the

they in

ers in

uced

pola

ach

gav

nd 9

6 ar

our

at 2

at the

s. [23,

er the

consi

3 a

cataly

alog

late (

ies o

allad

loride

tion a

aracte

n.

the

avai

rboxylate

tera

Th

yl est

ed in

, ga

ainin

levels

where

rela

‒6.7%). In this case the effective the

increa

indic

d by

lariza

hieve

ave 1

9.2%

re now

initi

298

hey re, 25] The

hese

siste

as th

lyst.

ogues

(3)

of d

dium

es u

as s

eriza

pyr

ailabl

ate us

ated

The

ster d

in Ta

ave

ining 1

ls of

the

laxat

‒6.7%). In this case the effective hyp

reas

icate

by s

ation

ieved

11.9%

% po

ow

ial g

K w

refle

The

e con

ent

hese

s of

In o

deut

ium-ca

unde

show

ation

razine

le.b

used

analo

relax

deriv

able

a

H n

f SAB

lab

tion

‒6.7%). In this case the effective perpo

se to

e tha

subs

ion lev

with

% p

olariz

100

goal

were

flect a

cor

nditi

with

se diff

pyra

orde

terat

cataly

der D

wn

n da

ne carbo

D2O/

as the

nalo

laxa

ivativ

e 1.

sligh

nucle

ABR

bel is

tim

‒6.7%). In this case the effective olariz

to 91

at re

strate

vels

ith deu

polar

izatio

00 and

of p

e fou

a we

rresp

itions

ith the

iffere

yrazi

der to

ted

lysed

D2,[20

in S

ata a

arbox

/THF

the starti

logue

ation

tives

Su

ht in

ei co

RE p

s in

times a

‒6.7%). In this case the effective T

izati

1 and

elaxa

e d

resu

deute

ariza

tion fo

nd 145

produ

und

eight

spond

s wa

e obs

ence

zinamid

to imp

deri

d reduc20, 26]

Sch

are

xylat

F ins

tarting

ues

n a

4-6

ubstr

incre

com

polar

in the

and

T1 va

ation

d 84

xatio

deute

sult. [

ratio

ation

for 5

45 se

duci

nd to d

ted r

nding

was 47

bser

ces su

amide

prove

rivativ

ductio

foll

cheme

pre

ate and

nstead

ng m

of

and

6 tha

rate

ease

mpared

rizatio

e 5-

pola

value

cata

84 seco

tion w

eratio20] T

tion a

n for

5-H

seco

cing

dec

resp

g av

7%,

rvat

sugg

de (1

ve o

tives

tion

llowe

e 2

esen

and

d of

mater

m

SA

at co

e 4,

e in

red

tion

-pos

lariz

es o

alys

econ

within

tion

The

at th

r 3-

H. Th

onds

a st

creas

pons

verag

, wh

ion

gest

(1) and

on th

s of

of th

ed b

2. Full

nted

ami

EtOD

rial a

methyl

SABR

onta

wit

n th

to 3

to it

sition

rizatio

of th

st ar

nds in

n th

an

mos

he 6

-H (

The T

s an

tron

se

se

ge

hile

of

t a

nd

he

1

he

by

Full

in

mide

OD.

and

thyl

BRE

ain

ith

he

3,

it.

ion,

ion

he

re

in

he

nd

st

6-

(a

T1

nd

ng

a

co

p

w

d

th

co

n

S

2

sh

S

re

co5J

th

p

rep

a

e

a

ch

vi

S

d

In

ca

se

N

5

o

in

in

re

a

n

o

p

te

d

rea

in

co

Tab

sol

Com

5

6

and

consi

prese

which

desir

that

comp

not a

SABR

2.5%

shorter

Sche

emo

coup

JH-H

the C

predic

epla

amen

enhan

althoug

change

visco

SABR

deute

In orde

cataly

serie

NHC

5 an

optim

increa

inform

espo

at 9.4

not a

obse

polar

temp

d22-IM

ealize

inform

condu

able

olution.

ompound

long

siste

sent w

Fro

h co

rable

wou

poun

a lon

RE

% po

ter. T

eme

ote to

pling

cou

We

CH3

ictio

lacing

enable

ance

ough

nge

osity

BRE

erat

rder

lyst

ies of

HC iso

and 6

timal

creasin

mati

onse

.4 T.

