S1B

Electronic Supplementary Information for

First Synthesis, Full Characterization, and Evidence for the Presence in Human Biological Fluids, of Sulphate and Glucuronide Conjugates, as a Result of Coffee Consumption.

René Fumeaux,† Candice Menozzi-Smarrito,† Angelique Stalmach,‡ Caroline Munari,† Karin Kraehenbuehl,† Heike Steiling,† Alan Crozier,‡ Gary Williamson,† and Denis Barron*,†

† Nestlé Research Center, PO Box 44, CH-1000 Lausanne 26, Switzerland. ‡Plant Products and Human Nutrition Group, Graham Kerr Building, Division of Ecology and Evolutionary Biology, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.

Part B: Purity control data

Abstract - A systematic investigation of the human metabolism of hydroxycinnamic acid conjugates was carried out. A set of 24 potential human metabolites of coffee polyphenols has been chemically prepared, and used as analytical standards for unequivocal identifications. These included glucuronide conjugates and sulphate esters of caffeic, ferulic, isoferulic, m-coumaric and p-coumaric acids as well as their dihydro derivatives. A particular focus has been made on caffeic and 3,4- dihydroxyphenylpropionic acid derivatives, especially the sulphate conjugates, for which regioselective preparation was particularly challenging, and have so far never been identified as human metabolites. Ten, out of the 24 synthesized conjugates have been identified in human plasma and/or urine after coffee consumption. A number of these conjugates were synthesized, characterized and detected as hydroxycinnamic acid metabolites for the first time. This was the case of dihydroisoferulic acid 3’-O- glucuronide, 3’-sulphate, as well as the sulphate and glucuronide derivatives of 3,4-dihydroxyphenylpropionic acid.

*To whom correspondence should be addressed. Nestlé Research Center, PO Box 44, CH-1000 Lausanne 26, Switzerland. Phone: + 41 21 785 9497. Fax: + 41 21 785 8554. e-mail: [email protected]

