Study on Synthesis and Pharmacological Research of Jiyuan Oridonin A Derivatives as Potential Anti-tumor Drugs

doi:10.6023/cjoc202207033

Abstract

Jiyuan oridonin A (JOA), a diterpenoid ingredient purified from Isodon rubescens collected in Jiyuan, Henan Province, exhibited a variety of anti-tumor activities. In order to further develop the medicinal potency of JOA, a series of its 14-OH benzoate derivatives were designed and synthesized, and then their anti-proliferative activities in vitro were evaluated. The results turned out that the anti-tumor activities of this series of derivatives had been improved compared with the those of JOA, and were much better than that of oridonin. Among them, 7α,20-olide-ent-kaur-16-en-11,15-dione-14β-yl 2-nitro-5- chlorobenzoate (OJW8-9) showed the best activity (IC₅₀=(0.478±0.109) μmol/L on SW-1990 cells). Further studies revealed that compound OJW8-9 inhibited the proliferation of SW-1990 cells by blocking cell cycle in the G2/M phase in a time- and concentration-dependent, and might induce apoptosis through reactive oxygen species (ROS) pathway.

Key words: ent-kaurene diterpene, Jiyuan oridonin A (JOA), anti-proliferative activity, reactive oxygen species (ROS) pathway

Cite this article

Ni Wang, Zijun Zheng, Xiaoping Jia, Mengyuan Zhao, Yalei Wang, Chen Zhou, Zhijia Wang, Zelin Xiao, Hongmin Liu, Yu Ke. Study on Synthesis and Pharmacological Research of Jiyuan Oridonin A Derivatives as Potential Anti-tumor Drugs[J]. Chinese Journal of Organic Chemistry, 2023, 43(2): 646-659.

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Compd.	R	Yield/%	Compd.	R	Yield/%
OJW1	H	85	OJW2-1	2-OCH₃	47
OJW2-2	3-OCH₃	75	OJW2-3	4-OCH₃	63
OJW2-4	2,3-(OCH₃)₂	63	OJW2-5	3,4-(OCH₃)₂	41
OJW2-6	3,4,5-(OCH₃)₃	82	OJW3-1	2-CH₃	64
OJW3-2	3-CH₃	67	OJW3-3	4-CH₃	36
OJW4-1	3-Cl	56	OJW4-2	4-Cl	74
OJW4-3	2,3-Cl₂	80	OJW4-4	2,6-Cl₂	78
JW5-1	2-Br	71	OJW5-2	3-Br	65
OJW5-3	4-Br	67	OJW6-1	2-F	85
OJW6-2	3-F	82	OJW6-3	4-F	76
OJW6-4	2,3,4-F₃	76	OJW6-5	2,3,4,5,6-F₅	54
OJW7-1	2-CF₃	48	OJW7-2	3-CF₃	52
OJW7-3	4-CF₃	67	OJW8-1	2-NO₂	85
OJW8-2	3-NO₂	79	OJW8-3	4-NO₂	71
OJW8-4	2,4-(NO₂)₂	64	OJW8-5	3,4-(NO₂)₂	56
OJW8-6	3,5-(NO₂)₂	74	OJW8-7	2-NO₂-5-OCH₃	69
OJW8-8	2-NO₂-5-CH₃	78	OJW8-9	2-NO₂-5-Cl	70
OJW8-10	2-NO₂-5-F	66	OJW8-11	3-NO₂-4-F	54
OJW9-1	2-I	76	OJW9-2	3-I	82
OJW9-3	4-I	78	OJW10-1	3-CH₂Br	37
OJW10-2	4-CH₂Br	27	OJW11	2-CH₃-3-F	37