as effi

served

rizati

peratu

IMes

zed

mati

ducte

2. E

on.

pound

ng live

nt w

with

om

conta

e pr

ould

ounds

ng a

resp

polariz

The

1)

to e

ng in

uplin

e so

gro

tions,

ng th

le

emen

h the

is co

y and

inv

ted

to se

can

f de

otopo

6, w

with

ng a

ation)

e of

. The

ffica

d p

ation

ture

es ca

(co

ation)

ed ha

Effect

pound

ved

with

hin 3

an

ain

robe

be

exh

as t

pon

ization

These re

occ

ester

the

ng th

ough

oup

this

he m

solv

ents

e be

cons

d he

nvestiga

analo

see

n be

eute

olog

when

h bo

as

). Th

f 6 c

The ca

aciou

pola

tra

e. This

ataly

orres

). Th

has

t of a

resp

the

3.

MR

a s

es d

see

hibit

thos

nse o

ion a

resu

curs

r, w

e SAB

hat w

ht to

in 6

is d3-

meth

vent

ach

est re

siste

ence

tigation

nalogu

if th

e red

erate

gues

n th

oth

deta

he p

corre

ataly

ious, s

arizat

ransf

This

lyst a

spon

he te

be

a de

spons

e rem

RI per

single

ue to

en

ited h

se o

of 7

achie

sults co

pre

with

ABR

woul

to fu

6 wit

-meth

thano

t eth

chieve

resu

tent

ce mo

tions

gues

the e

educe

ted a

s had

the c

the

tailed

polar

espon

lyst b

sligh

tion

sfer

reve

at 0°

nding

emp

en

deutera

Li

d

d

se.

emova

ersp

le p

to th

in a

highe

of 6.

7.8%

ieved

confirm

edom

the

RE ca

uld b

furthe

ith a

ethyl

anol-d

ethano

ed a

sults w

with

ore fa

ns ha

s of

effect

ced,

analo

had the

cataly

the T1

ed in

ariza

onds

bear

htly

n. In

effi

veale

°C a

ng to

pera

sho

terated

Ligand

IMes

d22-IM

IMes

d22-IM

This

val o

spectiv

proto

the red

an

her p

. Ho

% po

ved for

nfirm

mina

ass

cataly

be use

ther im

a CD

yl est

d4 s

nol-d

across

were

ith the

facile

arnes

f m

ct of

this

logue

the for

lyst

1 va

in Tab

ation

s to

ring

incre

In a

fficien

ed th

a ~63

to 20.4

ature

own

catal

gand

es

IMes

es

IMes

is in

of th

tive,

on,

educt

ech

proto

oweve

olariz

or 8

firm the

ately

ssocia

lyst

sed

mpro

CD3 g

ster pe

solve

d6,

cross

e stil

the a

le re

essin

methy

f rela

is pro

ues o

form sh

bea

values

able

n leve

to a ~

the

creasi

an e

ncy,

that w

6300

0.4%

e at

to

atalyst

S

36

36

35

35

increa

the st

, su

and

ction

cho p

ton

ver,

izatio

eve

erefo

ly at

ciated

bein

for

ove

roup

perfor

ent

the

this

ill ach

assoc

elaxa

ing

hyl p

laxa

ocess

of [I

show

ears

s and

le 2

vel of

~4200

e d24

sing

effor

, w

whe

00-fo

% p

whi

sign

and

Site

3-H:6-H:

3-H:6-H:

3-H:5-H:

3-H:5-H:

ase

stron

ubstra

d tw

ion in

plan

T1 v

r, 7 p

ion w

en t

ore t

t the

d 4J

ing

8.

the

p to

rform

with

e T

is se

achiev

ociated

xation

deut

pyra

ation

ss w

IrCl(

own

a d

nd

2 (a

of 1

00-f

4-IM

T1 v

rt t

we

en 6

old s

polariz

hich

ignific

d sub

in

ng 3

rate

wo 2

in che

nar

valu

prod

whic

thou

that

e nit

JH-H

mo

ese

o pro

med

h th

T1

eries

ieved

iated

ion th

utera

razine

n ca

was

l(COD

in Fi

d22-I

hyp

also

13.4

fold

Mes li

value

to f

tes

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clus

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prior

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eriment

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