The Presence of a Cyclohexyldiamine Moiety Confers Cytotoxicity to Pentacyclic Triterpenoids
Abstract
:1. Introduction
2. Results
3. Conclusions
4. Experimental
4.1. Cell Lines and Culture Conditions
4.2. Cytotoxicity Assay (SRB Assay)
4.3. General Procedure for the Synthesis of Acetates 1–4 (GPA)
4.4. General Procedure for the Synthesis of Amides 9–31 (GPB)
- 3β-Acetyloxy-olean-12-en-28-oic acid (1). Following GPA, compound 1 (4.89 g, 89%) was obtained as a colorless solid; Rf = 0.54 (hexanes/ethyl acetate, 3:1); m.p.: 259–263 °C (lit.: [29] 266–268 °C); = +74.1° (c 0.43, CHCl3) [lit.: [29] = +74.0° (c 1, CHCl3)]; MS (ESI, MeOH): m/z 499.1 ([M + H]+, 9), 521.3 (38%, [M + Na]+), 1019.4 (100%, [2M + Na]+).
- 3β-Acetoxy-urs-12-en-28-oic acid (2). Following GPA, compound 2 (4.89 g, 89%) was obtained as a colorless solid; Rf = 0.71 (toluene/ethyl acetate/heptane/formic acid, 80:26:10:5); m.p.: 287–290 °C (lit.: [30] 289–290 °C); = +68.9° (c 0.315, CHCl3) [lit.: [31] = +72.3° (c 0.5, CHCl3)]; MS (ESI, MeOH): m/z 499.0 ([M + H]+, 74), 516.3 (36%, [M + NH4]+), 521.5 (34%, [M + Na]+);
- 3β-Acetoxy-lup-20(29)-en-28-oic acid (3). Following GPA, compound 3 (4.90 g, 89%) was obtained as a colorless solid; Rf = 0.58 (hexanes/ethyl acetate, 4:1); m.p.: 281–283 °C (lit.: [32] 280–282 °C); = +25.6° (c 0.35, CHCl3) [lit.: [33] = +26.4° (c 0.54, CHCl3)]; MS (ESI, MeOH): m/z 487.1 (28%, [M− H]−) 995.3 (100%, [2M − H]−), 1018.2 (28%, [2M − 2H + Na]−).
- 3β-Acetoxy-20-oxo-30-norlupan-28-oic acid (4). Following GPA, compound 4 (13.8 g, 84%) was obtained as a colorless solid; Rf = 0.50 (toluene/ethyl acetate/heptane/formic acid, 80:26:10:5); m.p.: 268–270 °C (decomp.), (lit.: [34] 252–255 °C); = −9.1° (c 0.34, CHCl3) [lit.: [34] = −9.5° (c 0.8, CHCl3)]; MS (ESI, MeOH): m/z 999.3 (100%, [2M − H]−).
- Trans-cyclohexyl-1,4-diamine (5) and cis-cyclohexyl-1,4-diamine (6). These compounds were commercially obtained from Merck and used as received.
- (3β)-28-[(trans-4-Aminocyclohexyl)amino]-28-oxoolean-12-en-3-yl acetate (9). Following GPB, compound 9 (1.01 g, 84%) was obtained as a colorless solid; Rf = 0.66 (CHCl3/MeOH, 8:2); m.p.: 203–205 °C (decomp.); = +23.6° (c 0.35, MeOH); IR (ATR): ν = 3423 w, 2945 m, 1703 m, 1618 m, 1430 s, 1332 s, 1036 s, 817 s. 749 s cm−1; 1H NMR (500 MHz, CD3OD): δ = 6.64 (m, 1H, NH), 5.43 (t, J = 3.6 Hz, 1H, 12-H), 4.48 (dd, J = 11.2, 4.9 Hz, 1H, 3-H), 3.89 (s, 1H, 33-H), 3.35–3.32 (m, 1H, 36-H), 2.85–2.79 (m, 1H, 18-H), 2.20–2.07 (m, 1H, 16-Ha), 2.05 (s, 3H, 32-H), 1.99–1.28 (m, 25H, 34-H, 35-H, 37-H, 38-H, 1-Hb, 22-H, 2-H, 15-Ha, 6-H, 11-H, 7-H, 1-Ha, 21-H, 9-H, 19-Hb), 1.23 (s, 3H, 27-H), 1.22–1.02 (m, 3H, 15-Hb, 16-Hb, 19-Ha), 1.00 (s, 3H, 25-H), 0.98 (s, 3H, 29-H), 0.94 (s, 3H, 30-H), 0.91 (s, 3H, 24-H), 0.91 (s, 3H, 23-H), 0.89 (m, 1H, 5-H), 0.84 (s, 3H, 26-H) ppm; 13C NMR (126 MHz, CD3OD): δ = 179.8 (C-28), 145.5 (C-13), 123.9 (C-12), 82.4 (C-3), 56.6 (C-5), 49.9 (C-9), 49.5 (C-33), 47.7 (C-19), 47.5 (C-17), 46.3 (C-36), 43.8 (C-18), 43.1 (C-14), 40.7 (C-8), 39.3 (C-1), 38.7 (C-4), 38.1 (C-10), 35.1 (C-21), 34.2 (C-34, C-38), 33.8 (C-35, C-37), 33.5 (C-30), 31.6 (C-20), 28.5 (C-15), 28.5 (C-23), 28.1 (C-7), 27.8 (C-22), 26.3 (C-27), 24.5 (C-2), 24.5 (C-11), 24.0 (C-16), 23.9 (C-29), 21.1 (C-32), 19.3 (C-6), 18.1 (C-26), 17.1 (C-24), 15.9 (C-25) ppm; ESI, MeOH): m/z 595.4 (100%, [M + H]+), 1189.3 (5%, [2M + H]+); analysis calcd for C38H62N3O4 (594.91): C 76.72, H 10.50, N 4.71; found: C 76.49, H 10.71, N 4.55. Please see Supplementary Materials.
- (3β)-28-[(cis-4-Aminocyclohexyl)amino]-28-oxoolean-12-en-3-yl acetate (10). Following GPB, compound 10 (1.02 g, 85%) was obtained as a colorless solid; Rf = 0.673 (CHCl3/MeOH, 8:2); m.p.: 197–200 °C (decomposition); = +3.8° (c 0.14, CHCl3); IR (ATR): ν = 3406 w, 2944 m, 1704 m, 1621 m, 1524 s, 1428 s, 1313 s, 1099 m, 1028 s, 821 s, 763 m cm−1; 1H NMR (500 MHz, CD3OD): δ = 6.61–6.55 (m, 1H, NH), 5.37 (t, 1H, 12-H), 4.42 (d, 1H, 3-H), 3.60–3.52 (m, 1H, 33-H), 3.29–3.24 (m, 1H, 36-H), 2.10–1.93 (m, 1H, 18-H), 1.99 (s, 3H, 32-H), 1.93–1.85 (m, 8H, 34-H, 35-H, 37-H, 38-H), 1.85–1.21 (m, 14H, 1-Hb, 22-Ha, 2-H, 16-Ha, 15-Hb, 6-H, 11-Hb, 7-Hb, 1-Ha, 21-Hb, 9-H, 19-Hb), 1.16 (s, 3H, 27-H), 1.16–0.97 (m, 5H, 15-Ha,16-Hb,19-Ha, 21-Ha, 22-Hb), 0.94 (s, 3H, 26-H), 0.91 (s, 3H, 24-H), 0.88 (s, 3H, 25-H), 0.85 (s, 3H, 29-H), 0.84 (s, 3H, 30-H), 0.83–0.81 (m, 1H, 5-H), 0.78 (s, 3H, 23-H) ppm; 13C NMR (126 MHz, CDCl3): δ = 179.8 (C-28), 172.8 (C-31), 145.4 (C-13), 123.9 (C-12), 82.4 (C-3), 56.6 (C-5), 49.8 (C-9), 49.5 (C-33), 47.6 (C-19), 46.2 (C-17), 43.7 (C-18), 43.1 (C-14), 42.8 (C-36), 40.6 (C-21), 39.2 (C-8), 38.6 (C-4), 38.0 (C-1), 37.0 (C-10), 34.2 (C-7), 33.8 (C-34, C-38), 33.5 (C-29, C-30), 31.5 (C-35, C-37), 28.0 (C-20), 27.7 (C-22), 27.3 (C-15), 27.2 (C-16), 26.3 (C-27), 24.5 (C-2), 21.1 (C-32), 19.2 (C-6), 18.3 (C-23), 18.1 (C-26), 17.1 (C-24), 15.9 (C-25) ppm; MS (ESI, MeOH): m/z 595.4 (100%, [M + H]+), 1190.4 (8%, [2M + H]+); analysis calcd for C38H62N3O4 (594.91): C 76.72, H 10.50, N 4.71; found: C 76.59, H 10.75, N 4.46.
