Synthesis and Anti-tumor Activity of Tubulysins Analogues†

doi:10.7503/cjcu20160550

Abstract

Abstract:

Tubulysins family is a kind of natural compound with potent antitumor activity. To simplify the synthesis route and find new antitumor compounds is becoming a hotspot of research in recent years. Starting from 3-nitrobenzoic acid, after 7 steps transformations, 12 new tubulysin analogues were synthesized via the conformation restrain and bioisostere principle. These structures are featuring 3-substituted analine moieties. All these compounds are new compounds, and their structures were confirmed by ¹H nuclear magnetic resonance(NMR), ¹³C NMR, and high resolution mass spectrometer(HRMS). The antitumor activities were tested by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyetl trazolium bromide(MTT) method in vitro using MDA-MB-231 and MCF7 cells, and compound Ⅱb exhibited moderate antitumor activity(7.6 and 11.8 μmol/L).

Key words: Tubulysins, Analogue, Antitumor activity

CLC Number:

O621

TrendMD:

BAI Xinfa, MA Xuan, XIE Xiaoxia, SHAO Mingsha, GUO Ningning, YAN Ning, YAO Lei. Synthesis and Anti-tumor Activity of Tubulysins Analogues^†[J]. Chem. J. Chinese Universities, 2017, 38(1): 47.

Figures/Tables 7

Fig.1 Structures of Tubulysins and Pretubulysin

Scheme 1 Synthesis of Tubulysins derivatives Ⅰa—Ⅰea. NaOH/H+, r. t.; b. SOCl2, Et3N, L-Phe-OEt; c. H2/Pd, 35 ℃; d. EDC, HOBt, DIPEA, BOC-L-Leu, r. t.;e. EDC, HOBt, TFA, DIPEA, R-COOH, r. t.; f. LiOH/H+, r. t.

Scheme 2 Synthesis of Tubulysins derivatives Ⅱa—Ⅱga. SOCl2, Et3N, L-Phe-OMe; b. H2/Pd, 35 ℃; c. EDC, HOBt, DIPEA, Boc-L-Val, r. t.; d. TFA, r. t.;e. EDC, HOBt, DIPEA, BOC-L-Leu, r .t.; f. EDC, HOBt, TFA, DIPEA, R-COOH, r. t.; g. LiOH/H+, r. t.

Table 1 Melting points, IR and 1H NMR data of intermediates 2, 3 and 6

Compd.	m. p. /℃	IR(KBr), $ν ~$ /cm^-1	¹ H NMR(400 MHz, CDCl₃), δ
2	109.1—110.3	3339, 3051, 2999, 2925, 1732, 1645, 1527, 1448, 1352, 1225, 1109, 795, 760, 703, 697	8.79(t, J=1.9 Hz, 1H, ArH), 8.34(ddd, J=8.2, 2.2, 0.9 Hz, 1H, ArH), 8.29—8.22(m, 1H, ArH), 8.20(s, 1H, ArH), 7.84(d, J=8.2 Hz, 1H, ArH), 7.69(t, J=8.0 Hz, 1H, ArH), 7.40—7.34(m, 2H, ArH), 7.34—7.30(m, 1H, ArH), 7.27—7.23(m, 2H, ArH), 5.07(dt, J=8.2, 6.1 Hz, 1H, NH), 4.23(q, J=7.1 Hz, 2H, CH₂CH₃), 3.38—3.22(m, 2H, CH₂Ar), 1.28( t, J=7.1 Hz, 3H, CH₂CH₃)
3	89.3—90.2	3401, 3372, 3369, 3053, 2997, 2925, 2989, 1730, 1681, 1666, 1645, 1527, 1448, 1396, 1380, 1372, 1367, 1352, 1226, 1108, 796, 761, 699, 690	9.44(s, 1H, ArH), 8.49(d, J=7.6 Hz, 1H, ArH), 7.92(s, 1H, ArH), 7.84(s, 1H, ArH), 7.74(d, J=7.8 Hz, 1H, ArH), 7.36(d, J=7.3 Hz, 1H, ArH), 7.29(s, 2H, ArH), 7.26—7.21(m, 1H, ArH), 7.18(d, J=7.6 Hz, 1H, ArH), 5.75(s, 1H, NH), 5.17(dd, J=15.0, 7.2 Hz, 1H, NH), 4.53(s, 1H, CH), 4.23(q, J=7.1 Hz, 2H, CH₂CH₃), 3.41—3.22(m, 2H, CH₂Ar), 2.02(d, J=15.8 Hz, 1H, CH), 1.82(ddd, J=25.6, 13.7, 7.0 Hz, 3H, CH₂CH₃), 1.46—1.36 [m, 9H,(CH₃)₃], 1.26(t, J=7.1 Hz, 2H, CH₂), 1.03 [dd, J=13.3, 6.3 Hz, 6H,(CH₃)₂]
6	92.1—93.5	3398, 3389, 3374, 3370, 3052, 2999, 2926, 2990, 1731, 1686, 1675, 1662, 1645, 1397, 1381, 1375, 1366, 1352, 1225, 1109, 794, 765, 698, 693	9.42(s, 1H, ArH), 8.00(d, J=7.7 Hz, 1H, ArH), 7.92(s, 1H, ArH), 7.30(dd, J=14.6, 7.6 Hz, 4H, ArH), 7.25(d, J=7.2 Hz, 1H, NH), 7.16(d, J=6.9 Hz, 2H, ArH), 6.91(d, J=7.2 Hz, 1H, NH), 6.85(d, J=7.6 Hz, 1H, NH), 5.74(s, 1H, NH), 5.06(dd, J=13.4, 6.0 Hz, 1H, CH), 4.67—4.37(m, 1H, CH), 4.15(m, 1H, CH), 3.73(s, 3H, OMe), 3.25(qd, J=13.9, 5.9 Hz, 2H, CH₂Ar), 2.25(m, 1H, CH), 1.74(m, 1H, CH), 1.62(dd, J=9.4, 4.9 Hz, 2H, CH₂), 1.37 [s, 9H,(CH₃)₃], 1.00 [d, J=6.7 Hz, 6H,(CH₃)₂], 0.91 [d, J=6.5 Hz, 6H,(CH₃)₂]

