MCE 同位素标记物 Isotope-Labeled Compounds Handbook

Isotope-LabeledCompounds

Tetrabenazine-d6

L-Leucine-15N

L-Leucine-18O2

D-Glucose-13C6

MCE

MasterofBioactiveMolecules

1

1H

1H2H3H

1

012

23

2H(D)

3H

2H 13C 15N 18O

1) 2)

[1][2][3]

Electronshell

e-

e-

e-

n

p+

p+

n

p+

n

Hydrogen-1 Hydrogen-2,deuterium Hydrogen-3,tritium

massnumber:1 massnumber:2 massnumber:3

Figure1.Isotopeofhydrogen

CONTENTS

2

MCE

4

10

MCE

12

www.MedChemE

,QKLELWRUV̽6FUHHQLQJ/LEUDULHV̽3URWHLQV

(PharmaceuticalResearch)

Deutetrabenazine

Tetrabenazine

[3]

4)

5)

1)

2)

3)

6)

PET

[4]

DeuterationinDrugDesign

C

H

C

D

Mayleadto:

PKImprovement

ReductionofToxicity

ReductionofEpimerization

MechanismofAction

denovoDrugDesign

O

ND

HO

O

F

NH2O

O

DD

N

D3CO

H

F

N

O

D

NN

N

H

N

*

N

NNN

ND

EtO

N

N

D3CO

N

N

N

N

D

H

Tetrabenazine-d6

JNJ38877605-d

Thalidomideanalogue-d

Linoleicacidanalogue-d2

VX-984

1stapproveddrug

Figure2.Deuterationindrugdesign[4]

(MetabolicResearch)

UPLC/QTOFMS

MS/MS

JixiaYang

13C15N

Ƌ6\QXFOHLQ

7

(Ƌ6\Q)

[5]

(Proteomics)

(Glycomics)

MichaelJ.Bowman TetraplexStable-IsotopeCodedTag

TetraplexStable-IsotopeCodedTag

[6]

2

MCE

MasterofBioactiveMolecules

(StandardsforEnvironmentalAnalysis)

PCBsPBDEs

ChenchenHuang

GC-qMS

Cl/Br

PCBs/PBDEs

[7]

(ClinicalResearch)

13C

(BiomolecularNMR)

13C

15N

(TraceElementAnalysis)

LinardsKlavins

Ǝ182Ǝ151Ǝ13C,‰

+

0

-

[8]

38.28

35.51

36.26

33.63

33.81

32.93

30.29

25.65

29.21

29.00

28.09

1.86

0.03

2.56

3.68

1.27

-0.20

-2.17

-6.24

-5.57

-9.89

-12.87

-23.89

-25.31

-25.14

-27.30

-26.98

-27.97

-26.27

-24.05

-24.77

-26.63

-28.60

Latvia

Poland

Germany

6SDLQ

Portugal

Morocco

China

Peru

Argentina

Chile

Uruguay

)LJXUH /LJKWVWDEOHHOHPHQWLVRWRSHƎ13&Ǝ151Ǝ18O)ratiovaluesinblueberriesfromdifferentcountries[8]

3

www.MedChemE

,QKLELWRUV̽6FUHHQLQJ/LEUDULHV̽3URWHLQV

MCE

6RUDIHQLE Donafenib

6RUDIHQLEG Donafenib(Sorafenibd3) Sorafenib

[9]

6RUDIHQLE 6RUDIHQLEG

Cl

F

FF

O O

NN

H H

O

N

Cl

N

H

F

FF

O O

NN

H H

N

O DD

NDH

MCE

2H13C15N18O

1)

2)

͡

3)

͡

4)

5)

MCE

2H(D)

2H(D) 1 1 1

2H(D)

HY-B0590S

Tetrabenazine-d6

͡DWRP'