- (3β)-28-[(trans-4-Aminocyclohexyl)amino]-28-oxoursan-12-en-3-yl acetate (11). Following GPB, compound 11 (1.02 g, 85%) was obtained as a colorless solid; Rf = 0.66 (CHCl3/MeOH, 8:2); m.p.: 189–193 °C (decomp.); = +34.4° (c 0.31, MeOH); IR (ATR): ν = 3420 w, 2928 m, 1734 m, 1621 m, 1523 m,1314 s, 1244 s, 1096 s, 1027 s, 985 m, 902 m, 822 s cm−1; 1H NMR (500 MHz, CD3OD): δ = 6.90 (m, 1H, NH), 5.28 (t, J = 3.7 Hz, 1H, 12-H), 4.42 (m, 1H, 3-H), 3.64–3.51 (m, 1H, 33-H), 3.10–2.98 (m, 1H, 36-H), 2.16–2.12 (m, 1H, 18-H), 2.07–1.97 (m, 3H, 16-Hb, 35-Ha, 37-Ha), 1.99 (s, 3H, 30), 1.94–1.87 (m, 3H, 11, 21-Ha), 1.84–1.72 (m, 3H, 15-Hb, 34-Hb, 38-Hb), 1.69–1.26 (m, 17H, 1-Hb, 2-H, 6-H, 7-H, 9-H, 16-Ha, 19-H, 22-H, 34-Ha, 35-Hb, 37-Hb, 38-Ha), 1.10 (s, 3H, 27-H), 1.07–0.99 (m, 3H, 1-Ha, 15-Ha, 20-H), 0.95 (s, 3H, 25-H), 0.93 (s, 3H, 32-H), 0.87 (s, 3H, 26-H), 0.85 (s, 3H, 24-H), 0.84 (s, 3H, 23-H), 0.82–0.80 (m, 1H, 5-H), 0.79 (s, 3H, 29-H) ppm; 13C NMR (126 MHz, CD3OD): δ = 179.5 (C-28), 172.8 (C-31), 139.9 (C-13), 126.8 (C-12), 82.4 (C-3), 56.7 (C-5), 53.9 (C-18), 50.6 (C-36), 49.9 (C-9), 48.8 (C-17), 48.7 (C-33), 43.4 (C-14), 40.8 (C-19), 40.2 (C-20), 39.4 (C-1), 38.7 (C-8), 38.0 (C-4), 34.2 (C-10), 31.9 (C-7), 31.1 (C-21), 30.7 (C-38, C-34), 30.5 (C-37, C-35), 28.9 (C-15), 28.6 (C-23), 24.9 (C-16), 24.5 (C-2), 24.4 (C-11), 24.1 (C-27), 21.6 (C-32), 21.1 (C-30), 19.3 (C-6), 18.2 (C-29), 17.2 (C-24), 16.0 (C-25) ppm; MS (ESI, MeOH): m/z 595.4 (100%, [M + H]+), 1211.6 (4%, [2M + Na]+); analysis calcd for C38H62N3O4 (594.91): C 76.72, H 10.50, N 4.71; found: C 76.60, H 10.83, N 4.52.
- (3β)-28-[(Cis-4-Aminocyclohexyl)Amino]-28-Oxoursan-12-En-3-Yl Acetate (12). Following GPB, compound 12 (0.96 g, 80%) was obtained as a colorless solid; Rf = 0.67 (CHCl3/MeOH, 8:2); m.p.: 186–190 °C (decomp.); = +26.7° (c 0.10, CHCl3); IR (ATR): ν = 3416 m, 2929 m, 1625 m, 1520 m, 1326 s, 1245 s, 1028 s, 823 m cm−1; 1H NMR (500 MHz, CD3OD): δ = 6.52 (m, 1H, NH), 5.36 (t, J = 3.6 Hz, 1H, 12-H), 4.42 (dd, J = 11.0, 5.0 Hz, 1H, 3-H), 3.61–3.51 (m, 1H, 33-H), 3.28–3.26 (m, 1H, 36-H), 2.12–2.05 (m, 1H, 18-H), 1.99 (s, 3H, 30-H), 2.06–1.96 (m, 3H, 16-Hb, 35-Ha, 37-Ha), 1.96–1.89 (m, 3H, 11-H, 21-Ha), 1.89–1.75 (m, 3H, 15-Hb, 34-Hb, 38-Hb), 1.74–1.27 (m, 16H, 34-Ha, 35-Hb, 37-Hb,38-Ha, 1-Hb, 22-H, 2-H, 16-H, 6-H, 9-H, 7-H), 1.12 (s, 3H, 27-H), 1.08–1.00 (m, 3H, 1-Ha, 15-Ha, 20-H), 0.95 (s, 3H, 25-H), 0.94 (s, 3H, 32-H), 0.98 (m, 3H, 26-H), 0.85 (s, 3H, 24-H), 0.84 (s, 3H, 23-H), 0.83–0.81 (m, 1H, 5-H), 0.79 (s, 3H, 29-H) ppm; 13C NMR (126 MHz, CD3OD): δ = 179.7 (C-28), 172.8 (C-31), 140.4 (C-13), 127.0 (C-12), 82.3 (C-3), 56.6 (C-5), 54.6 (C-18), 49.8 (C-9), 49.6 (C-36), 49.0 (C-17), 48.8 (C-33), 43.5 (C-14), 40.9 (C-19), 40.0 (C-20), 39.4 (C-1), 38.7 (C-8), 38.0 (C-4), 34.1 (C-22), 31.9 (C-7), 29.0 (C-15), 28.6 (C-23), 28.0 (C-21), 27.1 (C-34, C-38), 27.0 (C-35, C-37), 25.2 (C-16), 24.5 (C-2), 24.4 (C-11), 23.9 (C-27), 21.5 (C-32), 21.1 (C-30), 19.2 (C-6), 18.1 (C-29), 17.6 (C-26), 17.2 (C-24), 16.1 (C-25) ppm; MS (ESI, MeOH): m/z 595.4 (100%, [M + H]+), 1189.4 (10%, [2M + H]+); analysis calcd for C38H62N3O4 (594.91): C 76.72, H 10.50, N 4.71; found: C 76.54, H 10.69, N 4.48.