Table 1 Melting points, IR and 1H NMR data of intermediates 2, 3 and 6

Compd.	m. p. /℃	IR(KBr), $ν ~$ /cm^-1	¹ H NMR(400 MHz, CDCl₃), δ
2	109.1—110.3	3339, 3051, 2999, 2925, 1732, 1645, 1527, 1448, 1352, 1225, 1109, 795, 760, 703, 697	8.79(t, J=1.9 Hz, 1H, ArH), 8.34(ddd, J=8.2, 2.2, 0.9 Hz, 1H, ArH), 8.29—8.22(m, 1H, ArH), 8.20(s, 1H, ArH), 7.84(d, J=8.2 Hz, 1H, ArH), 7.69(t, J=8.0 Hz, 1H, ArH), 7.40—7.34(m, 2H, ArH), 7.34—7.30(m, 1H, ArH), 7.27—7.23(m, 2H, ArH), 5.07(dt, J=8.2, 6.1 Hz, 1H, NH), 4.23(q, J=7.1 Hz, 2H, CH₂CH₃), 3.38—3.22(m, 2H, CH₂Ar), 1.28( t, J=7.1 Hz, 3H, CH₂CH₃)
3	89.3—90.2	3401, 3372, 3369, 3053, 2997, 2925, 2989, 1730, 1681, 1666, 1645, 1527, 1448, 1396, 1380, 1372, 1367, 1352, 1226, 1108, 796, 761, 699, 690	9.44(s, 1H, ArH), 8.49(d, J=7.6 Hz, 1H, ArH), 7.92(s, 1H, ArH), 7.84(s, 1H, ArH), 7.74(d, J=7.8 Hz, 1H, ArH), 7.36(d, J=7.3 Hz, 1H, ArH), 7.29(s, 2H, ArH), 7.26—7.21(m, 1H, ArH), 7.18(d, J=7.6 Hz, 1H, ArH), 5.75(s, 1H, NH), 5.17(dd, J=15.0, 7.2 Hz, 1H, NH), 4.53(s, 1H, CH), 4.23(q, J=7.1 Hz, 2H, CH₂CH₃), 3.41—3.22(m, 2H, CH₂Ar), 2.02(d, J=15.8 Hz, 1H, CH), 1.82(ddd, J=25.6, 13.7, 7.0 Hz, 3H, CH₂CH₃), 1.46—1.36 [m, 9H,(CH₃)₃], 1.26(t, J=7.1 Hz, 2H, CH₂), 1.03 [dd, J=13.3, 6.3 Hz, 6H,(CH₃)₂]
6	92.1—93.5	3398, 3389, 3374, 3370, 3052, 2999, 2926, 2990, 1731, 1686, 1675, 1662, 1645, 1397, 1381, 1375, 1366, 1352, 1225, 1109, 794, 765, 698, 693	9.42(s, 1H, ArH), 8.00(d, J=7.7 Hz, 1H, ArH), 7.92(s, 1H, ArH), 7.30(dd, J=14.6, 7.6 Hz, 4H, ArH), 7.25(d, J=7.2 Hz, 1H, NH), 7.16(d, J=6.9 Hz, 2H, ArH), 6.91(d, J=7.2 Hz, 1H, NH), 6.85(d, J=7.6 Hz, 1H, NH), 5.74(s, 1H, NH), 5.06(dd, J=13.4, 6.0 Hz, 1H, CH), 4.67—4.37(m, 1H, CH), 4.15(m, 1H, CH), 3.73(s, 3H, OMe), 3.25(qd, J=13.9, 5.9 Hz, 2H, CH₂Ar), 2.25(m, 1H, CH), 1.74(m, 1H, CH), 1.62(dd, J=9.4, 4.9 Hz, 2H, CH₂), 1.37 [s, 9H,(CH₃)₃], 1.00 [d, J=6.7 Hz, 6H,(CH₃)₂], 0.91 [d, J=6.5 Hz, 6H,(CH₃)₂]

Table 2 Melting points, yield, optical rotation, HRMS and IR data for target compounds Ⅰand Ⅱ

Compd.	m. p. /℃	Yield (%)		$[α] D 25$ /(°) (c 0.20, CH₃OH)		HRMS,m/z [M+1]⁺		IR(KBr), $ν ~$ /cm^-1
Ⅰa	98.0—99.3	43		-38.2		606.2755 (606.2750)		3455, 3360, 3310, 3088, 3051, 2999, 2966, 2926, 2891, 1761, 1678, 1661, 1655, 1645, 1554, 1495, 1446, 1385, 1376, 795, 760, 703, 697
Ⅰb	78.6—79.5	45				606.2755 (606.2750)		3445, 3370, 3310, 3078, 3050, 2996, 2966, 2925, 2890, 1760, 1673, 1661, 1652, 1641, 1557, 1508, 1448, 1388, 1376, 805, 766, 713, 690
Compd.	m. p. /℃		Yield (%)		$[α] D 25$ /(°) (c 0.20, CH₃OH)		HRMS,m/z [M+1]⁺	IR(KBr), $ν ~$ /cm^-1
Ⅰc	88.7—89.8		44		-26.3		566.2434 (566.2437)	3355, 3261, 3112, 3079, 3051, 3002, 2966, 2925, 2893, 1758, 1657, 1641, 1635, 1620, 1552, 1491, 1446, 1387, 1376, 795, 763, 705, 697
Ⅰd	135.5—136.4		47		-28.5		585.2092 (585.2172)	3452, 3350, 3291, 3067, 3045, 2988, 2969, 2927, 2890, 1759, 1674, 1658, 1643, 1625, 1550, 1495, 1437, 1385, 1371, 803, 765, 703, 688
Ⅰe	126.3—127.2		44		-30.8		615.2281 (615.2277)	3353, 3294, 3280, 3069, 3051, 3001, 2970, 2922, 2891, 1758, 1672, 1657, 1655, 1645, 1548, 1495, 1438, 1384, 1373, 800, 770, 703, 687
Ⅱ a	121.5—122.6		35		+35.1		622.3599 (622.3605)	3455, 3360, 3310, 3220, 3088, 3051, 2999, 2968, 2927, 2895, 1761, 1678, 1661, 1658, 1655, 1645, 1554, 1495, 1446, 1383, 1378, 795, 760, 703, 697
Ⅱ b	114.2—115.5		38				622.3599 (622.3605)	3457, 3359, 3310, 3222, 3086, 3050, 3001, 2963, 2927, 2889, 1761, 1678, 1663, 1659, 1654, 1642, 1554, 1493, 1447, 1385, 1376, 791, 770, 703, 687
Ⅱ c	105.5—106.2		36		-32.2		646.2880 (646.2877)	3433, 3362, 3298, 3226, 3099, 3046, 3005, 2966, 2930, 2890, 1759, 1666, 1660, 1652, 1646, 1638, 1556, 1525, 1491, 1445, 1389, 1372, 791, 776, 701, 689
Ⅱ d	142.1—143.5		39		-35.3		601.3029 (601.3026)	3455, 3346, 3332, 3202, 3096, 3040, 2998, 2973, 2929, 2888, 1765, 1672, 1669, 1657, 1650, 1641, 1558, 1491, 1445, 1389, 1376, 796, 771, 700, 691
Ⅱ e	95.3—96.5		40		-36.7		631.3136 (631.3132)	3448, 3344, 3308, 3231, 3068, 3048, 3000, 2966, 2928, 2891, 1762, 1675, 1660, 1656, 1653, 1647, 1552, 1491, 1445, 1385, 1371, 792, 776, 701, 689
Ⅱ f	108.2—109.4		37		-38.1		700.2631 (700.2710)	3436, 3346, 3229, 3210, 3069, 3038, 3002, 2969, 2926, 2890, 1765, 1677, 1661, 1656, 1649, 1640, 1551, 1490, 1445, 1386, 1379, 795, 774, 700, 678
Ⅱ g	103.5—104.5		36				700.2631 (700.2710)	3440, 3398, 3329, 3237, 3076, 3049, 2997, 2969, 2922, 2888, 1760, 1673, 1665, 1651, 1648, 1640, 1550, 1497, 1442, 1387, 1374, 789, 768, 699, 678