Compd.	R	Yield/%	Compd.	R	Yield/%
OJW1	H	85	OJW2-1	2-OCH₃	47
OJW2-2	3-OCH₃	75	OJW2-3	4-OCH₃	63
OJW2-4	2,3-(OCH₃)₂	63	OJW2-5	3,4-(OCH₃)₂	41
OJW2-6	3,4,5-(OCH₃)₃	82	OJW3-1	2-CH₃	64
OJW3-2	3-CH₃	67	OJW3-3	4-CH₃	36
OJW4-1	3-Cl	56	OJW4-2	4-Cl	74
OJW4-3	2,3-Cl₂	80	OJW4-4	2,6-Cl₂	78
JW5-1	2-Br	71	OJW5-2	3-Br	65
OJW5-3	4-Br	67	OJW6-1	2-F	85
OJW6-2	3-F	82	OJW6-3	4-F	76
OJW6-4	2,3,4-F₃	76	OJW6-5	2,3,4,5,6-F₅	54
OJW7-1	2-CF₃	48	OJW7-2	3-CF₃	52
OJW7-3	4-CF₃	67	OJW8-1	2-NO₂	85
OJW8-2	3-NO₂	79	OJW8-3	4-NO₂	71
OJW8-4	2,4-(NO₂)₂	64	OJW8-5	3,4-(NO₂)₂	56
OJW8-6	3,5-(NO₂)₂	74	OJW8-7	2-NO₂-5-OCH₃	69
OJW8-8	2-NO₂-5-CH₃	78	OJW8-9	2-NO₂-5-Cl	70
OJW8-10	2-NO₂-5-F	66	OJW8-11	3-NO₂-4-F	54
OJW9-1	2-I	76	OJW9-2	3-I	82
OJW9-3	4-I	78	OJW10-1	3-CH₂Br	37
OJW10-2	4-CH₂Br	27	OJW11	2-CH₃-3-F	37

Compound	MCF-7	Ec109	SW1990	MGC-803	Hela
Oridonin	8.415±0.440	23.359±3.460	8.858±0.360	12.227±0.211	40.863±9.594
JOA	2.101±0.174	4.319±0.688	4.188±0.512	3.778±0.375	6.010±0.191
O-JOA	1.087±0.179	2.269±0.036	1.009±0.127	1.704±0.074	1.757±0.099
OJW1	1.608±0.309	2.553±0.230	0.881±0.071	1.753±0.191	2.814±0.212
OJW2-1	1.745±0.182	2.970±0.038	1.125±0.133	1.634±0.173	2.966±0.278
OJW2-2	1.969±0.293	2.306±0.231	0.878±0.139	1.652±0.181	2.559±0.055
OJW2-3	1.862±0.250	3.302±0.367	1.059±0.170	3.122±0.556	3.640±0.034
OJW2-4	1.731±0.078	2.182±0.089	1.155±0.219	2.152±0.329	2.786±0.217
OJW2-5	3.114±0.488	5.181±0.138	0.771±0.120	2.421±0.133	4.032±0.182
OJW2-6	1.479±0.132	3.056±0.035	1.283±0.163	1.023±0.021	2.064±0.292
OJW3-1	2.742±0.125	3.273±0.080	1.134±0.106	1.222±0.168	4.174±0.296
OJW3-2	1.996±0.887	2.863±0.219	1.119±0.047	2.123±0.108	3.686±0.112
OJW3-3	3.195±0.312	5.524±0.128	2.920±0.398	4.109±0.492	6.834±0.444
OJW4-1	1.708±0.018	2.159±0.269	1.991±0.047	2.063±0.151	3.326±0.281
OJW4-2	1.976±0.153	2.816±0.258	2.314±0.909	3.463±0.326	3.763±0.494
OJW4-3	2.119±0.196	3.410±0.028	1.416±0.202	2.891±0.316	3.584±0.293
OJW4-4	1.619±0.049	2.939±0.028	1.796±0.249	1.513±0.079	3.168±0.614
OJW5-1	2.648±0.131	2.840±0.320	1.574±0.051	2.207±0.403	3.072±0.110
OJW5-2	1.660±0.231	3.133±0.176	1.114±0.163	3.133±0.617	3.182±0.103
OJW5-3	2.175±0.444	6.521±1.220	1.694±0.023	3.276±0.059	3.930±0.247
OJW6-2	1.661±0.046	2.447±0.061	1.314±0.279	3.573±0.316	3.664±0.352
OJW6-3	2.830±0.085	3.902±0.258	1.227±0.102	2.235±0.076	5.184±0.075
OJW6-4	1.604±0.063	1.902±0.125	0.969±0.048	2.416±0.216	3.314±0.289
OJW6-5	1.160±0.113	2.061±0.234	1.098±0.176	1.045±0.09	2.062±0.059
OJW7-1	2.413±0.065	4.268±0.174	1.687±0.181	3.407±0.689	6.863±0.297
OJW7-2	2.796±0.106	5.067±0.502	1.142±0.071	1.926±0.023	4.269±0.487
OJW7-3	1.839±0.145	2.556±0.110	1.601±0.101	2.258±0.310	4.085±0.180
OJW8-1	1.255±0.157	2.692±0.257	0.905±0.113	1.771±0.058	3.028±0.098
OJW8-2	1.183±0.071	3.153±0.255	1.348±0.212	1.886±0.300	3.097±0.424
OJW8-3	1.283±0.050	2.486±0.329	1.088±0.129	2.220±0.363	3.698±0.487
OJW8-4	1.013±0.038	2.967±0.017	0.708±0.073	2.350±0.025	2.767±0.112
OJW8-5	2.468±0.326	5.283±0.164	1.765±0.169	4.476±0.287	6.688±0.771
OJW8-6	0.667±0.081	2.653±0.208	0.938±0.005	1.471±0.318	3.265±0.290
OJW8-7	1.281±0.034	1.974±0.219	1.669±0.042	2.174±0.215	6.629±0.715
OJW8-8	1.701±0.124	2.501±0.174	1.871±0.040	2.265±0.066	7.854±0.098
OJW8-9	0.804±0.013	1.452±0.126	0.478±0.109	1.097±0.125	1.864±0.073
OJW8-10	2.309±0.056	2.777±0.280	1.557±0.223	2.196±0.263	9.159±1.309
OJW8-11	1.263±0.140	1.523±0.251	0.858±0.119	2.040±0.130	3.729±0.090
OJW9-1	2.101±0.131	5.364±0.416	1.130±0.166	1.887±0.135	4.322±0.323
OJW9-2	2.449±0.135	3.578±0.362	1.989±0.016	1.648±0.243	5.210±0.271
OJW9-3	1.957±0.022	3.444±0.101	1.152±0.197	2.187±0.143	3.664±0.425
OJW10-1	0.886±0.015	1.746±0.107	0.726±0.053	0.963±0.179	0.970±0.055
OJW10-2	1.506±0.179	3.137±0.191	0.936±0.019	1.908±0.225	5.179±0.509
OJW11	1.267±0.074	3.568±0.365	0.974±0.064	1.983±0.260	3.135±0.251