- (3β)-28-[(trans-4-Aminocyclohexyl)amino]-28-oxolup-20(29)-en-3-yl acetate (13). Following GPB, compound 13 (0.42 g, 70%) was obtained as a colorless solid; Rf = 0.595 (CHCl3/MeOH, 8:2); m.p.: 205–212 °C (decomp.); = +0.1° (c 0.17, MeOH); IR (ATR): ν = 2940 m, 1731 m, 1637 m, 1513 m, 1369 m, 1244 s, 1026 m, 978 m, 882 m, 751 s cm−1; 1H NMR (500 MHz, CDCl3): δ = 4.71 (s, 1H, 29-Ha), 4.57 (s, 1H, 29-Hb), 4.49–4.41 (m, 1H, 3-H), 3.96–3.80 (m, 1H, 36-H), 3.76–3.63 (m, 1H, 33-H), 3.22–3.03 (m, 1H, 19-H), 2.40 (td, J = 12.3, 3.6 Hz, 1H, 13), 2.02 (s, 3H, 32-H), 1.98–1.02 (m, 28H, 37-H, 35-H, 38-H, 34-H, 1-Ha, 22-Ha, 12-Ha, 2-H, 18-H, 16-H, 15-Ha, 6-H, 11-H, 7-H, 1-Hb, 21-Ha, 9-H, 15-Hb), 1.66 (s, 3H, 30-H), 1.01–0.96 (m, 2H, 1-Hb, 12-Hb), 0.94 (s, 3H, 27-H), 0.92 (s, 3H, 26-H), 0.82 (d, J = 1.5 Hz, 6H, 23-H, 24-H), 0.81 (s, 3H, 25-H), 0.78–0.73 (m, 1H, 5-H) ppm; 13C NMR (126 MHz, CDCl3): δ = 175.6 (C-28), 171.1 (C-31), 151.1 (C-20), 109.5 (C-29), 81.1 (C-3), 55.6 (C-17), 55.6 (C-5), 50.7 (C-9), 50.3 (C-18), 50.1 (C-33), 47.4 (C-19), 47.0 (C-36), 42.6 (C-14), 40.9 (C-8), 39.2 (C-13), 38.5 (C-22), 38.5 (C-1), 37.9 (C-10), 37.2 (C-4), 34.4 (C-7), 33.9 (C-16), 33.8 (C-34, C-38), 31.5 (C-35, C-37), 31.0 (C-21), 29.5 (C-15), 28.1 (C-23), 25.7 (C-12), 23.8 (C-2), 21.4 (C-32), 21.1 (C-11), 19.6 (C-30), 18.3 (C-6), 16.6 (C-24), 16.4 (C-25), 16.3 (C-26), 14.7 (C-27) ppm; MS (ESI, MeOH/CHCl3, 4:1): m/z 593.3 (100%, [M − H]−), 629.3 (80%, [M + Cl]−); analysis calcd for C38H62N3O4 (594.91): C 76.72, H 10.50, N 4.71; found: C 76.47, H 10.89, N 4.43.
- (3β)-28-[(Cis-4-Aminocyclohexyl)Amino]-28-Oxolup-20(29)-En-3-Yl Acetate (14). Following GPB, compound 14 (0.39 g, 65%) was obtained as a colorless solid; Rf = 0.634 (CHCl3/MeOH, 8:2); m.p.: 230–235 °C (decomp.); = +9.7° (c 0.19, MeOH); IR (ATR): ν = 2940 s, 1731 m, 1620 m, 1505 m, 1368 m, 1244 s, 1027 m, 978 m, 751 s cm−1; 1H NMR (500 MHz, CDCl3): δ = 4.73 (s, 1H, 29-Ha), 4.59 (s, 1H, 29-Hb), 4.46 (dd, J = 10.3, 5.7 Hz, 1H, 3-H), 4.00 (s, 1H, 36-H), 3.47 (s, 1H, 33-H), 3.10 (td, J = 11.0, 3.9 Hz, 1H, 19-H), 2.46 (dd, J = 11.7, 2.0 Hz, 1H, 13-H), 2.03 (s, 3H, 32-H), 2.02–1.05 (m, 28H, 37-H, 35-H, 38-H, 34-H, 1-Ha, 22-Ha, 12-Ha, 2-H, 18-H, 16-H, 15-Ha, 6-H, 11-H, 7-H, 1-Hb, 21-Ha, 9-H, 15-Hb), 1.67 (s, 3H, 30-H), 1.03–0.96 (m, 2H, 1-Ha, 12-Hb), 0.95 (s, 3H, 27-H), 0.92 (s, 3H, 26-H), 0.84 (s, 6H, 23-H, 24-H), 0.83 (s, 3H, 25-H), 0.80–0.75 (m, 1H, 5-H) ppm; 13C NMR (126 MHz, CDCl3): δ = 175.6 (C-28), 171.0 (C-31), 150.8 (C-20),109.5 (C-29), 80.9 (C-3), 55.6 (C-17), 55.4 (C-5), 50.5 (C-9), 50.0 (C-18), 48.0 (C-33), 46.7 (C-19), 44.3 (C-36), 42.4 (C-14), 40.8 (C-8), 38.5 (C-22), 38.4 (C-1), 37.8 (C-10), 37.7 (C-13), 37.1 (C-4), 34.4 (C-7), 33.8 (C-16), 30.9 (C-21), 29.7 (C-34, C-38), 29.4 (C-15), 27.9 (C-23), 26.9 (C-35, C-37), 25.6 (C-12), 23.7 (C-2), 21.3 (C-32), 21.0 (C-11), 19.5 (C-30), 18.0 (C-6), 16.5 (C-24), 16.3 (C-26), 16.2 (C-25), 14.6 (C-27) ppm; MS (ESI, MeOH/CHCl3, 4:1): m/z 595.5 (100%, [M + H]+); analysis calcd for C38H62N3O4 (594.91): C 76.72, H 10.50, N 4.71; found: C 76.55, H 10.83, N 4.61.