Table 2 Melting points, yield, optical rotation, HRMS and IR data for target compounds Ⅰand Ⅱ

Compd.	m. p. /℃	Yield (%)		$[α] D 25$ /(°) (c 0.20, CH₃OH)		HRMS,m/z [M+1]⁺		IR(KBr), $ν ~$ /cm^-1
Ⅰa	98.0—99.3	43		-38.2		606.2755 (606.2750)		3455, 3360, 3310, 3088, 3051, 2999, 2966, 2926, 2891, 1761, 1678, 1661, 1655, 1645, 1554, 1495, 1446, 1385, 1376, 795, 760, 703, 697
Ⅰb	78.6—79.5	45				606.2755 (606.2750)		3445, 3370, 3310, 3078, 3050, 2996, 2966, 2925, 2890, 1760, 1673, 1661, 1652, 1641, 1557, 1508, 1448, 1388, 1376, 805, 766, 713, 690
Compd.	m. p. /℃		Yield (%)		$[α] D 25$ /(°) (c 0.20, CH₃OH)		HRMS,m/z [M+1]⁺	IR(KBr), $ν ~$ /cm^-1
Ⅰc	88.7—89.8		44		-26.3		566.2434 (566.2437)	3355, 3261, 3112, 3079, 3051, 3002, 2966, 2925, 2893, 1758, 1657, 1641, 1635, 1620, 1552, 1491, 1446, 1387, 1376, 795, 763, 705, 697
Ⅰd	135.5—136.4		47		-28.5		585.2092 (585.2172)	3452, 3350, 3291, 3067, 3045, 2988, 2969, 2927, 2890, 1759, 1674, 1658, 1643, 1625, 1550, 1495, 1437, 1385, 1371, 803, 765, 703, 688
Ⅰe	126.3—127.2		44		-30.8		615.2281 (615.2277)	3353, 3294, 3280, 3069, 3051, 3001, 2970, 2922, 2891, 1758, 1672, 1657, 1655, 1645, 1548, 1495, 1438, 1384, 1373, 800, 770, 703, 687
Ⅱ a	121.5—122.6		35		+35.1		622.3599 (622.3605)	3455, 3360, 3310, 3220, 3088, 3051, 2999, 2968, 2927, 2895, 1761, 1678, 1661, 1658, 1655, 1645, 1554, 1495, 1446, 1383, 1378, 795, 760, 703, 697
Ⅱ b	114.2—115.5		38				622.3599 (622.3605)	3457, 3359, 3310, 3222, 3086, 3050, 3001, 2963, 2927, 2889, 1761, 1678, 1663, 1659, 1654, 1642, 1554, 1493, 1447, 1385, 1376, 791, 770, 703, 687
Ⅱ c	105.5—106.2		36		-32.2		646.2880 (646.2877)	3433, 3362, 3298, 3226, 3099, 3046, 3005, 2966, 2930, 2890, 1759, 1666, 1660, 1652, 1646, 1638, 1556, 1525, 1491, 1445, 1389, 1372, 791, 776, 701, 689
Ⅱ d	142.1—143.5		39		-35.3		601.3029 (601.3026)	3455, 3346, 3332, 3202, 3096, 3040, 2998, 2973, 2929, 2888, 1765, 1672, 1669, 1657, 1650, 1641, 1558, 1491, 1445, 1389, 1376, 796, 771, 700, 691
Ⅱ e	95.3—96.5		40		-36.7		631.3136 (631.3132)	3448, 3344, 3308, 3231, 3068, 3048, 3000, 2966, 2928, 2891, 1762, 1675, 1660, 1656, 1653, 1647, 1552, 1491, 1445, 1385, 1371, 792, 776, 701, 689
Ⅱ f	108.2—109.4		37		-38.1		700.2631 (700.2710)	3436, 3346, 3229, 3210, 3069, 3038, 3002, 2969, 2926, 2890, 1765, 1677, 1661, 1656, 1649, 1640, 1551, 1490, 1445, 1386, 1379, 795, 774, 700, 678
Ⅱ g	103.5—104.5		36				700.2631 (700.2710)	3440, 3398, 3329, 3237, 3076, 3049, 2997, 2969, 2922, 2888, 1760, 1673, 1665, 1651, 1648, 1640, 1550, 1497, 1442, 1387, 1374, 789, 768, 699, 678