D

D

D

O

D

O

D

H

D

N

CASNo.:1392826-25-3

HY-17357S

Nepafenac-d5

͡ DWRP ' D D D

DD

NH2

O

CASNo.:1246814-53-8

HY-10065S1

HY-B0304AS1

Axitinib-d3

N

Dapoxetine-d6hydrochloride

͡DWRP'

͡DWRP'

N

DD

6

N

O

H

DN

O

ONH

DDD

DDD

HCl

CASNo.:1126623-89-9

CASNo.:1246814-76-5

HY-16293S

HY-B0801S

Lurbinectedin-d3

O

D

Fexofenadine-d6

͡DWRP'

HN

N

DD

͡DWRP'

OH

SO

H

OH

O

N

HHO

O

DD

NN

O

D

NH2

H

D

O

HH

HO

DDOOH

CASNo.:N/A

OH

O

CASNo.:548783-71-7

O

4

MCE

MasterofBioactiveMolecules

HY-14914S

Azilsartan-d5

͡DWRP'

D

D

D

N

D

O

N

O

D

O

O

OH

HN

N

CASNo.:1346599-45-8

F

HY-131968

%06

N

N

͡DWRP'

O

NH

O

D

D

N

D

H

HN

N

O

CASNo.:1771691-34-9

HY-110228

Metformin-d6hydrochloride͡DWRP'

DD NH NH

DNNNH2

H

DDDHCl

HY-50895S

*HͤWLQLEG

͡DWRP'

O

N

DDD

N

D

N

O

O

D

Cl

NH

DDD

F

CASNo.:857091-32-8

HY-13562S

D

DD

Banoxantrone-d12

N

O

͡DWRP'

D

OH

O

HNDD

OH

O

HN

DD

N

D

CASNo.:1562067-05-3

D

O

DD

HY-B0673S

Pirfenidone-d5

͡ DWRP ' D

D D

DN

DO

HY-10997S O

Ibrutinib-d5N

͡ DWRP 'N N

N

N

NH2

D

D

O

D

CASNo.:1553977-17-5

DD

HY-13631AS

Exatecan-d5mesylate

͡ DWRP ' H2N

O

N

O

N

O

OH

O

F

D

D

6

OH

DDD

O

CASNo.:N/A

HY-A0093S

Mexiletine-d6hydrochloride͡DWRP'

D

DDD

D

O

DNH2

HCl

CASNo.:1185166-01-1

HY-15328

25-HydroxyVD2-d6

DD

͡DWRP'

OHD

D

DD

H

HO

CASNo.:1020719-62-3

HY-15321S

Etoricoxib-d4

͡DWRP'

OOD

6

D

D

N

D

Cl

N

CASNo.:1329835-60-0

HY-15777S

Ribociclib-d6

͡DWRP'

H

NNNN

O

N

D

N

ND

D

HN

D

DD

CASNo.:1262843-46-8

HY-15330

VD2-d3

͡ DWRP '

D

H

D

D

HO

CASNo.:11217448-46-8

HY-19939S

9;

D

N

N

͡DWRP'N

N

D

NH

N

ONH

CASNo.:1476074-39-1

CASNo.:1131345-14-6

HY-15285

Doxercalciferol-d3

͡ DWRP '

D

H

D

D

HOOH

CASNo.:N/A

HY-15332

Alfacalcidol-d6

DD

͡DWRP'

D

D

DD

H

HO

OH

CASNo.:1641940-94-4

CASNo.:1328934-40-2

HY-W010388AS

Creatine-d3hydrate

͡DWRP'

DD

D

O

H2N

N

OH

NHH2O

CASNo.:284664-86-4

HY-76814

Calcitriol-d6

HO

͡DWRP'

D

H

OH

D

OH

D

D

D

D

CASNo.:78782-99-7

5

www.MedChemE

,QKLELWRUV̽6FUHHQLQJ/LEUDULHV̽3URWHLQV

HY-B0141S

HY-32351S

Estradiol-d3

Calcifediol-d3

OH

͡DWRP'

HODD

͡DWRP'