- (3β)-28-[(trans-4-Aminocyclohexyl)amino]-20,28-dioxo-30-norlupan-3-yl acetate (15). Following GPB, compound 15 (0.385 g, 65%) was obtained as a colorless solid; Rf = 0.595 (CHCl3/MeOH, 8:2); m.p.: 251–255 °C (decomp.); = −17.0° (c 0.15, MeOH); IR (ATR): ν = 3384 w, 2941 s, 1710 m, 1633 m, 1516 m, 1368 m, 1025 m, 751 s cm−1; 1H NMR (500 MHz, CDCl3): δ = 4.49–4.41 (m, 1H, 3-H), 3.84–3.71 (m, 1H, 35-H), 3.46–3.27 (m, 1H, 19-H), 3.25–2.97 (m, 1H, 32-H), 2.33–2.18 (m, 1H, 13-H), 2.15 (s, 3H, 29-H), 2.07 (d, J = 15.8 Hz, 2H, 18-H, 21-Ha), 2.03 (s, 3H, 31-H), 1.94–1.81 (m, 1H, 16-Ha), 1.77–1.04 (m, 27-H, 36-H, 34-H, 37-H, 33-H, 22-H, 12-H, 2-H, 1-Ha, 16-Hb, 21-Hb, 15-Ha, 6-H, 11-H, 7-H, 9-H, 15-Hb), 0.98 (s, 3H, 27-H), 0.96–0.92 (m, 1H, 1-Hb), 0.90 (s, 3H, 26-H), 0.83–0.82 (m, 6H, 24-H, 25-H), 0.81 (s, 3H, 23-H), 0.80–0.76 (m, 1H, 5-H) ppm; 13C NMR (126 MHz, CDCl3): δ = 212.8 (C-20), 175.8 (C-28), 171.1 (C-30), 80.9 (C-3), 55.5 (C-5), 55.4 (C-17) 51.3 (C-19), 50.5 (C-9), 50.3 (C-33), 50.2 (C-18), 47.0 (C-36), 42.4 (C-14), 40.9 (C-8), 38.5 (C-1), 38.2 (C-22), 37.9 (C-10), 37.3 (C-4), 37.0 (C-13), 34.4 (C-7), 33.1 (C-16), 30.9 (C-33, C-37), 30.3 (C-29), 29.7 (C-36, C-34), 29.6 (C-15), 28.7 (C-21), 28.1 (C-23), 27.3 (C-12), 23.8 (C-2), 21.4 (C-31), 21.1 (C-11), 18.3 (C-6), 16.6 (C-24), 16.3 (C-25), 16.3 (C-26), 14.8 (C-27) ppm; MS (ESI, MeOH/CHCl3 4:1): m/z 597.4 (100%, [M + 2H]+); analysis calcd for C37H60N2O4 (596.88): C 74.45, H 10.13, N 4.69; found: C 74.19, H 10.32, N 4.42.
- (3β)-28-[(cis-4-Aminocyclohexyl)amino]-20,28-dioxo-30-norlupan-3-yl acetate (16). Following GPB, compound 16 (465 mg, 78%) was obtained as a colorless solid; Rf = 0.65 (CHCl3/MeOH, 8:2); m.p.: 257–260 °C (decomp.); = −9.1° (c 0.14, CHCl3); IR (ATR): ν = 2936 m, 1729 m, 1600 s, 1517 m, 1369 m, 1245 s, 988 s, 804 m, 7451 m cm−1; 1H NMR (500 MHz, CDCl3): δ = 4.58–4.26 (m, 1H, 3-H), 4.00–3.83 (m, 1H, 35-H), 3.43 (dt, J = 11.4, 6.0 Hz, 1H, 19-H), 3.11–2.85 (m, 1H, 32-H), 2.21 (dt, J = 11.8, 4.5 Hz, 1H, 13-H), 2.14 (s, 3H, 29-H), 2.09–2.03 (m, 2H, 18-H, 21-Ha), 2.01 (s, 3H, 31-H), 1.95–1.85 (m, 1H, 16-Hb), 1.77–1.01 (m, 27-H, 36-H, 34-H, 37-H, 33-H, 22-H, 12-H, 2-H, 1-Hb, 16-Hb, 15-H, 21-Hb, 6-H, 11-H, 7-H, 9-H), 0.97 (s, 3H, 27-H), 0.88 (s, 3H, 26-H), 0.87 (s, 1H, 1-Ha), 0.82 (s, 3H, 25-H), 0.81 (s, 3H, 24-H), 0.80 (s, 3H, 23-H), 0.79–0.73 (m, 1H, 5-H) ppm; 13C NMR (126 MHz, CDCl3): δ = 213.0 (C-20), 175.3 (C-28), 171.0 (C-30), 81.0 (C-3), 55.5 (C-17), 55.4 (C-5), 51.3 (C-19), 50.5 (C-9), 50.2 (C-18), 47.6 (C-32), 45.1 (C-35), 42.3 (C-14), 40.8 (C-8), 38.5 (C-1), 38.2 (C-22), 37.9 (C-10), 37.2 (C-4), 36.9 (C-13), 34.3 (C-7), 33.2 (C-16), 30.8 (C-37, C-33), 30.4 (C-29), 29.6 (C-15), 28.7 (C-21), 28.0 (C-23), 27.9 (C-36, C-34), 27.6 (C-12), 23.8 (C-2), 21.4 (C-31), 21.1 (C-11), 18.3 (C-6), 16.6 (C-24), 16.3 (C-25), 14.8 (C-27) ppm; MS (ESI, MeOH/CHCl3, 4:1): m/z 597.2 (95%, [M − H]−), 631.3 (100%, [M + Cl]−); analysis calcd for C37H60N2O4 (596.88): C 74.45, H 10.13, N 4.69; found: C 74.23, H 10.39, N 4.37.
- (3β)-28-[(2-Aminoethyl)amino]-28-oxoolean-12-en-3-yl acetate (17). This compound (0.69 g, 83%) was obtained from 1 following GPB as a colorless solid; [35,36] m.p. 211–214 °C (lit.: [36] 212–215 °C); = +38.3° (c 0.4, CHCl3) [lit.: [36] = +37.8° (c 0.35, CHCl3); MS (ESI, MeOH): m/z 541.2 (100%, [M + H]+).
- (3β)-28-[(2-Aminoethyl)amino]-28-oxours-12-en-3-yl acetate (18). This compound (0.81 g, 87%) was obtained from 2 following GPB as a colorless solid; [37,38,39,40] m.p. 202–205 °C (lit.: [37] 140–142 °C); = +39.0° (c 0.2, CHCl3) [lit.: [18] = +39.4° (c 0.555, CHCl3); MS (ESI, MeOH): m/z 541.3 (100%, [M + H]+).
- (3β)-28-[(2-Aminoethyl)amino]-28-oxolup-20(29)-en-3-yl acetate (19). This compound (0.86 g, 93%) was obtained from 3 following GPB as a colorless solid; [41] m.p. 150–153 °C (lit.: [18] 152–154 °C); = +8.1° (c 0.25, CHCl3) [lit.: [18] = +8.4° (c 0.33, CHCl3); MS (ESI, MeOH): m/z 541.2 (100%, [M + H]+).
- (3β)-28-[(2-Aminoethyl)amino]-20,28-dioxo-30-norlupan-3-yl acetate (20). This compound (0.80 g, 88%) was obtained from 4 following GPB as a colorless solid; [42] m.p. 231–234 °C (lit.: [19] 230–234 °C); = −8.5° (c 0.20, CHCl3) [lit.: [19] = −8.5° (c 0.16, CHCl3); MS (ESI, MeOH): m/z 543.1 (100%, [M + H]+).