Table 3 1H NMR and 13C NMR data of target compounds Ⅰ and Ⅱ

Compd.	¹H NMR(CD₃OD, 400 MHz), δ	¹³C NMR(CD₃OD, 100 MHz), δ
Ⅰa	8.19(s, 1H, ArH), 8.07(s, 1H, ArH), 7.61(dd, J=16.0, 8.0 Hz, 2H, ArH), 7.35(t, J=7.9 Hz, 1H, ArH), 7.16(dd, J=17.6, 7.2 Hz, 4H, ArH), 7.08(t, J=6.8 Hz, 1H, ArH), 4.66—4.59(m, 1H, CH), 4.45(dd, J=9.8, 4.6 Hz, 1H, CH), 3.30—3.25(m, 1H, CH₂Ar), 2.97(m, 1H, CH₂Ar), 2.69(s, 3H, NCH₃), 1.83(m, 3H, CHCH₂), 1.66 [m, 6H,(CH₂)₃], 1.51(d, J=12.5 Hz, 2H, CH₂), 1.33—1.14(m, 1H, CH), 0.91 [dd, J=10.8, 6.1 Hz, 6H,(CH₃)₂]	20.2, 22.0, 24.7, 29.7, 37.9, 40.5, 42.8, 52.6, 54.3, 55.2, 55.9, 68.4, 115.3, 117.5, 118.1, 121.8, 123.2, 126.1, 127.8, 129.3, 133.2, 137.7, 139.1, 150.1, 161.0, 161.5, 161.7, 167.9, 171.8
Ⅰb	8.29(s, 1H, ArH), 8.16(d, J=2.5 Hz, 1H, ArH), 7.71(d, J=6.6 Hz, 1H, ArH), 7.64(t, J=7.3 Hz, 1H, ArH), 7.44(t, J=7.9 Hz, 1H, ArH), 7.31—7.22(m, 4H, ArH), 7.19(d, J=6.5 Hz, 1H, ArH), 4.63(m, 1H, CH), 4.45(dd, J=9.8, 4.6 Hz, 1H, CH), 3.30—3.25(m, 1H, CH₂Ar), 2.97(m, 1H, CH₂Ar), 2.69(s, 3H, NCH₃), 1.83(m, 3H, CHCH₂), 1.66 [m, 6H,(CH₂)₃], 1.51(d, J=12.5 Hz, 2H, CH₂), 1.33—1.14(m, 1H, CH), 0.91 [dd, J=10.8, 6.1 Hz, 6H,(CH₃)₂]	20.3, 22.0, 24.7, 29.6, 37.9, 40.5, 42.8, 52.6, 54.3, 55.2, 55.9, 68.4, 115.3, 117.5, 118.2, 121.8, 123.2, 126.1, 127.8, 129.3, 133.2, 137.7, 139.1, 150.2, 161.0, 161.4, 161.7, 167.9, 171.9
Compd.	¹H NMR(CD₃OD, 400 MHz), δ	¹³C NMR(CD₃OD, 100 MHz), δ
Ⅰc	8.23(d, J=1.7 Hz, 1H, ArH), 8.09(s, 1H, ArH), 7.65(d, J=7.7 Hz, 1H, ArH), 7.59(dd, J=8.2, 1.1 Hz, 1H, ArH), 7.36(t, J=8.0 Hz, 1H, ArH), 7.18(d, J=4.4 Hz, 4H, ArH), 7.11(m, 1H, ArH), 4.58—4.45(m, 1H, CH), 3.93(q, J=15.6 Hz, 1H, CH), 3.34—3.23(m, 1H, CH₂Ar), 3.12(m, 1H, CH₂Ar), 2.84 [s, 6H, N(CH₃)₂], 1.62(m, 3H, CHCH₂), 1.24—1.16(m, 2H, CH₂), 0.92 [t, J=6.2 Hz, 6H,(CH₃)₂]	20.4, 22.0, 24.6, 36.9, 40.6, 43.0, 52.9, 57.8, 117.5, 121.9, 122.1, 123.7, 126.4, 128.1, 129.1, 132.9, 136.6, 138.9, 149.7, 161.2, 164.5, 168.1, 171.8
Ⅰd	8.17(s, 1H, ArH), 8.09(d, J=3.3 Hz, 1H, ArH), 7.85(dd, J=7.7, 1.8 Hz, 1H, ArH), 7.69(dd, J=11.0, 4.1 Hz, 2H, ArH), 7.55—7.19(m, 1H, ArH), 7.40(t, J=7.5 Hz, 1H, ArH), 7.23—7.10(m, 5H, ArH), 7.03(t, J=7.1 Hz, 2H, ArH), 6.98(t, J=7.5 Hz, 1H, ArH), 4.87—4.79(m, 2H, CH, CH), 3.32(d, J=5.1 Hz, 1H, CH₂Ar), 3.21(dd, J=13.2, 7.1 Hz, 1H, CH₂Ar), 1.90—1.68(m, 2H, CH₂), 1.23(dd, J=13.8, 6.0 Hz, 1H, CH), 1.01 [d, J=5.2 Hz, 6H,(CH₃)₂]	20.1, 22.0, 25.2, 35.8, 40.8, 55.1, 111.0, 116.9, 121.1, 121.8, 122.3, 123.5, 128.0, 129.1, 129.5, 130.2, 132.9, 133.7, 135.3, 138.2, 149.8, 158.9, 166.5, 168.4, 172.0
Ⅰe	8.36(s, 1H, ArH), 8.17(d, J=3.3 Hz, 1H, ArH), 7.96(dd, J=7.8, 1.7 Hz, 1H, ArH), 7.70(dd, J=11.7, 4.6 Hz, 2H, ArH), 7.58—7.48(m, 1H, ArH), 7.44(t, J=7.9 Hz, 1H, ArH), 7.32—7.25(m, 4H, ArH), 7.18(t, J=7.1 Hz, 2H, ArH), 7.08(t, J=7.5 Hz, 1H, ArH), 4.89—4.81(m, 2H, CH, CH), 4.01(s, 3H, OCH₃), 3.38(d, J=5.1 Hz, 1H, CH₂Ar), 3.25(dd, J=13.8, 7.6 Hz, 1H, CH₂Ar), 1.91—1.75(m, 2H, CH₂), 1.24(dd, J=13.3, 6.1 Hz, 1H, CH), 1.06 [d, J=5.8 Hz, 6H,(CH₃)₂]	20.9, 22.1, 24.9, 36.9, 41.4, 53.1, 55.3, 111.6, 117.6, 120.6, 121.0, 121.9, 122.1, 123.7, 126.5, 128.1, 129.0, 129.4, 130.8, 133.1, 133.2, 136.6, 139.1, 149.6, 157.8, 166.4, 168.0, 172.1
Ⅱa	7.98(d, J=8.8 Hz, 1H, ArH), 7.72(dd, J=8.0, 7.1 Hz, 1H, ArH), 7.45(dd, J=7.7 Hz, 1.3, 1H, ArH), 7.36(td, J=7.9, 1.6 Hz, 1H, ArH), 7.31—7.19(m, 4H, ArH), 7.15(td, J=7.1, 1.5 Hz, 1H, ArH), 4.78—4.63(m, 1H, CH), 4.53—4.40(m, 1H, CH), 4.36(d, J=7.6 Hz, 1H, CH), 3.35—3.29(m, 2H, CH₂Ar), 2.52(d, J=2.9 Hz, 1H, CH), 2.45(d, J=2.7 Hz, 3H, NCH₃), 2.15(dd, J=13.9, 6.9 Hz, 1H, CH), 1.94(d, J=8.1 Hz, 1H, CH₂), 1.81(d, J=13.0 Hz, 1H, CH₂), 1.68 [tdd, J=15.2, 10.9, 4.5 Hz, 6H,(CH₂)₃], 0.95 [ddd, J=11.5, 8.5, 4.5 Hz, 12H,(CH₃)₄]	17.2, 18.4, 20.3, 20.9, 22.0, 24.6, 29.2, 30.5, 39.9, 42.5, 46.3, 52.0, 54.9, 59.2, 67.8, 118.7, 122.4, 122.6, 125.6, 125.9, 127.7, 128.6, 129.1, 135.3, 138.0, 170.0, 170.6, 171.9, 172.1, 173.2