D

H

D

D

HD

H

H

HO

HO

H

HY-14654S

Aspirin-d3

͡ DWRP '

O

O

D

D

OOH

D

CASNo.:79037-37-9

CASNo.:140710-94-7

HY-17501S

HY-10201S

Bambuterol-d9hydrochloride

Sorafenib-d3

͡DWRP'

D

D

DDD

͡DWRP'

HN

D

D

Cl

HO

D

D

F

O

O

O

F

N

N

N

O

O

N

F

H

H

HCl

CASNo.:1794810-59-5

CASNo.:1130115-44-4

HY-N0570S1

HY-101392S

Hydroxytyrosol-d5

Harmane-d1

͡DWRP'

D

͡DWRP'

D

OH

HO

OH

DD

D

O DD

OND

N H

H

N

N

D

CASNo.:921943-73-9

HY-B0207AS

Pyridostigmine-d6bromide͡DWRP'

DD

O

N+

D

N

O

Br-

DD

D

CASNo.:2375858-08-3

HY-15162A

00$(G

͡ DWRP 'O O OO

O

N

HN

N

HO

O

D

DD

HN

N

D

D

H

DDD

CASNo.:N/A

HY-13609S

Deflazacort-d5

O

͡DWRP'

O

O

D

D

D

ND

HO

D

O

H

H

H

H

O

CASNo.:N/A

HY-B0273S

Sulfadiazine-d4

͡DWRP'

D

O

H

D

6

N

N

H2N

D

O

N

D

CASNo.:N/A

HY-B0510S2

Trimethoprim-d3

͡ DWRP ' D

ODD

H2NNNH2

O

NO

CASNo.:1189923-38-3

HY-14914S

Azilsartan-d5

DD

͡DWRP'

ND

D

O

O

D

O

N

O

OH

HN

N

CASNo.:2070009-72-0

HY-N0324S

Cholicacid-d4

͡DWRP'

OH

H

OH

D

H

O

D

H

H

HO

OH

DDH

CASNo.:116380-66-6

HY-B0801S

Fexofenadine-d6

DDO

͡DWRP'

DD

OH

D

HO

D

N

OH

CASNo.:1020719-78-1

CASNo.:1346599-45-8

HY-113468AS

HY-16060S

3-O-Methyldopa-d3

Apalutamide-d4

͡DWRP'

͡DWRP'

F

F

O

F

6

O

D

O

OH

N

N

D

NN

H

D

NH2

N

DF

HO

D

OD

CASNo.:586954-09-8

CASNo.:1638885-65-0

D

CASNo.:548783-71-7

HY-B0469S

Medroxyprogesterone-acetate-d3

͡ DWRP '

O

D

D

O

D

H

O

H

H

O

CASNo.:N/A

6

MCE

MasterofBioactiveMolecules

13C

13C13C

(12C)

