Supporting InformationA novel class of α- glucosidase and HMG-CoA reductase inhibitors from Ganoderma

leucocontextum and the anti-diabetic properties of ganomycin I in KK-Ay mice

Kai Wang, †, ‡, ┴ Li Bao, †, ┴ Ke Ma, †, ‡ Jinjin Zhang, †, ‡ Baosong Chen, †, ‡

Junjie Han, † Jinwei Ren, † Huajun Luo, § Hongwei Liu †, ‡, *

† State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of

Sciences, No.1 Beichenxi Road, Chaoyang District, Beijing 100101, P. R. China

‡ Cunji Collage of Medicine, University of Chinese Academy of Sciences, Beijing,

100049, P. R. China

§ Hubei Key Laboratory of Natural Products Research and Development, College of

Biological and Pharmaceutical Science, China Three Gorges University, Yichang,

443002, P. R. China

†Institute of Microbiology.

‡ University of Chinese Academy of Sciences.

§China Three Gorges University, Yichang, 443002, P. R. China

┴K. Wang, L. Bao contributed equally to this article.

* Corresponding Author Tel: +86 10 64806076; E-mail: liuhw@im.ac.cn (H-W, Liu)

Table of Contents

Figures Content Page

Scheme 1. Synthesis of ganomycin I (4). 3

S1 Effects of compound 4 on body weight in KK-AY mice 4

S2 1H NMR Spectrum of Compound 1 in CDCl35

S3 13C NMR Spectrum of Compound 1 in CDCl36

S4 HSQC Spectrum of Compound 1 in CDCl3 7

S5 HMBC Spectrum of Compound 1 in CDCl3 8

S6 1H NMR Spectrum of Compound 2 in CDCl39

S7 13C NMR Spectrum of Compound 2 in CDCl310

S8 HSQC Spectrum of Compound 2 in CDCl3 11

S9 HMBC Spectrum of Compound 2 in CDCl3 12

S10 1H NMR Spectrum of Compound 3 in CDCl313

S11 13C NMR Spectrum of Compound 3 in CDCl314

S12 HSQC Spectrum of Compound 3 in CDCl3 15

S13 HMBC Spectrum of Compound 3 in CDCl3 16

S14 1H NMR Spectrum of Compound 4 in CDCl317

S15 13C NMR Spectrum of Compound 4 in CDCl318

S16 1H NMR Spectrum of Compound 5 in CDCl319

S17 13C NMR Spectrum of Compound 5 in CDCl320

S18 1H NMR Spectrum of Compound 6 in CDCl321

S19 1H NMR Spectrum of Compound 7 in pyridine-d5 22

S20 13C NMR Spectrum of Compound 7 in pyridine-d523

S21 1H NMR Spectrum of Compound 8 in DMSO-d624

S22 13C NMR Spectrum of Compound 8 in DMSO-d625

S23 1H NMR Spectrum of Compound 9 in DMSO-d626

S24 13C NMR Spectrum of Compound 9 in DMSO-d6 27

Table S1 1H and 13C NMR data of 4-8 28

Scheme 1. Synthesis of ganomycin I (4). Reagents and conditions. (a)MOMCl,K2CO3,

acetone, 0 , 95%; (b) (EtO)℃ 2POCH2CO2Et, NaH, THF, 0 , 95%; (c)DIBAL-H,℃

CH2Cl2, hexane, -78 to 0 , 98%; (d) 2-mercaptobenzothiazole, Ph℃ ℃ 3P, diethyl

azodicarboxylate (DEAD), THF, 0 , 85%; (e) AD-mix-α, MeSO℃ 2NH2, tBuOH, H2O,

0 , 89%; (f) ℃ mCPBA, CH2Cl2, -78 . 90%; (g) DBU, CH℃ 2Cl2, -10 , 85%; (h) Ph℃ 3P,

CCl4, reflux, 95%; (i) β-methallyl alcohol, nBuLi, TMEDA, Et2O, -78 to room℃

temp, them geranyl chloride, 92%; (j) MnO2, hexane, 95%; (k) NaClO2, NaH2PO4, 2-

methyl-2-butene, tBuOH, H2O, 0 to room temp, 88%; (l) Cl℃ 3C6H2COCl, DIPEA,

DMAP, toluene; (m) Grubbs 1st catalyst, CH2Cl2, 75% (two steps); (n) TsOH, EtOH,

85%. (TMEDA = tetramethylethylenediamine, DIPEA = diisopropylefhylamine,

DMAP = 4-(dimethylamino) pyridine, Grubbs 1st catalyst = [(PCy3)2Cl2Ru=CHPh].

(Operated as the original synthesis donor of Yajima et al.)

Figure S1. Effects of compound 4 on body weight in KK-Ay mice. Values are mean ±

SEM (n = 7 for KK-Ay mice); *P<0.05, **P<0.01, ***P<0.001, versus KK-Aymodel

group. Con, , C57BL/6J mice control; KK-M, ,KK-Ay model; Ros-10, ,

rosiglitazone 10 mg/kg; GI-h, ganomycin I (4) 5 mg/kg; GI-l, GI-l 1 mg/kg.