Ⅱ b	7.95(d, J=12.5 Hz, 1H, ArH), 7.68(dd, J=19.6, 8.2 Hz, 1H, ArH), 7.45(d, J=7.9 Hz, 1H, ArH), 7.37(t, J=7.9 Hz, 1H, ArH), 7.24(q, J=7.2 Hz, 3H, ArH), 7.15(t, J=6.6 Hz, 1H, ArH), 4.60—4.47(m, 1H, CH), 4.48—4.37(m, 1H, CH), 4.38—4.26(m, 1H, CH), 3.50(d, J=9.6 Hz, 1H, CH₂Ar), 3.13(s, 1H, CH₂Ar), 2.94—2.72(m, 1H, CH), 2.15(ddd, J=40.8, 24.7, 14.9 Hz, 2H, CH₂), 1.86(dd, J=26.9, 15.5 Hz, 2H, CH₂), 1.69 [dt, J=13.8, 9.6 Hz, 4H,(CH₂)₂], 1.10—0.84 [m, 12H,(CH₃)₄]	17.2, 18.4, 20.2, 21.1, 22.0, 24.6, 29.3, 30.9, 40.1, 42.5, 45.9, 52.1, 55.0, 59.2, 67.8, 118.8, 122.4, 122.7, 125.6, 125.9, 127.7, 128.6, 129.3, 135.4, 138.0, 170.1, 170.3, 171.9, 174.4, 174.9
Ⅱc	8.63(t, J=1.9 Hz, 1H, ArH), 8.33—8.25(m, 1H, ArH), 8.15(d, J=7.8 Hz, 1H, ArH), 7.63(d, J=8.0 Hz, 1H, ArH), 7.61—7.54(m, 1H, ArH), 7.34(d, J=7.8 Hz, 1H, ArH), 7.27(t, J=7.9 Hz, 1H, ArH), 7.22—7.13(m, 4H, ArH), 7.12—7.05(m, 1H, ArH), 4.73(dd, J=9.5, 4.9 Hz, 1H, CH), 4.65(dd, J=9.4, 4.3 Hz, 1H, CH), 4.26(t, J=6.6 Hz, 1H, CH), 3.30(s, 1H, CH₂Ar), 3.13—2.93(m, 1H, CH₂Ar), 2.07(dd, J=13.2, 6.7 Hz, 1H, CH), 1.64 [ddd, J=26.5, 10.3, 5.4 Hz, 3H, CHCH₂], 0.99—0.81 [m, 12H,(CH₃)₄]	20.5, 22.0, 24.8, 30.9, 36.8, 40.1, 52.7, 54.3, 59.5, 118.9, 122.1, 122.7, 123.0, 125.8, 126.3, 128.1, 128.6, 128.8, 129.6, 133.2, 134.8, 135.5, 137.2, 138.1, 148.2, 166.5, 168.5, 170.9, 173.4, 173.6
Compd.	¹H NMR(CD₃OD, 400 MHz), δ	¹³C NMR(CD₃OD, 100 MHz), δ
Ⅱd	7.92—7.83(m, 1H, ArH), 7.76(d, J=7.4 Hz, 2H, ArH), 7.57(d, J=5.3 Hz, 1H, ArH), 7.43(s, 1H, ArH), 7.34(dd, J=14.3, 7.0 Hz, 3H, ArH), 7.23(t, J=7.8 Hz, 1H, ArH), 7.14(dd, J=14.2, 7.4 Hz, 4H, ArH), 7.03(t, J=7.0 Hz, 1H, ArH), 4.63(d, J=9.8 Hz, 2H, CH), 4.27(d, J=7.4 Hz, 1H, CH), 3.00(dd, J=13.7, 8.3 Hz, 1H, CH₂Ar), 2.06(dd, J=13.6, 6.8 Hz, 1H, CH), 1.76—1.52(m, 3H, CHCH₂), 0.95—0.81 [m, 12H,(CH₃)₄]	17.3, 17.9, 18.1, 18.4, 30.5, 37.8, 55.6, 58.9, 59.4, 117.1, 125.8, 127.0, 127.6, 128.1, 128.8, 129.3, 131.3, 134.1, 134.7, 135.7, 137.6, 143.6, 144.3, 161.0, 169.0, 170.5, 171.3, 172.8
Ⅱe	8.06(d, J=6.2 Hz, 1H, ArH), 8.03—7.95(m, 1H, ArH), 7.85—7.77(m, 1H, ArH), 7.66—7.59(m, 1H, ArH), 7.56(d, J=7.8 Hz, 1H, ArH), 7.49(t, J=7.8 Hz, 1H, ArH), 7.44—7.34(m, 4H, ArH), 7.34—7.24(m, 2H, ArH), 7.17(t, J=7.5 Hz, 1H, ArH), 4.93(dd, J=9.3, 4.6 Hz, 1H, CH), 4.86(t, J=7.1 Hz, 1H, CH), 4.46(d, J=7.5 Hz, 1H, CH), 4.10(s, 3H, OCH₃), 3.47(d, J=4.8 Hz, 1H, CH₂Ar), 3.22(dd, J=13.8, 9.4 Hz, 1H, CH₂Ar), 2.34—2.24(m, 1H, CH), 1.89—1.77(m, 3H, CHCH₂), 1.13 [ddd, J=18.5,8.7, 4.4 Hz, 12H,(CH₃)₄]	19.3, 20.7, 22.0, 24.7, 30.8, 36.8, 40.8, 52.3, 55.1, 59.3, 111.5, 118.9, 120.5, 121.1, 122.7, 123.0, 126.3, 128.0, 128.6, 128.9, 130.6, 132.9, 134.9, 137.4, 138.2, 139.5, 157.6, 166.7, 170.7, 171.5, 173.5
Ⅱf	7.73(s, 1H, ArH), 7.40(d, J=8.6 Hz, 1H, ArH), 7.32(d, J=7.4 Hz, 2H, ArH), 7.21(t, J=7.6 Hz, 2H, ArH), 7.14(s, 1H, ArH), 7.00(t, J=7.3 Hz, 1H, ArH), 4.64(dd, J=9.5, 4.0 Hz, 1H, CH), 4.33(d, J=8.1 Hz, 1H, CH), 4.28—4.19(m, 1H, CH), 3.35(d, J=9.3 Hz, 2H, CH₂Ar), 2.91(dd, J=13.3, 9.6 Hz, 1H, CH), 2.14(d, J=7.3 Hz, 1H, CH), 1.82—1.69 [m, 4H,(CH₂)₂], 1.70—1.48 [m, 4H,(CH₂)₂], 1.40(d, J=11.1 Hz, 3H, CHCH₂), 1.02—0.64 [m, 12H,(CH₃)₄]	18.9, 21.1, 22.5, 24.4, 25.1, 25.6, 31.2, 36.6, 41.5, 41.8, 56.3, 56.8, 59.7, 62.1, 70.9, 114.5, 119.3, 125.6, 125.9, 127.6, 128.9, 131.9, 136.8, 137.0, 140.3, 167.4, 171.1, 172.4, 173.1, 174.9
Ⅱg	7.73(s, 1H, ArH), 7.40(d, J=8.6 Hz, 1H, ArH), 7.32(d, J=7.4 Hz, 2H, ArH), 7.21(t, J=7.6 Hz, 2H, ArH), 7.14(s, 1H, ArH), 7.00(t, J=7.3 Hz, 1H, ArH), 4.64(dd, J=9.5, 4.0 Hz, 1H, CH), 4.33(d, J=8.1 Hz, 1H, CH), 4.28—4.19(m, 1H, CH), 3.35(d, J=9.3 Hz, 2H, CH₂Ar), 2.91(dd, J=13.3, 9.6 Hz, 1H, CH), 2.14(d, J=7.3 Hz, 1H, CH), 1.82—1.69 [m, 4H,(CH₂)₂], 1.70—1.48 [m, 4H,(CH₂)₂], 1.40(d, J=11.1 Hz, 3H, CHCH₂), 1.02—0.64 [m, 12H,(CH₃)₄]	18.8, 21.1, 22.6, 24.4, 25.1, 25.6, 31.2, 36.6, 41.5, 41.9, 56.3, 56.8, 59.7, 62.0, 70.9, 114.5, 119.5, 125.6, 125.9, 127.4, 128.9, 131.9, 136.8, 137.0, 140.3, 167.9, 171.1, 172.1, 173.6, 174.9

