Supporting information. Design, Synthesis, and Cancer Cell Growth Inhibitory Activity of Triphenylphosphonium Derivatives of the Triterpenoid Betulin

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1 Supporting information Design, Synthesis, and Cancer Cell Growth Inhibitory Activity of Triphenylphosphonium Derivatives of the Triterpenoid Betulin Olga V. Tsepaeva, Andrey V. Nemtarev, Timur I. Abdullin, Leysan R. Grigor eva, Elena V. Kuznetsova, Rezeda A. Akhmadishina, Liliya E. Ziganshina, Hanh H. Cong, and Vladimir F. Mironov A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center of Russian Academy of Sciences, Arbuzov Street, 8, , Kazan, Russian Federation Kazan (Volga Region) Federal University, Kremlevskaya Street, 18, , Kazan, Tatarstan, Russian Federation *To whom correspondence should be addressed. Tel: +7 (843) address: S1

2 Table of Contents 1) Figure S1. Representative concentration-cell viability curves for cancer cell lines and human skin fibroblasts treated with the compound 9 (MTT assay). Page S5 2) Figure S2. 1 H NMR (CDCl 3, 400 MHz) spectrum of compound 2 Page S6 3) Figure S3. 1 H NMR (CDCl 3, 400 MHz) spectrum of compound 3 Page S7 4) Figure S4. 1 H NMR (CDCl 3, 400 MHz) spectrum of compound 4 Page S8 5) Figure S5. 1 H NMR (CDCl 3, 400 MHz) spectrum of compound 5 Page S9 6) Figure S6. 1 H NMR (CDCl 3, 400 MHz) spectrum of compound 6 Page S10 7) Figure S7. 1 H NMR (CDCl 3, 400 MHz) spectrum of compound 7 Page S11 8) Figure S8. 1 H NMR (CDCl 3, 400 MHz) spectrum of compound 8 Page S12 9) Figure S9. 1 H NMR (CDCl 3, 400 MHz) spectrum of compound 9 Page S13 10) Figure S10. 1 H NMR (CDCl 3, 400 MHz) spectrum of compound 10 Page S14 11) Figure S11. 1 H NMR (CDCl 3, 400 MHz) spectrum of compound 11 Page S15 12) Figure S12. 1 H NMR (CDCl 3, 400 MHz) spectrum of compound 12 Page S16 13) Figure S13. 1 H NMR (CDCl 3, 400 MHz) spectrum of compound 13 Page S17 14) Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum of compound 3 Page S18 15) Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum fragment of compound 3 Page S19 16) Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum of compound 4 Page S20 17) Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum fragment of compound 4 Page S21 S2

3 18) Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum of compound 8 Page S22 19) Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum fragment of compound 8 Page S23 20) Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum of compound 9 Page S24 21) Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum fragment of compound 9 Page S25 22) Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum of compound 10 Page S26 23) Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum fragment of compound 10 Page S27 24) Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum of compound 11 Page S28 25) Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum fragment of compound 11 Page S29 26) Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum of compound 12 Page S30 27) Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum fragment of compound 12 Page S31 28) Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum of compound 13 Page S32 29) Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum fragment of compound 13 Page S33 30) Figure S P-{ 1 H} NMR (CDCl 3, 162 MHz) spectrum of compound 8 Page S34 31) Figure S P-{ 1 H} NMR (CDCl 3, 162 MHz) spectrum of compound 9 Page S35 32) Figure S P-{ 1 H} NMR (CDCl 3, 162 MHz) spectrum of compound 10 Page S36 33) Figure S P-{ 1 H} NMR (CDCl 3, 162 MHz) spectrum of compound 11 Page S37 S3

4 34) Figure S P-{ 1 H} NMR (CDCl 3, 162 MHz) spectrum of compound 12 Page S38 35) Figure S P-{ 1 H} NMR (CDCl 3, 162 MHz) spectrum of compound 13 Page S39 36) Figure S36. IR (KBr) spectrum of compound 2 Page S40 37) Figure S37. IR (KBr) spectrum of compound 3 Page S41 38) Figure S38. IR (KBr) spectrum of compound 4 Page S42 39) Figure S39. IR (KBr) spectrum of compound 5 Page S43 40) Figure S40. IR (KBr) spectrum of compound 6 Page S44 41) Figure S41. IR (KBr) spectrum of compound 7 Page S45 42) Figure S42. IR (KBr) spectrum of compound 8 Page S46 43) Figure S43. IR (KBr) spectrum of compound 9 Page S47 44) Figure S44. IR (KBr) spectrum of compound 10 Page S48 45) Figure S45. IR (KBr) spectrum of compound 11 Page S49 46) Figure S46. IR (KBr) spectrum of compound 12 Page S50 47) Figure S47. IR (KBr) spectrum of compound 13 Page S51 48) Table S48. Inhibitory Concentrations (IC 50, µм) of compounds 2-7 for Different Human Cells in vitro (MTT Assay) Page S52 S4