HY-50896S1

Erlotinib-13C6 H

͡DWRP13C H13C13C13CH

HN13C13C13C

OONH

OON

CASNo.:1211107-68-4

HY-N0437S1

Progesterone-13C5

͡DWRP13C O 13CH

13C 3

H

H213C

HH

13C

O

13C

H

CASNo.:2687960-32-1

HY-14605BS

Rasagiline-13C3mesylateracemic

͡DWRP13C

H2

HN

13C

13C

O

13CH

6

OH

CASNo.:1216757-55-9

O

HY-Y0252S

L-Proline-13C5

͡DWRP13C

H2 O

13CH13C

H213C13C OH

H213CNH

CASNo.:201740-83-2

HY-Y0479S3

L-Lacticacid-2-13C1

͡DWRP13C

O

H

13C OH

OH

CASNo.:740788-63-0

6 7

HY-B1732S1

DL-3-Phenylalanine-13C

͡DWRP13C

H2

O

13C

OH

NH2

CASNo.:286425-42-1

HY-N0683S

Ƌ9LWDPLQ( &

͡DWRP13C

13C OH

13C13C

O13C13C13C

CASNo.:2140857-08-3

HY-17598S

Rafoxanide-13C6

͡DWRP13C

O

O

I

C

13

N

Cl

Cl

13

C

13

C

H

13

C

C

13

OH

13

C

I

CASNo.:1353867-98-7

HY-W010407S

Cyanuricacid-13C3

͡DWRP13C

O

HN13CNH

O13CN13CO

H

CASNo.:201996-37-4

HY-N0486S1

L-Leucine-13C

͡DWRP13C

O

13COH

NH2

CASNo.:74292-94-7

13

HY-N0216S1

Benzoicacid-13C6

͡DWRP13C

H

O

H13C

13C

OH

13C

H13C

13

13CH

HC

CASNo.:125945-98-4

HY-15306S

(E/Z)-Eltrombopag-13C4

͡DWRP13C

13CH3

N13C

H

OH

N13C

N

OH

13C

N

O

O

CASNo.:1217230-31-3

HY-B0289S

Erdosteine-13C4

͡DWRP13C

6

O

O

O

13C

613C

OH

N

13

13

H

H2C

H2C

CASNo.:N/A

HY-115584S

Lufenuron-13C6

͡DWRP13C

H

F

Cl

13C

O

F

FO

O13C

13C

F

13C

13CF

F

F

N

N

13C

Cl

FH

H

H

CASNo.:N/A

HY-15407AS

Sacubitril-13C4hemicalciumsalt͡DWRP13C

H2

O

O

13C

13C

0.5Ca2+

13C

13C

N

O-H2

H

O

CASNo.:N/A

O

7

www.MedChemE

,QKLELWRUV̽6FUHHQLQJ/LEUDULHV̽3URWHLQV

15N

15N (14N)7815N

HY-41877S

HY-N0390S

Succinimide-15N

L-Glutamine-15N

͡DWRP15N

͡DWRP15N

H

O

O

15N

O

O

H2N

15

OH

CASNo.:80143-57-3

NH2

CASNo.:32807-36-6

HY-W008371S

HY-Z0283S

Fmoc-Met-OH-15N

Benzamide-15N

͡DWRP15N

͡DWRP15N

O

H

15NH2

O

15N

6

OO

OH

CASNo.:934183-50-3

CASNo.:31656-62-9

HY-Y0271S

HY-19821S

Urea-15N2

Fmoc-Ile-OH-15N

͡DWRP15N

͡DWRP15N

O

H

H215N

15NH2

O

15N

CASNo.:2067-80-3

CASNo.:204633-89-6

OO

OH

HY-Y1117S

HY-Y0978S

Melamine-15N3

Boc-Glycine-15N

͡DWRP15N

15NH2

͡DWRP15N

H

O

15

HY-N0473S1

L-Tyrosine-15N

͡DWRP15N

O

OH

HO15NH2

CASNo.:35424-81-8

HY-N0667S2

L-Asparagine-15N2monohydrate͡DWRP15N

O

H215NOH

O 15NH2

HOH

CASNo.:287484-32-6

HY-N0455AS

L-Arginine-15N2hydrochloride͡DWRP15N

15NH O

H215NNOH

H NH2HCl

CASNo.:204633-92-1

HY-101037S

Sarcosine-15N

͡DWRP15N

H O

N

N

O

15N

OH

H215N

N

15NH2

O

CASNo.:287476-11-3

CASNo.:106665-75-2

HY-N0326S

HY-W017443S1

15N

CASNo.:N/A

HY-N0470S

OH

L-Methionine-15N1

L-Asparagine-amide-15N

͡DWRP15N

͡DWRP15N

O

O

6

OH

H215N

OH

ONH2

15NH2

HOH

CASNo.:82572-25-6

CASNo.:204451-47-8

L-Lysine-15N2hydrochloride͡DWRP15N

O

H215NOH

15NH2

HCl

CASNo.:1217460-44-0

8

MCE

MasterofBioactiveMolecules

2H 13C 15N

HY-B1640S

Ethacrynicacid-13C2,d5

HY-90001S1

Ritonavir-13C,d3

HY-B0495S

Lamotrigine-13C3,d3

͡DWRP'͡DWRP13C

DD

O

D

DD

Cl

CASNo.:N/A

Cl

HY-70050AS1

Alosetron-13C,d3

͡DWRP'D͡DWRP13CDD

13C

N

H2

13C OH

O13C

O

͡ DWRP '