Table 3 1H NMR and 13C NMR data of target compounds Ⅰ and Ⅱ

Compd.	¹H NMR(CD₃OD, 400 MHz), δ	¹³C NMR(CD₃OD, 100 MHz), δ
Ⅰa	8.19(s, 1H, ArH), 8.07(s, 1H, ArH), 7.61(dd, J=16.0, 8.0 Hz, 2H, ArH), 7.35(t, J=7.9 Hz, 1H, ArH), 7.16(dd, J=17.6, 7.2 Hz, 4H, ArH), 7.08(t, J=6.8 Hz, 1H, ArH), 4.66—4.59(m, 1H, CH), 4.45(dd, J=9.8, 4.6 Hz, 1H, CH), 3.30—3.25(m, 1H, CH₂Ar), 2.97(m, 1H, CH₂Ar), 2.69(s, 3H, NCH₃), 1.83(m, 3H, CHCH₂), 1.66 [m, 6H,(CH₂)₃], 1.51(d, J=12.5 Hz, 2H, CH₂), 1.33—1.14(m, 1H, CH), 0.91 [dd, J=10.8, 6.1 Hz, 6H,(CH₃)₂]	20.2, 22.0, 24.7, 29.7, 37.9, 40.5, 42.8, 52.6, 54.3, 55.2, 55.9, 68.4, 115.3, 117.5, 118.1, 121.8, 123.2, 126.1, 127.8, 129.3, 133.2, 137.7, 139.1, 150.1, 161.0, 161.5, 161.7, 167.9, 171.8
Ⅰb	8.29(s, 1H, ArH), 8.16(d, J=2.5 Hz, 1H, ArH), 7.71(d, J=6.6 Hz, 1H, ArH), 7.64(t, J=7.3 Hz, 1H, ArH), 7.44(t, J=7.9 Hz, 1H, ArH), 7.31—7.22(m, 4H, ArH), 7.19(d, J=6.5 Hz, 1H, ArH), 4.63(m, 1H, CH), 4.45(dd, J=9.8, 4.6 Hz, 1H, CH), 3.30—3.25(m, 1H, CH₂Ar), 2.97(m, 1H, CH₂Ar), 2.69(s, 3H, NCH₃), 1.83(m, 3H, CHCH₂), 1.66 [m, 6H,(CH₂)₃], 1.51(d, J=12.5 Hz, 2H, CH₂), 1.33—1.14(m, 1H, CH), 0.91 [dd, J=10.8, 6.1 Hz, 6H,(CH₃)₂]	20.3, 22.0, 24.7, 29.6, 37.9, 40.5, 42.8, 52.6, 54.3, 55.2, 55.9, 68.4, 115.3, 117.5, 118.2, 121.8, 123.2, 126.1, 127.8, 129.3, 133.2, 137.7, 139.1, 150.2, 161.0, 161.4, 161.7, 167.9, 171.9
Compd.	¹H NMR(CD₃OD, 400 MHz), δ	¹³C NMR(CD₃OD, 100 MHz), δ
Ⅰc	8.23(d, J=1.7 Hz, 1H, ArH), 8.09(s, 1H, ArH), 7.65(d, J=7.7 Hz, 1H, ArH), 7.59(dd, J=8.2, 1.1 Hz, 1H, ArH), 7.36(t, J=8.0 Hz, 1H, ArH), 7.18(d, J=4.4 Hz, 4H, ArH), 7.11(m, 1H, ArH), 4.58—4.45(m, 1H, CH), 3.93(q, J=15.6 Hz, 1H, CH), 3.34—3.23(m, 1H, CH₂Ar), 3.12(m, 1H, CH₂Ar), 2.84 [s, 6H, N(CH₃)₂], 1.62(m, 3H, CHCH₂), 1.24—1.16(m, 2H, CH₂), 0.92 [t, J=6.2 Hz, 6H,(CH₃)₂]	20.4, 22.0, 24.6, 36.9, 40.6, 43.0, 52.9, 57.8, 117.5, 121.9, 122.1, 123.7, 126.4, 128.1, 129.1, 132.9, 136.6, 138.9, 149.7, 161.2, 164.5, 168.1, 171.8
Ⅰd	8.17(s, 1H, ArH), 8.09(d, J=3.3 Hz, 1H, ArH), 7.85(dd, J=7.7, 1.8 Hz, 1H, ArH), 7.69(dd, J=11.0, 4.1 Hz, 2H, ArH), 7.55—7.19(m, 1H, ArH), 7.40(t, J=7.5 Hz, 1H, ArH), 7.23—7.10(m, 5H, ArH), 7.03(t, J=7.1 Hz, 2H, ArH), 6.98(t, J=7.5 Hz, 1H, ArH), 4.87—4.79(m, 2H, CH, CH), 3.32(d, J=5.1 Hz, 1H, CH₂Ar), 3.21(dd, J=13.2, 7.1 Hz, 1H, CH₂Ar), 1.90—1.68(m, 2H, CH₂), 1.23(dd, J=13.8, 6.0 Hz, 1H, CH), 1.01 [d, J=5.2 Hz, 6H,(CH₃)₂]	20.1, 22.0, 25.2, 35.8, 40.8, 55.1, 111.0, 116.9, 121.1, 121.8, 122.3, 123.5, 128.0, 129.1, 129.5, 130.2, 132.9, 133.7, 135.3, 138.2, 149.8, 158.9, 166.5, 168.4, 172.0
Ⅰe	8.36(s, 1H, ArH), 8.17(d, J=3.3 Hz, 1H, ArH), 7.96(dd, J=7.8, 1.7 Hz, 1H, ArH), 7.70(dd, J=11.7, 4.6 Hz, 2H, ArH), 7.58—7.48(m, 1H, ArH), 7.44(t, J=7.9 Hz, 1H, ArH), 7.32—7.25(m, 4H, ArH), 7.18(t, J=7.1 Hz, 2H, ArH), 7.08(t, J=7.5 Hz, 1H, ArH), 4.89—4.81(m, 2H, CH, CH), 4.01(s, 3H, OCH₃), 3.38(d, J=5.1 Hz, 1H, CH₂Ar), 3.25(dd, J=13.8, 7.6 Hz, 1H, CH₂Ar), 1.91—1.75(m, 2H, CH₂), 1.24(dd, J=13.3, 6.1 Hz, 1H, CH), 1.06 [d, J=5.8 Hz, 6H,(CH₃)₂]	20.9, 22.1, 24.9, 36.9, 41.4, 53.1, 55.3, 111.6, 117.6, 120.6, 121.0, 121.9, 122.1, 123.7, 126.5, 128.1, 129.0, 129.4, 130.8, 133.1, 133.2, 136.6, 139.1, 149.6, 157.8, 166.4, 168.0, 172.1
Ⅱa	7.98(d, J=8.8 Hz, 1H, ArH), 7.72(dd, J=8.0, 7.1 Hz, 1H, ArH), 7.45(dd, J=7.7 Hz, 1.3, 1H, ArH), 7.36(td, J=7.9, 1.6 Hz, 1H, ArH), 7.31—7.19(m, 4H, ArH), 7.15(td, J=7.1, 1.5 Hz, 1H, ArH), 4.78—4.63(m, 1H, CH), 4.53—4.40(m, 1H, CH), 4.36(d, J=7.6 Hz, 1H, CH), 3.35—3.29(m, 2H, CH₂Ar), 2.52(d, J=2.9 Hz, 1H, CH), 2.45(d, J=2.7 Hz, 3H, NCH₃), 2.15(dd, J=13.9, 6.9 Hz, 1H, CH), 1.94(d, J=8.1 Hz, 1H, CH₂), 1.81(d, J=13.0 Hz, 1H, CH₂), 1.68 [tdd, J=15.2, 10.9, 4.5 Hz, 6H,(CH₂)₃], 0.95 [ddd, J=11.5, 8.5, 4.5 Hz, 12H,(CH₃)₄]	17.2, 18.4, 20.3, 20.9, 22.0, 24.6, 29.2, 30.5, 39.9, 42.5, 46.3, 52.0, 54.9, 59.2, 67.8, 118.7, 122.4, 122.6, 125.6, 125.9, 127.7, 128.6, 129.1, 135.3, 138.0, 170.0, 170.6, 171.9, 172.1, 173.2