- (3β)28-(1,4-Diazabicyclo[3.2.2]nonyl-4-yl)-28-oxoolean-12-en-3-yl acetate (25). Following GPB from 1 (626 mg, 1.26 mmol) and 7 (500 mg, 2.51 mmol), 25 (462 mg, 73%) was obtained as colorless solid; m.p. 271–274 °C; Rf = 0.7 (CHCl3/MeOH, 9:1); [α]D = +20.5° (c 0.15, CHCl3); IR (ATR): ν = 2943 br, 1732 m, 1621 m, 1463 w, 1393 m, 1363 m, 1243 s, 1174 m, 1140 m, 1115 w, 1026 m, 1005 m, 749 m cm−1; 1H NMR (400 MHz, CDCl3): δ = 6.15–5.99 (m, 2H, 34-H), 5.27–5.24 (m, 1H, 12-H), 4.76 (m, 1H, 39-H), 4.51–4.44 (m, 1H, 3-H), 4.38–3.99 (m, 5H, 35-Ha + 37-H2 + 40-H2), 3.75 (t, J = 12.0 Hz, 1H, 35-Hb), 3.04 (d, J = 13.6 Hz, 1H, 18-H), 2.38–2.25 (m, 2H, 38-H2), 2.24–2.11 (m, 2H, 41-H2), 2.03 (s, 3H, 32-H3), 2.00–1.81 (m, 3H, 11-H2 + 16-Ha), 1.61 (m, 7H, 1-Ha + 6-Ha + 9-H + 15-Ha + 19-Ha + 22-H2), 1.48–1.16 (m, 10H, 1-Hb + 2-H2 + 6-Hb + 7-H2 + 16-Hb + 19-Hb + 21-H2), 1.13 (s, 3H, 26-H3), 0.92 (s, 3H, 23-H3), 0.91 (s, 3H, 25-H3), 0.90 (s, 3H, 30-H3), 0.86 (s, 3H, 29-H3), 0.84 (s, 3H, 24H3), 0.81 (s, 1H, 5-H), 0.67 (s, 3H, 27-H3) ppm; 13C NMR (101 MHz, CDCl3): δ = 174.9 (C-28), 171.0 (C-31), 144.1 (C-13), 122.0 (C-12), 80.9 (C-3), 72.4 (C-34), 55.4 (C-35), 55.3 (C-5), 47.9 (C-37), 47.6 (C-10), 46.1 (C-17), 45.2 (C-39), 43.7 (C-18), 41.9 (C-14), 40.9 (C-40), 39.1 (C8), 38.1 (C-22), 37.7 (C-20), 37.0 (C-4), 33.8 (C-1), 33.5 (C-21), 32.9 (C-23), 32.8 (C-16), 32.5 (C-7), 28.0 (C-29), 27.9 (C-15), 25.8 (C-26), 24.0 (C-38), 23.5 (C-41), 23.3 (C-19), 22.6 (C-2), 22.5 (C-11), 21.3 (C-32), 18.2 (C-6), 17.0 (C-25), 16.6 (C-24), 15.4 (C-27), 14.1 (C-30), 8.6 (C-9) ppm; MS (ESI, MeOH): m/z = 607.5 (100%, [M + H]+), 608.5 (40%, [M + 2H]+); analysis calcd for C39H62N2O3 (606.94): C 77.18, H 10.30, N 4.62; found: C 76.84, H 10.58, N 4.45.
- (3β)28-(1,4-Diazabicyclo[3.2.2]non-4-yl)-28-oxolup-20(29)en-3-yl acetate (26). Following GPB from 3 (250 mg, 0.50 mmol) and 7 (249 mg, 1.25 mmol), 26 (228 mg, 74%) was obtained as a colorless solid; m.p. 242–246 °C; Rf = 0.4 (DCM/MeOH, 9:1); [α]D = −0.9° (c 0.17, CHCl3); IR (ATR): ν = 2941 m, 1731 m, 1624 m, 1475 m, 1398 m, 1385 m, 1242 s, 1117 m, 1028 m, 978 m, 749 m cm−1; 1H NMR (500 MHz, CDCl3): δ = 4.72 (d, J = 2.3 Hz, 1H, 29-Ha), 4.62 (dq, J = 4.6, 2.5 Hz, 1H, 39-H), 4.58 (dt, J = 2.4, 1.4 Hz, 1H, 29-Hb), 4.49–4.45 (m, 1H, 3-H), 3.79–3.64 (m, 2H, 34-H2), 3.16–2.88 (m, 7H, 13-H + 19-H2 + 35-H + 37-H2 + 40-H2), 2.12 (dt, J = 13.5, 3.5 Hz, 1H, 41-Ha), 2.04 (s, 3H. 32-H3), 2.02–1.89 (m, 5H, 1-Ha + 16-Ha + 21-Ha + 22-Ha + 41-Hb), 1.89–1.45 (m, 14H, 2-H2 + 7-H2 + 12-H2 + 15-Ha + 18-H2 + 30-H3 + 38-H2), 1.44–1.06 (m, 7H, 6-H2 + 9-H + 11-H2 + 16-Hb + 22-Hb), 0.96 (s, 3H, 27-H3), 0.94 (s, 3H, 25-H3), 0.92–0.89 (m, 3H, 1-Hb + 15-Hb + 21-Hb), 0.86 (s, 3H, 23-H3), 0.85 (s, 3H, 26-H3), 0.84 (s, 3H, 24-H3), 0.79 (dd, J = 8.7, 3.3 Hz, 1H, 5-H) ppm; 13C NMR (126 MHz, CDCl3): δ = 173.3 (C-28), 171.0 (C-31), 151.4 (C-20), 109.1 (C-29), 81.0 (C-3), 55.6 (C-5), 55.2 (C-17), 53.0 (C-18), 50.8 (C-9), 47.4 (C-39), 46.8 (C-37), 46.3 (C-35), 45.7 (C-19), 45.2 (C-34), 41.9 (C-14), 40.7 (C-8), 38.4 (C-1), 37.8 (C-4), 37.2 (C-10), 36.9 (C-13), 36.2 (C-22), 34.3 (C-7), 32.5 (C-40), 31.5 (C-16), 29.9 (C-21), 27.9 (C-23), 26.6 (C-15), 26.5 (C41 + C38), 25.6 (C-12), 23.7 (C-2), 21.3 (C-32), 21.2 (C-11), 19.7 (C-30), 18.2 (C-6), 16.5 (C-24), 16.3 (C-25), 16.1 (C-26), 14.7 (C-27) ppm; MS (ESI, MeOH): m/z = 607.6 (100%, [M + H]+), 608.6 (45%, [M + 2H]+), 1214.2 (5%, [2M + 2H]+); analysis calcd for C39H62N2O3 (606.94): C 77.18, H 10.30, N 4.62; found: C 76.97, H 10.51, N 4.44.