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S2B

Table of contents

1. Purity control data of analytical standards 1-24 ...... S4B 2. HPLC control of analytical standards 1-24 (Method A) ...... S5B Figure S1: (E)-p-Coumaric acid 4’-O- β -D-glucuronide 1a (280 nm)...... S5B Figure S2: (E)-m-Coumaric acid 3’-O- β -D-glucuronide 2a (280 nm)...... S5B Figure S3: (E)- 4’-O- β -D-glucuronide 3a (280 nm)...... S6B Figure S4: (E)- and (Z)-Isoferulic acid 3’-O- β -D-glucuronides 4a + 4b (280 nm)...... S6B Figure S5: (E)- and (Z)-Caffeic acid 3’-O- β -D-glucuronides 5a + 5b (280 nm)...... S7B Figure S6: (E)- and (Z)-Caffeic acid 4’-O-β-D-glucuronides 6a + 6b (280 nm). S7B Figure S7: (E)-p-Coumaric acid 4’-sulphate 7 (280 nm)...... S8B Figure S8: (E)-m-Coumaric acid 3’-sulphate 8 (280 nm)...... S8B Figure S9: (E)-Ferulic acid 4’-sulphate 9 (280 nm)...... S9B Figure S10: (E)-Isoferulic acid 3’-sulphate 10 (280 nm)...... S9B Figure S11: (E)- and (Z)-Caffeic acid 3’-sulphates 11a + 11b (280 nm)...... S10B Figure S12: (E)- and (Z)-Caffeic acid 4’-sulphates 12a + 12b (280 nm)...... S10B Figure S13: Dihydro-p-coumaric acid 4’-O- β -D-glucuronide 13 (280 nm). .... S11B Figure S14: Dihydro-m-coumaric acid 3’-O- β -D-glucuronide 14 (210 nm). ... S11B Figure S15: Dihydroferulic acid 4’-O- β -D-glucuronide 15 (280 nm)...... S12B Figure S16: Dihydroisoferulic acid 3’-O- β -D-glucuronide 16 (280 nm)...... S12B Figure S17: Dihydrocaffeic acid 3’-O- β -D-glucuronide 17 (280 nm)...... S13B Figure S18: Dihydrocaffeic acid 4’-O- β -D-glucuronide 18 (280 nm)...... S13B Figure S19: Dihydro-p-coumaric acid 4’-sulphate 19 (210 nm)...... S14B Figure S20: Dihydro-m-coumaric acid 3’-sulphate 20 (210 nm)...... S14B Figure S21: Dihydroferulic acid 4’-sulphate 21 (280 nm)...... S15B Figure S22: Dihydroisoferulic acid 3’-sulphate 22 (280 nm)...... S15B Figure S23: Dihydrocaffeic acid 3’-sulphate 23 (280 nm)...... S16B Figure S24: Dihydrocaffeic acid 4’-sulphate 24 (280 nm)...... S16B 3. 1H and 13C NMR spectra of analytical standards 1-24 ...... S17B Figure S25: (E)-p-Coumaric acid 4’-O- β -D-glucuronide 1a ...... S17B Figure S26: (E)-m-Coumaric acid 3’-O- β -D-glucuronide 2a...... S18B Figure S27: (E)-Ferulic acid 4’-O- β -D-glucuronide 3a...... S19B Figure S28: (E)- and (Z)-Isofeulic acid 3’-O- β -D- glucuronides 4a + 4b...... S20B Figure S29: (E)- and (Z)-Caffeic acid 3’-O- β -D- glucuronides 5a + 5b...... S21B Figure S30: (E)- and (Z)-Caffeic acid 4’-O- β -D- glucuronides 6a + 6b...... S22B Figure S31: (E)-p-Coumaric acid 4’-sulphate 7...... S23B Figure S32: (E)-m-Coumaric acid 3’-sulphate 8...... S24B Figure S33: (E)-Ferulic acid 4’-sulphate 9...... S25B Figure S34: (E)-Isoferulic acid 3’-sulphate 10...... S26B Figure S35: (E)- and (Z)-Caffeic acid 3’- sulphates 11a + 11b...... S27B Figure S36: (E)- and (Z)-Caffeic acid 4’- sulphates 12a + 12b...... S28B Figure S37: Dihydro-p-coumaric acid 4’-O- β -D-glucuronide 13...... S29B Figure S38: Dihydro-m-coumaric acid 3’-O- β -D-glucuronide 14...... S30B Figure S39: Dihydroferulic acid 4’-O- β -D-glucuronide 15...... S31B Figure S40: Dihydroisoferulic acid 3’-O- β -D-glucuronide 16...... S32B Figure S41: Dihydrocaffeic acid 3’-O- β -D-glucuronide 17...... S33B Figure S42: Dihydrocaffeic acid 4’-O- β -D-glucuronide 18...... S34B Figure S43: Dihydro-p-coumaric acid 4’-sulphate 19...... S35B

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S3B

Figure S44: Dihydro-m-coumaric acid 3’-sulphate 20...... S36B Figure S45: Dihydroferulic acid 4’-sulphate 21...... S37B Figure S46: Dihydroisoferulic acid 3’-sulphate 22...... S38B Figure S47: Dihydrocaffeic acid 3’-sulphate 23...... S39B Figure S48: Dihydrocaffeic acid 4’-sulphate 24...... S40B