Figure S2. 1H NMR Spectrum of Compound 1 in CDCl3

Figure S3. 13C NMR Spectrum of Compound 1 in CDCl3

Figure S4. HSQC Spectrum of Compound 1 in CDCl3

Figure S5. HMBC Spectrum of Compound 1 in CDCl3

Figure S6. 1H NMR Spectrum of Compound 2 in CDCl3

Figure S7. 13C NMR Spectrum of Compound 2 in CDCl3

Figure S8. HSQC Spectrum of Compound 2 in CDCl3

Figure S9. HMBC Spectrum of Compound 2 in CDCl3

Figure S10. 1H NMR Spectrum of Compound 3 in CDCl3

Figure S11. 13C NMR Spectrum of Compound 3 in CDCl3

Figure S12. HSQC Spectrum of Compound 3 in CDCl3

Figure S13. HMBC Spectrum of Compound 3 in CDCl3

Figure S14. 1H NMR Spectrum of Compound 4 in CDCl3

Figure S15. 1H NMR Spectrum of Compound 4 in CDCl3

Figure S16. 1H NMR Spectrum of Compound 5 in CDCl3

Figure S17. 13C NMR Spectrum of Compound 5 in CDCl3

Figure S18. 13C NMR Spectrum of Compound 6 in CDCl3

Figure S19. 13C NMR Spectrum of Compound 7 in pyridine-d5

Figure S20. 13C NMR Spectrum of Compound 7 in pyridine-d5

0 Figure S21. 1H NMR Spectrum of Compound 8 in DMSO-d6

Figure S22. 13C NMR Spectrum of Compound 8 in DMSO-d6

Figure S23. 1H NMR Spectrum of Compound 9 in DMSO-d6

Figure S24. 13C NMR Spectrum of Compound 9 in DMSO-d6Table S1. 1H and 13C NMR data of 4-8

No. 4 (CDCl3) 5 (CDCl3) 6 (CDCl3) 7 (pyridine-d5) 8 (DMSO-d6)δH (m, J in Hz) δc δH (m, J in Hz) δc δH (m, J in Hz) δH (m, J in Hz) δc δH (m, J in Hz) δc

1 6.17 (d, 15.1) 78.9 3.62 (d, 7.4) 31.9 108.3 187.8

2 7.23 (d, 15.1) 149.3 6.00 (t, 7.4) 141.4 3.45 (dd, 19.1, 10.3);3.08 (m)

7.92 (s) 147.7 6.39 (s) 149.7

3 132.6 131.5 3.08 (m) 135.8 135.44 2.31 (t, 6.8) 25.8 2.28 (m) 26.7 2.36 (m);1.83 (m) 2.46 (m) 26.1 2.31 (t, 7.1) 26.05 2.23 (dd, 14.0, 6.8) 25.8 2.13 (dd, 14.8, 7.2) 26.5 2.12 (m) 2.33 (m) 26.6 2.21 (dd, 14.5, 7.1) 26.76 5.06 (m) 124.3 5.05 (m) 122.8 5.10 (m) 5.20 (t, 7.0) 123.7 5.17 (t, 7.1) 123.37 136.9 136.5 137.1 136.78 1.96 (m) 39.7 1.99 (m) 39.7 2.06 (t, 7.6) 1.98 (m) 40.4 2.04 (t, 7.1) 40.19 2.02 (dd, 14.5, 7.1) 26.7 1.90 (dd, 14.7, 7.0) 26.7 1.99 (dd, 14.5, 7.6) 2.09 (m) 27.4 1.95 (dd, 14.1, 7.1) 26.810 5.06 (m) 149.8 5.05 (m) 124.4 5.10 (m) 5.16 (t, 7.2) 125.3 5.06 (t, 7.5) 124.111 131.6 131.3 131.7 131.112 1.65 (s) 25.4 1.64 (s) 25.8 1.60 (s) 1.67 (s) 26.2 1.62 (s) 26.813 1.57 (s) 17.8 1.58 (s) 17.8 1.68 (s) 1.57 (s) 18.2 1.59 (s) 18.014 1.55 (s) 16.2 1.52 (s) 16.2 1.60 (s) 1.55 (s) 16.5 1.55 (s) 16.415 175.9 174.2 172.4 172.116 122.6 124.6 124.6 124.517 147.0 149.1 149.8 149.718 6.66 (m) 117.1 6.70 (d, 8.2) 117.0 7.22 (s) 7.83 (d, 2.6) 118.7 7.09 (d, 8.2) 118.319 6.66 (m) 116.8 6.62 (m) 117.4 7.08 (m) 7.17 (m) 118.7 6.93 (m) 118.420 149.8 148.7 152.1 153.821 6.59 (d, 2.5) 113.0 6.62 (m) 115.1 6.88 (d, 2.3) 7.17 (m) 115.7 6.39 (s) 115.822 3.45 (s) 52.3