- (3β)28-(1,4-Diazabicyclo[3.2.2]non-4-yl)-20,28-dioxo-30-norlupan-3-yl acetate (27). Following GPB from 4 (250 mg, 0.49 mmol) and 7 (238 mg, 1.19 mmol), 27 (270 mg, 99%) was obtained as a colorless solid; m.p. 253 °C (decomp.); Rf = 0.3 (DCM/MeOH/, 9:1); [α]D = −8.7° (c 0.21, CHCl3); IR (ATR): ν = 2940 br, 1731 m, 1622 m, 1367 m, 1243 s, 1026 m, 978 m, 772 s cm−1; 1H NMR (400 MHz, CDCl3): δ = 4.60 (s, 1H, 39-H), 4.46 (dd, J = 10.5, 5.5 Hz, 1H, 3-H), 3.71 (m, 2H, 34-H2), 3.25 (td, J = 11.3, 3.5 Hz, 1H, 19-H), 3.18–2.88 (m, 6H, 35-H2 + 37-H2 + 40-H2), 2.79 (td, J = 12.0, 3.8 Hz, 1H, 13-H), 2.16 (s, 3H, 29-H3), 2.15–2.05 (m, 2H, 18-H + 21-Ha), 2.03 (s, 3H, 32-H3), 2.01–1.80 (m, 2H, 16-Ha + 21-Hb), 1.79–1.55 (m, 6H, 15-Ha + 16-Hb + 38-H2 + 41-H2), 1.54–1.11 (m, 14H, 1-Ha + 2-Ha + 6-H2 + 7-H2 + 9-H + 11-H2 + 12-H2 + 15-Hb + 22-H2), 1.05 (dd, J = 13.4, 3.5 Hz, 1H, 2-Hb), 0.98 (s, 3H, 27-H3), 0.96 (s, 1H, 1-Hb), 0.93 (s, 3H, 26-H3), 0.83 (m, 6H, 23-H3 + 25-H3), 0.82 (s, 3H, 24-H3), 0.81–0.76 (m, 1H, 5-H) ppm; 13C NMR (126 MHz CDCl3): δ = 213.1 (C-20), 173.3 (C-28), 171.0 (C-31), 80.9 (C-3), 55.5 (C-5), 55.1 (C-17), 52.9 (C-18), 50.7 (C-9), 50.1 (C-19), 47.4 (C-39), 46.8 (C-35), 46.2 (C-37), 46.2 (C-40), 44.9 (C-34), 41.8 (C-14), 40.6 (C-8), 38.4 (C-1), 37.8 (C-4), 37.1 (C-10), 37.1 (C-22), 35.9 (C-13), 35.7 (C-16), 34.2 (C-7), 32.0 (C-38), 30.3 (C-29), 29.9 (C-15), 28.9 (C-21), 27.9 (C-24), 27.5 (C-41), 27.3 (C-12), 23.7 (C-2), 21.3 (C-32), 21.2 (C-11), 18.1 (C-6), 16.5 (C-23), 16.2 (C-25), 16.0 (C-26), 14.7 (C-27) ppm; MS (ESI, MeOH): m/z = 609.5 (25%, [M + H]+); analysis calcd for C38H60N2O4 (608.91): C 74.96, H 9.93, N 4.60; found: C 74.72, H 10.13, N 4.48.
- (3β)28-(1,3-Diazabicyclo[3.2.2]nonyl-3-yl)-28-oxoolean-12-en-3-yl acetate (28). Following GPB from 1 (375 mg, 0.75 mmol) and 8 (300 mg, 1.52 mmol), 28 (462 mg, 73%) was obtained as an off-white solid; m.p. 130 °C (decomp.); Rf = 0.3 (CHCl3/MeOH, 98:2); [α]D = +10.5° (c 0.16, CHCl3); IR (ATR): ν = 3221 brw, 2942 brm, 1731 m, 1610 m, 1530 m, 1446 s, 1366 m, 1244 s, 1026 s, 655 s cm−1; 1H NMR (400 MHz, MeOH-d4): δ = 5.83 (ddt, J = 9.9, 3.7, 1.7 Hz, 1H, 34-Ha), 5.72–5.66 (m, 1H, 34-Hb), 5.36 (t, J = 3.7 Hz, 1H, 12-H), 4.45 (dd, J = 10.9, 5.0 Hz, 1H, 3-H), 3.46 (d, J = 6.5 Hz, 1H, 39-Ha), 3.27 (d, J = 6.7 Hz, 1H, 39-Hb), 3.21 (dt, J = 8.9, 2.8 Hz, 1H, 18-H), 2.84 (dq, J = 15.0, 5.9 Hz, 2H, 36-H2), 2.73 (m, 3H, 18-H + 40-H2), 2.28 (q, J = 2.5 Hz, 2H, 37-H2), 2.14–2.05 (m, 2H, 9-H + 11-Ha), 2.02 (s, 3H, 32-H3), 1.97–1.87 (m, 4H, 2-H2 + 11-Hb + 15-Ha) 1.84–1.73 (m, 2H, 6-Ha + 19-Ha), 1.69–1.51 (m, 7H, 16-Ha + 21-H2 + 38-H2 + 41-H2), 1.51–1.20 (m, 7H, 1-H2 + 6-Hb + 7-H2 + 22-H2), 1.18 (s, 3H, 26-H3), 1.16–0.99 (m, 3H, 15-Hb + 16-Hb + 19-Hb), 0.97 (s, 3H, 25-H3), 0.94 (s, 3H, 30-H3), 0.91 (s, 3H, 23-H3), 0.88 (s, 3H, 29-H3), 0.87 (s, 3H, 24-H3), 0.85 (s, 1H, 5-H), 0.79 (s, 3H, 27-H3) ppm; 13C NMR (101 MHz, MeOH-d4): δ = 179.3 (C-28), 171.5 (C-31), 143.7 (C-13), 124.9 (C-34), 123.2 (C-34),122.7 (C-12), 81.1 (C-3), 56.1 (C-40), 55.3 (C-5), 49.6 (C36), 47.1 (C-38), 46.3 (C-17), 46.2 (C-19), 41.5 (C-14), 41.3 (C-18), 39.3 (C-8), 37.9 (C-1), 37.3 (C-20), 36.7 (C-4), 35.7 (C-39), 34.1 (C-21), 33.7 (C-10), 32.8 (C-16), 32.5 (C-22), 32.1(C-23), 30.2(C-7), 27.2 (C-29), 27.1 (C-15), 25.0 (C-26), 24.6 (C-41),23.4 (C-38) 23.2 (C-37), 23.1 (C-11), 22.6 (C-30), 22.2 (C-2), 19.7 (C-32), 17.9 (C-6), 16.5 (C-27), 15.7 (C-24), 14.5 (C-25) ppm; MS (ESI, MeOH): m/z = 607.4 (100%, [M + H]+), 608.4 (60%, [M + 2H]+); analysis calcd for C39H62N2O3 (606.94): C 77.18, H 10.30, N 4.62; found: C 76.93, H 10.56, N 4.49.
- (3β)28-(1,3-Diazabicyclo[3.2.2]nonyl)-3-yl)-28-oxours-12-en-3-yl acetate (29). Following GPB from 2 (375 mg, 0.75 mmol) and 8 (404 mg, 2.03 mmol), 29 (332 mg, 73%) was obtained as a colorless solid; m.p. 135–139 °C (decomp.); Rf = 0.35 (DCM/MeOH, 96:4); [α]D = +28.6° (c 0.14, CHCl3); IR (ATR): ν = 2924 br, 1733 s, 1651 m, 1455 m, 1369 m, 1243 s, 1141 w, 1026 m, 653 m cm−1; 1H NMR (500 MHz, CDCl3): δ = 5.77 (m, 1H, 34-Ha), 5.67 (m, 1H, 34-Hb), 5.27 (t, J = 3.7 Hz, 1H, 12-H), 4.60–4.44 (dd, J = 10.0, 6.0 Hz, 1H, 3-H), 3.41–3.19 (m, 2H, 39-H2), 3.07 –2.82 (m, 2H, 36-H2), 2.64 (dt, J = 10.8, 5.2 Hz, 1H, 40-Ha), 2.53 (dt, J = 9.0, 5.5 Hz, 2H, 18-H, 40-Hb), 2.29–2.10 (m, 3H, 11-H2 + 16-Ha), 2.06 (s, 3H, 32-H3), 2.02–1.83 (m, 6H, 19-H + 1-Ha + 2-H2 + 7-H2), 1.80–1.70 (m, 3H, 15-Ha + 37-H2), 1.64 (m, 4H, 6-Ha + 21-Ha + 22-H2), 1.59–1.25 (m, 10H, 6-Hb + 9-H + 16-Hb + 20-H2 + 21-Hb + 38-H2 + 41-H2), 1.09 (s, 3H, 27-H3), 1.08–0.95 (m, 2H, 1-Hb + 15-Hb), 0.96 (s, 3H, 25-H3), 0.94 (s, 3H, 30-H3) 0.89 (s, 3H, 29-H3), 0.88 (s, 3H, 24-H3), 0.87 (s, 3H, 23-H3), 0.85–0.81 (m, 1H, 5-H), 0.79 (s, 3H, 26-H3) ppm; 13C NMR (126 MHz, CDCl3): δ = 178.1 (C-28), 171.0 (C-31), 139.2 (C-13), 125.8(C-12), 125.2 (C-34), 125.1 (C-34), 80.9 (C-3), 56.7 (C-18), 55.2(C-5), 53.9 (C-19), 52.3 (C-36), 50.3 (C-40), 47.8 (C-17), 47.5 (C-9), 42.4 (C-14), 39.8 (C-38), 39.6 (C-8), 39.1 (C-20), 38.3 (C-1), 37.7 (C-4), 37.3 (C-37), 36.9 (C-10), 36.2 (C-7), 36.2 (C-39), 32.7(C-22), 31.0 (C-21), 28.1 (C-24), 27.9 (C-16), 26.3 (C-11), 24.9 (C-41), 23.5 (C-2), 23.5 (C-15), 23.2 (C-27), 21.3 (C-32), 21.2 (C-25), 18.2 (C-6), 17.3 (C-29), 17.0 (C-26), 16.7 (C-23), 15.6 (C-30) ppm; MS (ESI, MeOH): m/z = 607.3 (100%, [M + H]+), 608.3 (65%; [M + 2H]+; m/z = 605.3 (100%, [M − H]−); analysis calcd for C39H62N2O3 (606.94): C 77.18, H 10.30, N 4.62; found: C 76.87, H 10.57, N 4.43.