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S4B

1. Purity control data of analytical standards 1-24

Table S1: Purity control of analytical standards 1-24. No Compound LC-HRMS data HPLC % Quantification purity data of sulphate (nm) ester content - 1a (E)-p-Coumaric acid 4’-O- [M-H] Calc for C15H15O9: 99 (280) - β-D-glucuronide 339.0716; found: 339.0721. - 2a (E)-m-Coumaric acid 3’-O- [M-H] calc for C15H15O9: 97 (280) - β-D-glucuronide 339.0716; found: 339.0719. - 3a (E)-Ferulic acid 4’-O-β-D- [M-H] calc for C16H17O10: 99 (280) - glucuronide 369.0821; found: 369.0834. - 4a + (E)- and (Z)-Isoferulic acid [M-H] calc for C16H17O10: 99 (280) - 4b 3’-O-β-D-glucuronides 369.0821; found: 369.0825. - 13 Dihydro-p-coumaric acid [M-H] calc for C15H17O9: 99 (280) - 4’-O-β-D-glucuronide 341.0872; found: 341.0882. - 14 Dihydro-m-coumaric acid [M-H] calc for C15H17O9: 99 (210) - 3’-O-β-D-glucuronide 341.0872; found: 341.0878. - 15 Dihydroferulic acid 4’-O-β- [2M-H] calc for C32H39O20: 99 (280) - D-glucuronide 743.2040; found: 743.2019. - 16 Dihydroisoferulic acid 3’-O- [M-H] calc for C16H19O10: 98 (280) - β-D-glucuronide 371.0978; found: 371.0974. - 5a + (E)- and (Z)-Caffeic acid 3’- [M-H] calc for C15H15O10: 94 (280) - 5b O-β-D-glucuronides 355.0665; found: 355.0653. - 6a + (E)- and (Z)-Caffeic acid 4’- [M-H] calc for C15H15O10: 99 (280) - 6b O-β-D-glucuronides 355.0665; found: 355.0664. - 17 Dihydrocaffeic acid 3’-O-β- [M-H] calc for C15H17O10: 99 (280) - D-glucuronide 357.0821; found: 357.0816. - 18 Dihydrocaffeic acid 4’-O-β- [M-H] calc for C15H17O10: 98 (280) - D-glucuronide 357.0821; found: 357.0824. - 7 (E)-p-Coumaric acid 4’- [M-H] calc for C9H7O6S: 98 (280) 2.81 μmol/mg sulphate 242.9963; found: 242.9994 - 8 (E)-m-Coumaric acid 3’- [M-H] calc for C9H7O6S: 98 (280) 2.70 μmol/mg sulphate 242.9963; found: 243.0001 - 9 (E)-Ferulic acid 4’-sulphate [M-H] calc for C10H9O7S: 98 (280) 1.93 μmol/mg 273.0069; found: 273.0099 - 10 (E)-Isoferulic acid 3’- [M-H] calc for C10H9O7S: 98 (280) 1.57 μmol/mg sulphate 273.0069; found: 273.0112 - 11a (E)- and (Z)-Caffeic acid 3'- [M-H] calc for C9H7O7S: 97 (280) 2.30 μmol/mg + sulphates 258.9912; found: 258.9960 11b - 12a (E)- and (Z)-Caffeic acid 4'- [M-H] calc for C9H7O7S: 95 (280) 1.91 μmol/mg + sulphates 258.9912; found: 258.9955 12b - 19 Dihydro-p-coumaric acid [M-H] calc for C9H9O6S: 98 (210) 2.22 μmol/mg 4’-sulphate 245.0119; found: 245.0164 - 20 Dihydro-m-coumaric acid [M-H] calc for C9H9O6S: 98 (210) 2.10 μmol/mg 3’-sulphate 245.0119; found: 245.0161 - 21 Dihydroferulic acid 4’- [M-H] calc for C10H11O7S: 97 (280) 1.57 μmol/mg sulphate 275.0225; found: 275.0270 - 22 Dihydroisoferulic acid 3’- [M-H] calc for C10H11O7S: 98 (280) 2.15 μmol/mg sulphate 275.0225; found: 275.0270 - 23 Dihydrocaffeic acid 3'- [M-H] calc for C9H9O7S: 98 (280) 1.75 μmol/mg sulphate 261.0069; found: 261.0115 - 24 Dihydrocaffeic acid 4'- [M-H] calc for C9H9O7S: 98 (280) 1.55 μmol/mg sulphate 261.0069; found: 261.0108

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S5B

2. HPLC control of analytical standards 1-24 (Method A)

DAD1 A, Sig=280,10 Ref=550,100 (LFO\LFO00299.D) mA U 5.419

800

600

400

200

0

2.5 5 7.5 10 12.5 15 17.5 20 min

Figure S1: (E)-p-Coumaric acid 4’-O- β -D-glucuronide 1a (280 nm).

mA U

600 6.179

500

400

300

200

100 6.065

0

4 6 8 10 12 14 16 18 20 22 min

Figure S2: (E)-m-Coumaric acid 3’-O- β -D-glucuronide 2a (280 nm).