͡ DWRP 13C

6

D

D

D

O

OH

N

C

13

H

H

O

N

N

N

N

N

6

O

H

O

CASNo.:N/A

HY-12651AS

Primaquine-13C,d3

͡ DWRP '

͡ DWRP 13C

D

N

͡ DWRP '

͡ DWRP 13CD D D

Cl13CNN

Cl 13C 13C

H2NN NH2

CASNo.:1246815-13-3

HY-B0373S

Tiopronin-13C,d3

͡DWRP'

͡DWRP13C

6H

H

O

D

N

N N

ONH

CASNo.:N/A

HY-B0421S1

Mycophenolicacid-13C,d3

͡ DWRP ' D

͡ DWRP 13C D13CD

OO O

OH

O OH

CASNo.:2455553-76-9

HY-16637S2

Folicacid-13C5,15N1

͡ DWRP 13C

͡DWRP

15

N

O

O

C

OH

13

13

H2

C

OH

O

13

C

N

15

N

H

13

C

13

C

HN

N

H

H

O

2

H2

N

N

N

H

CASNo.:N/A

HY-B0389S

D-Glucose-13C6,d7

͡ DWRP '

͡ DWRP13CDOHDOHOHO13C13C13C13C13C13CD

D DHODHOD

CASNo.:201417-01-8

D

NH2

D13CO

N

H

CASNo.:N/A

HY-135330

Lamivudine-13C,15N2

͡DWRP13C

͡DWRP15N

O

6

OH

13C

O

O

15N

15N

H2N

CASNo.:1391052-30-4

HY-W017443S

L-Asparagine-13C4,15N2

͡ DWRP 13C

͡ DWRP 15N H2 O

H215N13C13C13CH13COH

O 15NH2

HOH

CASNo.:202406-87-9

HY-I0626S

Cytosine-13C2,15N2

͡DWRP13C

͡DWRP15N

H

H215N13

15N

O

C

13C

15N

CASNo.:285978-06-5

D

13C

OH

DOH

H

CASNo.:1189695-13-3

HY-107372S

Uridinetriphosphate-13C9,15N2

͡DWRP13C

͡DWRP15N

H2

O

O

O

OH

O

H13C

O

P

O

P

O

P

OH

15

N

13C

13

13

C

H

15

C13

OH

OH

OH

13C

N13

CH

13

CH

O

13C

CHHO

OH

H

CASNo.:285978-18-9

HY-N0667S

/$VSDUDJLQH&1G

͡DWRP13C

͡DWRP15N

O

D

15N

D

͡DWRP'

D

13C

13C

13C

O

D

15N

D13C

D

D

D

O

CASNo.:1217464-18-0

HY-N0666S1

L-Asparticacid-13C4,15N

͡DWRP13C

͡DWRP15N

O

H2

13CH13C

OH

HO

13C13C

15NH2

O

CASNo.:202468-27-7

9

www.MedChemE

,QKLELWRUV̽6FUHHQLQJ/LEUDULHV̽3URWHLQV

(MFA)

13C 15N

[10]

Metabolite

extraction

BiofluidsCellsandmedia

Tissues

6DPSOHFROOHFWLRQDQGSUHSDUDWLRQ

Metabolomicdataacquistion

Glucose

Acetyl-CoA

Oxaloacetate

Citrate

value

Malate

3

10

TCAcycle

log

-

Fumarate

Ƌ.*

6XFFLQDWH

Functionalandmechanisticvaildation

Metabolicfluxanalysis

VolcanoPlot

Heatmap

20

Group1

15

10

Group2

5

0.