- (3β)28-(1,3-Diazabicyclo[3.2.2]non-3-yl)-28-oxolup-20(29)-en-3-yl acetate (30). Following GPB from 3 (200 mg, 0.40 mmol) and 8 (238 mg, 1.19 mmol), 30 (125 mg, 95%) was obtained as an amorphous colorless solid; Rf = 0.30 (DCM/MeOH, 98:2); [α]D = +5.5° (c 0.17, CHCl3); IR (ATR): ν = 2942 m, 1732 m, 1638 m, 1450 m, 1368 m, 1243 s, 1027 m, 978 m, 881 m, 772 m, 653 m cm−1; 1H NMR (400 MHz, CDCl3): δ = 5.75 (m, 1H, 34-Ha), 5.66 (m, 1H, 34-Hb), 4.72 (d, J = 2.4 Hz, 1H, 29-Ha), 4.59 (dt, J = 2.5, 1.4 Hz, 1H, 29-Hb), 4.51–4.42 (m, 1H, 3-H), 3.37 (qt, J = 13.9, 6.8 Hz, 2H, 39-H2), 3.11–2.92 (m, 3H, 19-H + 36-Ha + 40-Ha), 2.65–2.52 (m, 4H, 36-Hb + 40-Hb), 2.37 (td, J = 12.4, 3.6 Hz, 1H, 9-H), 2.17 (tp, J = 5.7, 2.9, 2.3 Hz, 2H, 13-H + 18-H), 2.03 (s, 3H, 32-H3), 2.00–1.72 (m, 4H, 1-Ha + 12-Ha + 21-Ha + 22-Ha), 1.68 (m, 4H, 21-Hb + 30-H3), 1.66–1.56 (m, 6H, 2-H2 + 6-Ha + 11-Ha + 15-Ha + 22-Hb), 1.55–0.97 (m, 14H, 1-Hb + 6-Hb + 7-H2 + 11-Hb + 12-Hb + 15-Hb + 16-H2 + 37-H2 + 38-H + 41-H2), 0.95 (s, 3H, 27-H3), 0.93 (s, 3H, 26-H3), 0.84 (s, 3H, 23-H3), 0.83 (s, 3H, 25-H3), 0.82 (s, 3H, 24-H3), 0.80–0.74 (m, 1H, 5-H) ppm; 13C NMR (126 MHz, CDCl3): δ = 177.7 (C-28), 171.0 (C-31), 151.0 (C-20), 118.9 (C-34), 109.4 (C-29), 80.9 (C-3), 55.9 (C36), 55.4 (C-5), 50.5 (C-9), 50.3(C-40), 50.1 (C-18), 49.2 (C-17), 46.8 (C-19), 42.4 (C-14), 40.8 (C-8), 38.4 (C-13), 38.1 (C-1), 37.8 (C-4), 37.7 (C-38), 37.1 (C-10), 34.3 (C-22), 34.2 (C-7), 33.0 (C-16), 30.9 (C-21), 29.5 (C-15), 27.9 (C-23), 25.6 (C-12), 25.4 (C-41), 23.7 (C-2), 21.8 (C-37), 21.3 (C-32), 21.0 (C-11), 19.4 (C-30), 18.2 (C-6), 16.5 (C-24), 16.2 (C-25), 16.2 (C-26), 14.6 (C-27) ppm; MS (ESI, MeOH): m/z = 607.3 (100%, [M + H]+, 1241.9 (5%, [2M + 3H2O + 2H]2+); analysis calcd for C39H62N2O3 (606.94): C 77.18, H 10.30, N 4.62; found: C 76.81, H 10.53, N 4.41.
- (3β)28-(1,4-Diazabicyclo[3.2.2]non-4-yl)-20,28-dioxo-30-norlupan-3-yl-acetate (31). Following GPB from 4 (250 mg, 0.39 mmol) and 8 (238 mg, 1.19 mmol), 31 (178 mg, 73%) was obtained as a colorless solid; m.p. 130–132 °C; Rf = 0.40 (DCM/MeOH, 95:5); [α]D = −7.0° (c 0.15, CHCl3); IR (ATR): ν = 2942 brm, 1732 m, 1656 m, 1517 m, 1449 m, 1363 m, 1244 m, 1195 m, 1026 m, 979 m, 772 m, 654 m cm−1; 1H NMR (500 MHz, CDCl3): δ = 5.89–5.64 (m, 2H, 34-H2), 4.45 (dd, J = 11.0, 5.2 Hz, 1H, 3-H), 3.52 (m, 2H, 39-H2), 3.37 (m, 2H, 36-H2), 3.33–3.18 (m, 1H, 19-H), 2.87 (dt, J = 26.8, 6.1 Hz, 2H, 40-H2), 2.42–2.30 (m, 2H, 37-H2), 2.29–2.17 (m, 1H, 13-H), 2.14 (s, 3H, 29-H3), 2.12–2.04 (m, 2H, 18-H + 38-H), 2.02 (s, 3H, 32-H3), 2.00–1.81 (m, 1H, 21-Ha), 1.67–1.11 (m, 18H, 1-Ha + 2-Ha + 6-H2 + 7-H2 + 9-H + 11-H2 + 12-H2 + 15-H2 + 16-Ha + 22-H2 + 41-H2), 1.05 (m, 3H, 2-Hb + 16-Hb + 21-Hb), 0.97 (s, 3H, 27-H3), 0.94–0.91 (m, 1H, 1-Hb), 0.89 (s, 3H, 26-H3), 0.84–0.80 (m, 9H, 23-H3 + 24-H3 + 25-H3), 0.79–0.73 (m, 1H, 5-H) ppm; 13C NMR (126 MHz, CDCl3): δ = 212.7 (C-20), 176.8 (C-28), 170.9 (C-31), 125.6 (C-34), 80.8 (C-3), 56.2 (C36), 55.7 (C-17), 55.4 (C-5), 51.3 (C-4), 51.2 (C-19), 50.4 (C-9), 50.0 (C-18), 49.4 (C-40), 42.2 (C-14), 40.7 (C-8), 38.3 (C-1), 37.8 (C-38), 37.8 (C-22), 37.1 (C-10), 36.8 (C-13), 35.0 (C-39), 34.2 (C-7), 32.6 (C-16), 30.1 (C-29), 29.5 (C-15), 28.6 (C-21), 27.9 (C-24), 27.9 (C-25), 27.7 (C-12), 27.2 (C-41), 23.8 (C-2), 23.6 (C-37), 21.3 (C-32), 20.9 (C-11), 18.2 (C-6), 16.5 (C-23), 16.2 (C-26), 14.6 (C-27) ppm; MS (ESI, MeOH): m/z = 609.2 (100%, [M + H]+), 610.2 (50%; [M + 2H]+); analysis calcd for C38H60N2O4 (608.91): C 74.96, H 9.93, N 4.60; found: C 74.76, H 10.14, N 4.41.