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S6B

mA U

500 5.832

400

300

200

100

0

4 6 8 10 12 14 16 18 20 min

Figure S3: (E)-Ferulic acid 4’-O- β -D-glucuronide 3a (280 nm).

mA U 6.531

350

300

250

200

150

100

50

0

4 6 8 10 12 14 16 18 20 22 min

Figure S4: (E)- and (Z)-Isoferulic acid 3’-O-β-D-glucuronides 4a + 4b (280 nm).

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S7B

mA U 5.882

300

250

200

150

100

50 5.987

0

4 6 8 10 12 14 16 18 20 22 min

Figure S5: (E)- and (Z)-Caffeic acid 3’-O- β -D-glucuronides 5a + 5b (280 nm).

mA U 5.281 500

400

300

200

100

0

4 6 8 10 12 14 16 18 20 22 min

Figure S6: (E)- and (Z)-Caffeic acid 4’-O-β-D-glucuronides 6a + 6b (280 nm).

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S8B

mA U 5.556

700

600

500

400

300

200

100

0

4 6 8 10 12 14 16 18 20 22 min

Figure S7: (E)-p-Coumaric acid 4’-sulphate 7 (280 nm).

mA U 5.855

1000

800

600

400

200

0

4 6 8 10 12 14 16 18 20 22 min

Figure S8: (E)-m-Coumaric acid 3’-sulphate 8 (280 nm).

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S9B

mA U 5.633

1000

800

600

400

200

0

4 6 8 10 12 14 16 18 20 22 min

Figure S9: (E)-Ferulic acid 4’-sulphate 9 (280 nm).

mA U 6.085 1000

800

600

400

200

0

4 6 8 10 12 14 16 18 20 22 min

Figure S10: (E)-Isoferulic acid 3’-sulphate 10 (280 nm).

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S10B

mA U 5.495

400

300

200

100

0

4 6 8 10 12 14 16 18 20 22 min

Figure S11: (E)- and (Z)-Caffeic acid 3’-sulphates 11a + 11b (280 nm).

mA U 5.291 1000

800

600

400

200 5.178

0

4 6 8 10 12 14 16 18 20 22 min

Figure S12: (E)- and (Z)-Caffeic acid 4’-sulphates 12a + 12b (280 nm).

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S11B

mA U 5.418

40

35

30

25

20

15

10

5

0 5.766

4 6 8 10 12 14 16 18 20 22 min

Figure S13: Dihydro-p-coumaric acid 4’-O- β -D-glucuronide 13 (280 nm).

mA U 5.934

300

200

100

0

-100

-200

-300

4 6 8 10 12 14 16 18 20 22 min

Figure S14: Dihydro-m-coumaric acid 3’-O- β -D-glucuronide 14 (210 nm).

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S12B

mA U 5.781

40

30

20

10

0

4 6 8 10 12 14 16 18 20 22 min

Figure S15: Dihydroferulic acid 4’-O- β -D-glucuronide 15 (280 nm).

mA U 6.322

60

50

40

30

20

10

0 5.916 6.171

4 6 8 10 12 14 16 18 20 22 min

Figure S16: Dihydroisoferulic acid 3’-O- β -D-glucuronide 16 (280 nm).

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S13B

mA U 5.463 60

50

40

30

20

10

0

4 6 8 10 12 14 16 18 20 22 min

Figure S17: Dihydrocaffeic acid 3’-O- β -D-glucuronide 17 (280 nm).

DAD1 A, Sig=280,10 Ref=550,100 (LFO\LFO00252.D) mA U 5.229

70

60

50

40

30

20

10 5.414 0

4 6 8 10 12 14 16 18 20 22 min

Figure S18: Dihydrocaffeic acid 4’-O- β -D-glucuronide 18 (280 nm).

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S14B

mA U 5.082

200

100

0

-100

-200

-300

4 6 8 10 12 14 16 18 20 22 min

Figure S19: Dihydro-p-coumaric acid 4’-sulphate 19 (210 nm).

mA U

300 5.339

200

100

0

-100

-200

-300

5 7.5 10 12.5 15 17.5 20 22.5 25 min

Figure S20: Dihydro-m-coumaric acid 3’-sulphate 20 (210 nm).

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S15B

mA U 5.253

35

30

25

20

15

10

5 5.824 0

4 6 8 10 12 14 16 18 20 22 min

Figure S21: Dihydroferulic acid 4’-sulphate 21 (280 nm).

mA U 5.601

100

80

60

40

20

0

4 6 8 10 12 14 16 18 20 22 min

Figure S22: Dihydroisoferulic acid 3’-sulphate 22 (280 nm).