M1

2

4

6

8

10

Metabolites

Metabolomicdataanalysis

5

Pyrimidinemetabolism

-log103value

4

1

TCAcycle

2

3

3

4

5

2

Impact

0.1

1

0.3

0.5

0 0.2 0.4

Pathwayimpact

Metabolicpathwayanalysis

Figure4.WorkflowofLC-MSbasedmetabolomics[10]

10

MCE

MasterofBioactiveMolecules

NADPH

(OxPPP)THF

(IDH1)

(MEI)

NADPH

NADPH

DNA

(OxPPP)

(Non-OxPPP)

M

(<1-13C>glucose

<12-13C>glucose)

(13C)

13CO2

OxPPP

<1-13C>glucose

M+1

Non-OxPPP

5

<12-13C>glucose

Non-OxPPP

M+1M+2

M+2

5[11][12]

$

C1

[1-13C]glucosefeeding

D-Glucose

Oxidative

C1

C1

PPP

G6P

G-1,5--6P

6PG

C1

C1

C1

G3P

C1

F6P

Ru5P

Ribose

TK

C1

C1

Non-xidative

C5C6

C

PPP

Histidine

Xu5P

R5P

TK

E4P

G3P

C1

C3

TA

63

%

C1

[1,2-13C]glucosefeeding

C2

D-Glucose

Oxidative

C1

C1

C1

6PGC2

PPP

G6P

C2

C2

G-1,5--6P

C1

C1

C1C2

C1

G3P

C2

Non-xidativeF6PC2

Ru5P

Ribose

PPP

TK

C1

C1

C4C5C6

C2

C2

C

Xu5P

R5P

Histidine

E4P

G3P

TK

C1C2C3C4

TA

63

Legends

OxPPP

None-OxPPP

1.0

[12C]

[13C]

Absenceofgene

ProportionalMIDs

0.8

0.6

0.4

0.2

0

m0

m1

m2

m3

m4

+LVP]

[C1-6]

Legends

OxPPP

None-OxPPP

[12C]

1.0

[13C]

ProportionalMIDs

Absenceofgene

0.8

0.6

0.4

0.2

0

m0

m1

m2

m3

m4

+LVP]

[C1-6]

Figure5.Movementof13ClabelthroughOxPPPandnon-OxPPPinR.solanacearumF1C1[11]

11

www.MedChemE

,QKLELWRUV̽6FUHHQLQJ/LEUDULHV̽3URWHLQV

MCE

MCE

2HD1313C

1515N

MCE

MCE

MCE

MCE

D 13C

15N 18O

(

13C )

(AA)

20

(TCA)

Ƌ

(EMP)

6

A

Bƌ

37

(C2-C6)

(C7-C12)

(>C14)

VAVB VCVDVE

16

(C16-C19)

MCE

12

MCE

MasterofBioactiveMolecules

HY-32349S

25-hydroxyVitaminD2-d3

͡DWRP'

D

OH

D

HD

HO

H

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HY-Y0966S

Glycine-15N

͡ DWRP 15N

O

H215NOH

CASNo.:7299-33-4

HY-B0350S

Butyricacid-d7

͡ DWRP '

DD O

D OH

DDDD

CASNo.:73607-83-7

HY-B0389A

D-Glucose-13C6

͡DWRP13C

OH

OH

H2

13

13

O

13CH

HC

H

HC

13

HO

13C

13C

C

H

OH

OH

CASNo.:110187-42-3

HY-B0141S

Estradiol-d3

͡DWRP'

HO

DD

H

D

HY-32351S

Calcifediol-d3

͡DWRP'

D

OH

D

HD

HO

H

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HY-N0486S3

L-Leucine-15N

͡ DWRP 15N

O

OH

15NH2

CASNo.:59935-31-8

HY-N0420S

Succinicacid-d6