Ⅱ b	7.95(d, J=12.5 Hz, 1H, ArH), 7.68(dd, J=19.6, 8.2 Hz, 1H, ArH), 7.45(d, J=7.9 Hz, 1H, ArH), 7.37(t, J=7.9 Hz, 1H, ArH), 7.24(q, J=7.2 Hz, 3H, ArH), 7.15(t, J=6.6 Hz, 1H, ArH), 4.60—4.47(m, 1H, CH), 4.48—4.37(m, 1H, CH), 4.38—4.26(m, 1H, CH), 3.50(d, J=9.6 Hz, 1H, CH₂Ar), 3.13(s, 1H, CH₂Ar), 2.94—2.72(m, 1H, CH), 2.15(ddd, J=40.8, 24.7, 14.9 Hz, 2H, CH₂), 1.86(dd, J=26.9, 15.5 Hz, 2H, CH₂), 1.69 [dt, J=13.8, 9.6 Hz, 4H,(CH₂)₂], 1.10—0.84 [m, 12H,(CH₃)₄]	17.2, 18.4, 20.2, 21.1, 22.0, 24.6, 29.3, 30.9, 40.1, 42.5, 45.9, 52.1, 55.0, 59.2, 67.8, 118.8, 122.4, 122.7, 125.6, 125.9, 127.7, 128.6, 129.3, 135.4, 138.0, 170.1, 170.3, 171.9, 174.4, 174.9
Ⅱc	8.63(t, J=1.9 Hz, 1H, ArH), 8.33—8.25(m, 1H, ArH), 8.15(d, J=7.8 Hz, 1H, ArH), 7.63(d, J=8.0 Hz, 1H, ArH), 7.61—7.54(m, 1H, ArH), 7.34(d, J=7.8 Hz, 1H, ArH), 7.27(t, J=7.9 Hz, 1H, ArH), 7.22—7.13(m, 4H, ArH), 7.12—7.05(m, 1H, ArH), 4.73(dd, J=9.5, 4.9 Hz, 1H, CH), 4.65(dd, J=9.4, 4.3 Hz, 1H, CH), 4.26(t, J=6.6 Hz, 1H, CH), 3.30(s, 1H, CH₂Ar), 3.13—2.93(m, 1H, CH₂Ar), 2.07(dd, J=13.2, 6.7 Hz, 1H, CH), 1.64 [ddd, J=26.5, 10.3, 5.4 Hz, 3H, CHCH₂], 0.99—0.81 [m, 12H,(CH₃)₄]	20.5, 22.0, 24.8, 30.9, 36.8, 40.1, 52.7, 54.3, 59.5, 118.9, 122.1, 122.7, 123.0, 125.8, 126.3, 128.1, 128.6, 128.8, 129.6, 133.2, 134.8, 135.5, 137.2, 138.1, 148.2, 166.5, 168.5, 170.9, 173.4, 173.6
Compd.	¹H NMR(CD₃OD, 400 MHz), δ	¹³C NMR(CD₃OD, 100 MHz), δ
Ⅱd	7.92—7.83(m, 1H, ArH), 7.76(d, J=7.4 Hz, 2H, ArH), 7.57(d, J=5.3 Hz, 1H, ArH), 7.43(s, 1H, ArH), 7.34(dd, J=14.3, 7.0 Hz, 3H, ArH), 7.23(t, J=7.8 Hz, 1H, ArH), 7.14(dd, J=14.2, 7.4 Hz, 4H, ArH), 7.03(t, J=7.0 Hz, 1H, ArH), 4.63(d, J=9.8 Hz, 2H, CH), 4.27(d, J=7.4 Hz, 1H, CH), 3.00(dd, J=13.7, 8.3 Hz, 1H, CH₂Ar), 2.06(dd, J=13.6, 6.8 Hz, 1H, CH), 1.76—1.52(m, 3H, CHCH₂), 0.95—0.81 [m, 12H,(CH₃)₄]	17.3, 17.9, 18.1, 18.4, 30.5, 37.8, 55.6, 58.9, 59.4, 117.1, 125.8, 127.0, 127.6, 128.1, 128.8, 129.3, 131.3, 134.1, 134.7, 135.7, 137.6, 143.6, 144.3, 161.0, 169.0, 170.5, 171.3, 172.8
Ⅱe	8.06(d, J=6.2 Hz, 1H, ArH), 8.03—7.95(m, 1H, ArH), 7.85—7.77(m, 1H, ArH), 7.66—7.59(m, 1H, ArH), 7.56(d, J=7.8 Hz, 1H, ArH), 7.49(t, J=7.8 Hz, 1H, ArH), 7.44—7.34(m, 4H, ArH), 7.34—7.24(m, 2H, ArH), 7.17(t, J=7.5 Hz, 1H, ArH), 4.93(dd, J=9.3, 4.6 Hz, 1H, CH), 4.86(t, J=7.1 Hz, 1H, CH), 4.46(d, J=7.5 Hz, 1H, CH), 4.10(s, 3H, OCH₃), 3.47(d, J=4.8 Hz, 1H, CH₂Ar), 3.22(dd, J=13.8, 9.4 Hz, 1H, CH₂Ar), 2.34—2.24(m, 1H, CH), 1.89—1.77(m, 3H, CHCH₂), 1.13 [ddd, J=18.5,8.7, 4.4 Hz, 12H,(CH₃)₄]	19.3, 20.7, 22.0, 24.7, 30.8, 36.8, 40.8, 52.3, 55.1, 59.3, 111.5, 118.9, 120.5, 121.1, 122.7, 123.0, 126.3, 128.0, 128.6, 128.9, 130.6, 132.9, 134.9, 137.4, 138.2, 139.5, 157.6, 166.7, 170.7, 171.5, 173.5
Ⅱf	7.73(s, 1H, ArH), 7.40(d, J=8.6 Hz, 1H, ArH), 7.32(d, J=7.4 Hz, 2H, ArH), 7.21(t, J=7.6 Hz, 2H, ArH), 7.14(s, 1H, ArH), 7.00(t, J=7.3 Hz, 1H, ArH), 4.64(dd, J=9.5, 4.0 Hz, 1H, CH), 4.33(d, J=8.1 Hz, 1H, CH), 4.28—4.19(m, 1H, CH), 3.35(d, J=9.3 Hz, 2H, CH₂Ar), 2.91(dd, J=13.3, 9.6 Hz, 1H, CH), 2.14(d, J=7.3 Hz, 1H, CH), 1.82—1.69 [m, 4H,(CH₂)₂], 1.70—1.48 [m, 4H,(CH₂)₂], 1.40(d, J=11.1 Hz, 3H, CHCH₂), 1.02—0.64 [m, 12H,(CH₃)₄]	18.9, 21.1, 22.5, 24.4, 25.1, 25.6, 31.2, 36.6, 41.5, 41.8, 56.3, 56.8, 59.7, 62.1, 70.9, 114.5, 119.3, 125.6, 125.9, 127.6, 128.9, 131.9, 136.8, 137.0, 140.3, 167.4, 171.1, 172.4, 173.1, 174.9
Ⅱg	7.73(s, 1H, ArH), 7.40(d, J=8.6 Hz, 1H, ArH), 7.32(d, J=7.4 Hz, 2H, ArH), 7.21(t, J=7.6 Hz, 2H, ArH), 7.14(s, 1H, ArH), 7.00(t, J=7.3 Hz, 1H, ArH), 4.64(dd, J=9.5, 4.0 Hz, 1H, CH), 4.33(d, J=8.1 Hz, 1H, CH), 4.28—4.19(m, 1H, CH), 3.35(d, J=9.3 Hz, 2H, CH₂Ar), 2.91(dd, J=13.3, 9.6 Hz, 1H, CH), 2.14(d, J=7.3 Hz, 1H, CH), 1.82—1.69 [m, 4H,(CH₂)₂], 1.70—1.48 [m, 4H,(CH₂)₂], 1.40(d, J=11.1 Hz, 3H, CHCH₂), 1.02—0.64 [m, 12H,(CH₃)₄]	18.8, 21.1, 22.6, 24.4, 25.1, 25.6, 31.2, 36.6, 41.5, 41.9, 56.3, 56.8, 59.7, 62.0, 70.9, 114.5, 119.5, 125.6, 125.9, 127.4, 128.9, 131.9, 136.8, 137.0, 140.3, 167.9, 171.1, 172.1, 173.6, 174.9