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Compound | A375 | HT29 | MCF-7 | A2780 | FaDu | NIH 3T3 |
---|---|---|---|---|---|---|
OA | >30 | >30 | >30 | >30 | >30 | >30 |
UA | 15.4 ± 1.0 | 12.4 ± 1.1 | 14.7 ± 0.4 | 17.3 ± 0.9 | 18.2 ± 1.7 | 16.3 ± 1.4 |
BA | 17.7 ± 0.4 | 16.8 ± 2.0 | 12.3 ± 1.1 | 9.4 ± 1.1 | 13.7 ± 0.9 | 19.3 ± 1.1 |
PA | >30 | >30 | >30 | >30 | >30 | >30 |
1 | 13.1 ± 1.1 | 20.5 ± 1.7 | 12.9 ± 1.9 | 9.4 ± 0.5 | 11.8 ± 0.9 | 17.5 ± 1.5 |
2 | 11.4 ± 1.4 | 17.3 ± 1.5 | 12.1 ± 1.2 | 8.3 ± 0.9 | 10.7 ± 0.8 | 16.4 ± 1.7 |
3 | 19.2 ± 1.7 | 21.3 ± 2.0 | 11.0 ± 0.5 | 18.3 ± 0.5 | 7.2 ± 1.2 | >30 |
4–8 | >30 | >30 | >30 | >30 | >30 | >30 |
9 | 1.8 ± 0.3 | 1.7 ± 0.2 | 2.0 ± 0.3 | 2.1 ± 0.2 | 2.0 ± 0.1 | 1.8 ± 0.4 |
10 | 2.4 ± 0.2 | 2.9 ± 0.1 | 2.8 ± 0.6 | 2.7 ± 0.2 | 2.9 ± 0.2 | 2.2 ± 0.2 |
11 | 1.9 ± 0.2 | 2.6 ± 0.1 | 2.5 ± 0.4 | 2.6 ± 0.3 | 2.6 ± 0.1 | 1.9 ± 0.3 |
12 | 1.9 ± 0.3 | 2.4 ± 0.1 | 2.4 ± 0.4 | 2.3 ± 0.2 | 2.5 ± 0.1 | 1.9 ± 0.2 |
13 | 0.9 ± 0.1 | 0.6 ± 0.1 | 1.3 ± 0.4 | 1.0 ± 0.1 | 1.0 ± 0.1 | 1.0 ± 0.1 |
14 | 1.3 ± 0.2 | 0.8 ± 0.1 | 1.2 ± 0.4 | 1.2 ± 0.35 | 1.1 ± 0.2 | 1.1 ± 0.1 |
15 | 0.9 ± 0.1 | 2.1 ± 0.1 | 2.8 ± 0.4 | 1.8 ± 0.2 | 1.5 ± 0.1 | 0.5 ± 0.1 |
16 | n.s. | n.s. | n.s. | n.s. | n.s. | n.s. |
DX | n.d. | 0.9 ± 0.2 | 1.1 ± 0.3 | 0.02 ± 0.01 | 1.7 ± 0.3 | 0.06 ± 0.03 |
Compound | HT29 | MCF-7 | A2780 | NIH 3T3 |
---|---|---|---|---|
17 | 2.0 ± 0.2 | 1.7 ± 0.2 | 3.1 ± 0.1 | 2.1 ± 0.1 |
18 | 1.8 ± 0.1 | 2.0 ± 0.1 | 2.3 ± 0.1 | 2.6 ± 0.3 |
19 | 1.0 ± 0.3 | 1.3 ± 0.1 | 1.4 ± 0.2 | 1.4 ± 0.1 |
20 | 3.3 ± 1.2 | 3.1 ± 0.1 | 3.2 ± 0.2 | 2.1 ± 0.1 |
21 | 1.3 ± 0.1 | 1.7 ± 0.2 | 1.7 ± 0.1 | 1.7 ± 0.1 |
22 | 1.9 ± 0.3 | 2.0 ± 0.1 | 2.1 ± 0.1 | 2.1 ± 0.1 |
23 | 1.0 ± 0.1 | 1.4 ± 0.1 | 1.9 ± 0.1 | 0.9 ± 0.1 |
24 | 2.4 ± 0.3 | 2.8 ± 0.1 | 3.1 ± 0.1 | 0.7 ± 0.1 |
Compound | A375 | HT29 | MCF-7 | A2780 | FaDu | NIH 3T3 |
---|---|---|---|---|---|---|
25, 26 | n.s. | n.s. | n.s. | n.s. | n.s. | n.s. |
27 | 2.3 ± 0.2 | 5.2 ± 0.2 | 4.2 ± 0.8 | 3.9 ± 0.4 | 2.7 ± 0.4 | 2.2 ± 0.2 |
28, 29 | n.s. | n.s. | n.s. | n.s. | n.s. | n.s. |
30 | 4.7 ± 0.2 | 4.8 ± 0.3 | 6.0 ± 0.9 | 5.5 ± 0.4 | 6.3 ± 0.5 | 9.3 ± 0.7 |
31 | 6.0 ± 0.5 | 8.2 ± 0.3 | 6.3 ± 0.5 | 6.4 ± 0.3 | 6.2 ± 0.6 | 5.0 ± 0.4 |
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Hoenke, S.; Christoph, M.A.; Friedrich, S.; Heise, N.; Brandes, B.; Deigner, H.-P.; Al-Harrasi, A.; Csuk, R. The Presence of a Cyclohexyldiamine Moiety Confers Cytotoxicity to Pentacyclic Triterpenoids. Molecules 2021, 26, 2102. https://doi.org/10.3390/molecules26072102
Hoenke S, Christoph MA, Friedrich S, Heise N, Brandes B, Deigner H-P, Al-Harrasi A, Csuk R. The Presence of a Cyclohexyldiamine Moiety Confers Cytotoxicity to Pentacyclic Triterpenoids. Molecules. 2021; 26(7):2102. https://doi.org/10.3390/molecules26072102
Chicago/Turabian StyleHoenke, Sophie, Martin A. Christoph, Sander Friedrich, Niels Heise, Benjamin Brandes, Hans-Peter Deigner, Ahmed Al-Harrasi, and René Csuk. 2021. "The Presence of a Cyclohexyldiamine Moiety Confers Cytotoxicity to Pentacyclic Triterpenoids" Molecules 26, no. 7: 2102. https://doi.org/10.3390/molecules26072102