5 Cell viability (%) PC-3 Cell viability (%) MCF-7 0 1E-4 1E Concentration (µm) 0 1E-4 1E Concentration (µm) Cell viability (%) MCF-7/Vinb 1E-6 1E-5 1E-4 1E Concentration (µm) Cell viability (%) HSF 1E-4 1E Concentration (µm) Figure S1. Representative concentration-cell viability curves for cancer cell lines and human skin fibroblasts treated with the compound 9 (MTT assay). S5

6 Figure S2. 1 H NMR (CDCl 3, 400 MHz) spectrum of bromide 2. S6

7 Figure S3. 1 H NMR (CDCl 3, 400 MHz) spectrum of bromide 3. S7

8 Figure S4. 1 H NMR (CDCl 3, 400 MHz) spectrum of bromide 4. S8

9 Figure S5. 1 H NMR (CDCl 3, 400 MHz) spectrum of bromide 5. S9

10 Figure S6. 1 H NMR (CDCl 3, 400 MHz) spectrum of bromide 6. S10

11 Figure S7. 1 H NMR (CDCl 3, 400 MHz) spectrum of bromide 7. S11

12 Figure S8. 1 H NMR (CDCl 3, 400 MHz) spectrum of phosphonium salt 8. S12

13 Figure S9. 1 H NMR (CDCl 3, 400 MHz) spectrum of phosphonium salt 9. S13

14 Figure S10. 1 H NMR (CDCl 3, 400 MHz) spectrum of phosphonium salt 10. S14

15 Figure S11. 1 H NMR (CDCl 3, 400 MHz) spectrum of phosphonium salt 11. S15

16 Figure S12. 1 H NMR (CDCl 3, 400 MHz) spectrum of phosphonium salt 12. S16

17 Figure S13. 1 H NMR (CDCl 3, 400 MHz) spectrum of phosphonium salt 13. S17

18 Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum of bromide 3. S18

19 Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum fragment of bromide 3. S19

20 Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum of bromide 4. S20

21 Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum fragment of bromide 4. S21

22 Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum of phosphonium salt 8. S22

23 Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum fragment of phosphonium salt 8. S23

24 Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum of phosphonium salt 9. S24

25 Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum fragment of phosphonium salt 9. S25

26 Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum of phosphonium salt 10. S26

27 Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum fragment of phosphonium salt 10. S27

28 Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum of phosphonium salt 11. S28

29 Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum fragment of phosphonium salt 11. S29

30 Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum of phosphonium salt 12. S30

31 Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum fragment of phosphonium salt 12. S31

32 Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum of phosphonium salt 13. S32

33 Figure S C-{ 1 H} NMR (CDCl 3, MHz) spectrum fragment of phosphonium salt 13. S33

34 Figure S P-{ 1 H} NMR (CDCl 3, 162 MHz) spectrum of phosphonium salt 8. S34

35 Figure S P-{ 1 H} NMR (CDCl 3, 162 MHz) spectrum of phosphonium salt 9. S35

36 Figure S P-{ 1 H} NMR (CDCl 3, 162 MHz) spectrum of phosphonium salt 10. S36

37 Figure S P-{ 1 H} NMR (CDCl 3, 162 MHz) spectrum of phosphonium salt 11. S37

38 Figure S P-{ 1 H} NMR (CDCl 3, 162 MHz) spectrum of phosphonium salt 12. S38

39 Figure S P-{ 1 H} NMR (CDCl 3, 162 MHz) spectrum of phosphonium salt 13. S39

40 Figure S36. IR (KBr) spectrum of bromide 2. S40

41 Figure S37. IR (KBr) spectrum of bromide 3. S41

42 Figure S38. IR (KBr) spectrum of bromide 4. S42

43 Figure S39. IR (KBr) spectrum of bromide 5. S43

44 Figure S40. IR (KBr) spectrum of bromide 6. S44

45 Figure S41. IR (KBr) spectrum of bromide 7. S45

46 Figure S42. IR (KBr) spectrum of phosphonium salt 8. S46

47 Figure S43. IR (KBr) spectrum of phosphonium salt 9. S47

48 Figure S44. IR (KBr) spectrum of phosphonium salt 10. S48

49 Figure S45. IR (KBr) spectrum of phosphonium salt 11. S49

50 Figure S46. IR (KBr) spectrum of phosphonium salt 12. S50

51 Figure S47. IR (KBr) spectrum of phosphonium salt 13. S51

52 IC 50, µм compound PC-3 MCF-7 МСF-7/Vinb HSF ± ± ± ± ± ± ± ± ± ± ± 9.36 > ± ± ± ± ± ± ± ± ± ± ± ± 8.26 betuline ± ± ± ± Table S48. Inhibitory Concentrations (IC 50, µм) of compounds 2-7 for Different Human Cells in vitro (MTT Assay) S52