Table 4 Antitumor activity of target compounds in vitro

Compd.	IC₅₀/(μmol·L^-1)		Compd.	IC₅₀/(μmol·L^-1)
Compd.	MDA-MB-231		MCF7	MDA-MB-231	MCF7
Ⅰa	>20	>20	Ⅱa	17.1	>20
Ⅰb	>20	>20	Ⅱb	7.6	11.8
Ⅰc	>20	>20	Ⅱc	16.3	>20
Ⅰd	>20	>20	Ⅱd	>20	15.5
Ⅰe	>20	>20	Ⅱe	16.3	>20
Taxol	<0.01	0.006	Ⅱf	>20	>20
			Ⅱg	>20	>20

References 20

[1]	Sasse F., Sieinmetz H., Heil J., Höfle G., Reichenbach H., J. Antibiot., 2000, 59(9), 879—885
[2]	Kaur G., Hollingshead M., Holbeck S., Schauer-Vukasinovic V., Camalier R. F., Dömling A., Agarwal S., Biochem. J., 2006, 396(2), 235—242
[3]	Khalil M.W., Sasse F., Luensdorf H., Elnakady Y. A., Reichenbach H.,ChemBioChem, 2006, 7(4), 678—683
[4]	Steinmetz H., Glaser N., Herdtweck E., Sasse F., Reichenbach H., Höfle G., Angew. Chem. Int. Ed., 2004, 43(37), 4888—4892
[5]	Peltier H. M., McMahon J. P., Patterson A. W., Ellman J. A., J. Am. Chem. Soc., 2006, 128(50), 16018—16019
[6]	Sani M., Fossati G., Huguenot F., Zanda M., Angew. Chem., 2007, 119(19), 3596—3599
[7]	Pando O., Dörner S., Preusentanz R., Denkert A., Porzel A., Richter W., Wessjohann L., Org. Lett., 2009, 11(24), 5567—5569
[8]	Ullrich A., Chai Y., Pistorius D., Elnakady Y. A., Herrmann J. E., Weissman K. J., Kazmaier U., Müller R., Angew. Chem. Int. Ed., 2009, 48(24), 4422—4425
[9]	Braig S., Wiedmann R. M., Liebl J., Singer M., Kubisch R., Schreiner L., Abhari B. A., Wagner E., Kazmaier U., Fulda S., Vollmar A. M., Cell Death Dis., 2014, 5(1), e1001
[10]	Kubisch R., von Gamm M., Braig S., Ullrich A., Burkhart J. L., Colling L., Hermann J., Scherer O., Müller R., Werz O., Kazmaier U., Vollmar A. M., J. Nat. Prod., 2014, 77(3), 536—542
[11]	Burkhart J. L., Müller R., Kazmaier U., Eur. J. Org. Chem., 2011, 2011(16), 3050—3059
[12]	Hwang J. Y., Attia R. R., Zhu F.,Yang L., Lemoff A., Jeffries C., Connelly M. C., Guy R. K., J. Med. Chem., 2012, 55(5), 2301—2310
[13]	Shearer B. G., Chao E. Y., Uehling D. E., Deaton D. N., Cowan C., Sherman B. W., Milliken T., Faison W., Brown K., Adkisond K. K., Lee F., J. Med. Chem., 2002, 45(3), 567—583
[14]	Wang Z. J., Sun X. H., Liu Y. F., Chen B., Shen S. Q., Jin R. Y., Ma H. X., Chem. J. Chinese Universities,2015, 36(7), 1315—1320
	(王子剑, 孙晓红, 刘源发, 陈邦, 沈生强, 靳如意, 马海霞. 高等学校化学学报, 2015, 36(7), 1315—1320)
[15]	Stodulski M., Mamińska A., Mlynarski J., Tetrahedron: Asymmetry,2011, 22(4), 464—467
[16]	Parka Y., Lee J. K., Ryu J. S., Synlett., 2015, 26(8), 1063—1068
[17]	Li Y., Di F., Wang D., Chen W., Wan Y. Y., Li Z. M., Chem. Res. Chinese Universities,2015, 31(6), 952—957
[18]	Chen Q., Lin J., Zhao D., Zhu X., Chem. Res. Chinese Universities,2016, 32(5), 792—796
[19]	Murray B. C., Peterson M. T., Fecik R. A., Nat. Prod. Rep., 2015, 32(5), 654—662
[20]	Xu X. M., Gregory K. F., Yao L., Mini-Rev. Med. Chem., 2013, 13(11), 1572—1578