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S16B

mA U 4.818

200

175

150

125

100

75

50

25

0

4 6 8 10 12 14 16 18 20 22 min

Figure S23: Dihydrocaffeic acid 3’-sulphate 23 (280 nm).

mA U 4.701

140

120

100

80

60

40

20

0

4 6 8 10 12 14 16 18 20 22 min

Figure S24: Dihydrocaffeic acid 4’-sulphate 24 (280 nm).

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3. 1H and 13C NMR spectra of analytical standards 1-24

O O COOH HO OH OH

HO

O

Figure S25: (E)-p-Coumaric acid 4’-O- β -D-glucuronide 1a.

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S18B

Figure S26: (E)-m-Coumaric acid 3’-O- β -D-glucuronide 2a.

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OCH3 O O COOH HO OH OH

HO

O

Figure S27: (E)-Ferulic acid 4’-O- β -D-glucuronide 3a.

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OCH3

O O COOH HO OH HO OH 4a:Major O + OCH3

O O COOH HO OH OH OH O 4b:Minor

Figure S28: (E)- and (Z)-Isoferulic acid 3’-O- β -D-glucuronides 4a + 4b.

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S21B

OH

O O COOH HO OH HO OH 5a:Major O + OH

O O COOH HO OH OH OH O 5b:Minor

Figure S29: (E)- and (Z)-Caffeic acid 3’-O- β -D-glucuronide 5a + 5b.

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S22B

OH O O COOH HO OH OH

HO 6a:Major O + OH O O COOH HO OH OH

OH 6b:Minor O

Figure S30: (E)- and (Z)-Caffeic acid 4’-O- β -D-glucuronide 6a + 6b.

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- OSO3

-O

O

Figure S31: (E)-p-Coumaric acid 4’-sulphate 7.

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S24B

- OSO3 -O

O

Figure S32: (E)-m-Coumaric acid 3’-sulphate 8.

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S25B

- OSO3

OCH3 -O

O

Figure S33: (E)-Ferulic acid 4’-sulphate 9.

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S26B

OCH3

- OSO3 -O

O

Figure S34: (E)-Isoferulic acid 3’-sulphate 10.

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Figure S35: (E)- and (Z)-Caffeic acid 3’-sulphates 11a + 11b.

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Figure S36: (E)- and (Z)-Caffeic acid 4’-sulphates 12a + 12b.

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S29B

O O COOH HO OH OH

HO

O

Figure S37: Dihydro-p-coumaric acid 4’-O- β -D-glucuronide 13.

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S30B

O O COOH HO OH HO OH O

Figure S38: Dihydro-m-coumaric acid 3’-O- β -D-glucuronide 14.

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S31B

OCH3 O O COOH HO OH OH

HO

O

Figure S39: Dihydroferulic acid 4’-O- β -D-glucuronide 15.

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S32B

OCH3

O O COOH HO OH HO OH O

Figure S40: Dihydroisoferulic acid 3’-O- β -D-glucuronide 16.

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S33B

OH

O O COOH HO OH HO OH O

Figure S41: Dihydrocaffeic acid 3’-O- β -D-glucuronide 17.

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S34B

OH O O COOH HO OH OH

HO

O

Figure S42: Dihydrocaffeic acid 4’-O- β -D-glucuronide 18.

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S35B

- OSO3

-O

O

Figure S43: Dihydro-p-coumaric acid 4’-sulphate 19.

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S36B

- OSO3 -O

O

Figure S44: Dihydro-m-coumaric acid 3’-sulphate 20.

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S37B

- OSO3

OCH3 -O

O

Figure S45: Dihydroferulic acid 4’-sulphate 21.

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S38B

OCH3

- OSO3 -O

O

Figure S46: Dihydroisoferulic acid 3’-sulphate 22.

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S39B

OH

- OSO3 -O

O

Figure S47: Dihydrocaffeic acid 3’-sulphate 23.

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010 S40B

- OSO3

OH -O

O

Figure S48: Dihydrocaffeic acid 4’-sulphate 24.

Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2010