Design, Synthesis and Biological Evaluation of Novel. Deguelin-Based Heat Shock Protein 90 (HSP90) Inhibitors

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1 Design, Synthesis and Biological Evaluation of Novel Deguelin-Based Heat Shock Protein 90 (HSP90) Inhibitors Targeting Proliferation and Angiogenesis Dong-Jo Chang, Hongchan An, Kyoung-suk Kim, Hyun Ho Kim, Jinkyung Jung, Jung Min Lee, Nam-Jung Kim, Young Taek Han, Hwayoung Yun, Sujin Lee, Geumwoo Lee, Seungbeom Lee, Ju Sung Lee, Jong-Ho Cha, Ji-Hyeon Park, Ji Won Park, Su-Chan Lee, Sang Geon Kim, Jeong Hun Kim, Ho-Young Lee, Kyu-Won Kim, and Young-Ger Suh *, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul , Korea Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital & Department of phthalmology, College of Medicine, Seoul National University, Seoul , Korea S1

2 Supporting Information Table of contents I. Purity and peak attributions (Table 1): S3~S4 II. III. IV. HPLC chromatograms of 1, 14, 21, 54, 56, 69 and 72: S5~S11 HPLC chromatograms of precusors of 56, 69 and 72: S12~S14 Figure 1. Treatment of deguelin, 54, 69 and 72 at 50% epiboly (5.3hpf): S15 V. Figure 2. Treatments of 54, 69 and 72 at 24 hpf: S16 VI. Figure 3. Zebrafish viability by deguelin, 54, 69 and 72 at 72 hpf:s17 S2

3 I. Purity and peak attributions Table 1. Purity and Peak Attributions of the Final Products Compound No HPLC Method-1 a Method-2 b Method-3 c Deguelin, % (R t = min) 98.3% (R t = min) % (R t = min) % (R t = min) 100% (R t = min) 100% (R t = min) 100% (R t = 7.56 min) 98.6% (R t = min) 100% (R t = 6.65 min) 95.0% (R t = 6.66 min) S3

4 % (R t = 6.09 min) 97.5% (R t = 6.93 min) 48.5% (R t = 6.60 min), 50.1% ( R t = min) 98.9% (R t = min) 100% (R t = 8.33 min) % (R t = 6.82 min) % (R t = min) 100% (R t = min) 97.4% (R t = min) 99.1% (R t = min) % (R t = min) S4

5 54.9% (R t = min) % (R t = min) 95.8% (R t = min) 95.5% (R t = min) % 95.7% (R t = min) (R t = min) 50.1% (R t = min) 50.2% (R t = min) 49.8% (R t = min) 99.3% (R t = min) 99.7% (R t = min) 49.3% (R t = min) S5

6 % (R t = min) 95.1% (R t = 8.12 min) 99.9% (R t = 8.87 min) 98.7% (R t = min) 97.3% (R t = min) a. Method 1: Gilson, CHIRALPAK AD-H ( mm) with solvent system R (n-hexane/i-propanol = 90:10) at a flow of 1 ml / min b. Method 2: Waters, CHIRALPAK AD-H ( mm) with solvent system R (n-hexane/i-propanol = 90:10) at a flow of 1 ml / min c. Method 3: Gilson, CHIRALPAK AD-H ( mm) with solvent system R (n-hexane/i-propanol = 75:25) at a flow of 1 ml / min S6

7 II. HPLC chromatograms of 1, 14, 21, 54, 56, 69 and 72 Gilson, CHIRALPAK AD-H ( mm) Compound: Deguelin, 1 Mobile phase: n-hexane = 90%, i-propanol = 10% Purity: 99.3% R t = min S7

8 Gilson, CHIRALPAK AD-H ( mm) Compound: 14 H Mobile phase: n-hexane = 90%, i-propanol = 10% Purity: 98.6% R t = min S8

9 Gilson, CHIRALPAK AD-H ( mm) Compound: 21 CNH 2 Mobile phase: n-hexane = 90%, i-propanol = 10% Purity: 100% R t = 8.33 min S9

10 Gilson, CHIRALPAK AD-H ( mm) Compound: 54 Mobile phase: n-hexane = 90%, i-propanol = 10% Purity: 99.7% R t = min S10

11 Gilson, CHIRALPAK AD-H ( mm) Compound: 56 Mobile phase: n-hexane = 90%, i-propanol = 10% Purity: 49.3%, 50.7% (enantiomeric mixture) R t = min, R t = min S11

12 Gilson, CHIRALPAK AD-H ( mm) Compound: 69 Mobile phase: n-hexane = 90%, i-propanol = 10% Purity: 98.7% (enantiomeric excess 97.4%) R t = min S12

13 Gilson, CHIRALPAK AD-H ( mm) Compound: 72 Mobile phase: n-hexane = 90%, i-propanol = 10% Purity: 97.3% (enantiomeric excess 94.6%) R t = min S13

14 III. HPLC chromatograms of precursors of 56, 69 and 72 Gilson, CHIRALCEL D-H ( mm) Compound: precursor of 56 H Mobile phase: n-hexane = 75%, i-propanol = 25% Purity: 52.4%, 47.6% (enantiomeric mixture) R t = 6.49 min, R t = 7.66 min S14

15 Gilson, CHIRALCEL D-H ( mm) Compound: precursor of 69 H Mobile phase: n-hexane = 75%, i-propanol = 25% Purity: 97.3% (enantiomeric excess 94.6%) R t = 5.73 min S15

16 Gilson, CHIRALCEL D-H ( mm) Compound: precursor of 72 H Mobile phase: n-hexane = 75%, i-propanol = 25% Purity: 98.6% (enantiomeric excess 97.2%) R t = 6.96 min S16

17 IV. Figure 1. Treatment of deguelin, 54, 69 and 72 at 50% epiboly (5.3 hpf) S17

18 V. Figure 2. Treatments of 54, 69 and 72 at 24 hpf S18

19 VI. Figure 3. Zebrafish viability by deguelin, 54, 69 and 72 at 72 hpf S19

Supporting Information-II. Asymmetric Synthesis of Drug-like Spiro[chroman-3,3'- indolin]-2'-ones through Aminal-catalysis

Supporting Information-II. Asymmetric Synthesis of Drug-like Spiro[chroman-3,3'- indolin]-2'-ones through Aminal-catalysis Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry Supporting Information-II Asymmetric Synthesis of Drug-like Spiro[chroman-3,3'- indolin]-2'-ones through Aminal-catalysis D.