Compound	MCF-7	Ec109	SW1990	MGC-803	Hela
Oridonin	8.415±0.440	23.359±3.460	8.858±0.360	12.227±0.211	40.863±9.594
JOA	2.101±0.174	4.319±0.688	4.188±0.512	3.778±0.375	6.010±0.191
O-JOA	1.087±0.179	2.269±0.036	1.009±0.127	1.704±0.074	1.757±0.099
OJW1	1.608±0.309	2.553±0.230	0.881±0.071	1.753±0.191	2.814±0.212
OJW2-1	1.745±0.182	2.970±0.038	1.125±0.133	1.634±0.173	2.966±0.278
OJW2-2	1.969±0.293	2.306±0.231	0.878±0.139	1.652±0.181	2.559±0.055
OJW2-3	1.862±0.250	3.302±0.367	1.059±0.170	3.122±0.556	3.640±0.034
OJW2-4	1.731±0.078	2.182±0.089	1.155±0.219	2.152±0.329	2.786±0.217
OJW2-5	3.114±0.488	5.181±0.138	0.771±0.120	2.421±0.133	4.032±0.182
OJW2-6	1.479±0.132	3.056±0.035	1.283±0.163	1.023±0.021	2.064±0.292
OJW3-1	2.742±0.125	3.273±0.080	1.134±0.106	1.222±0.168	4.174±0.296
OJW3-2	1.996±0.887	2.863±0.219	1.119±0.047	2.123±0.108	3.686±0.112
OJW3-3	3.195±0.312	5.524±0.128	2.920±0.398	4.109±0.492	6.834±0.444
OJW4-1	1.708±0.018	2.159±0.269	1.991±0.047	2.063±0.151	3.326±0.281
OJW4-2	1.976±0.153	2.816±0.258	2.314±0.909	3.463±0.326	3.763±0.494
OJW4-3	2.119±0.196	3.410±0.028	1.416±0.202	2.891±0.316	3.584±0.293
OJW4-4	1.619±0.049	2.939±0.028	1.796±0.249	1.513±0.079	3.168±0.614
OJW5-1	2.648±0.131	2.840±0.320	1.574±0.051	2.207±0.403	3.072±0.110
OJW5-2	1.660±0.231	3.133±0.176	1.114±0.163	3.133±0.617	3.182±0.103
OJW5-3	2.175±0.444	6.521±1.220	1.694±0.023	3.276±0.059	3.930±0.247
OJW6-2	1.661±0.046	2.447±0.061	1.314±0.279	3.573±0.316	3.664±0.352
OJW6-3	2.830±0.085	3.902±0.258	1.227±0.102	2.235±0.076	5.184±0.075
OJW6-4	1.604±0.063	1.902±0.125	0.969±0.048	2.416±0.216	3.314±0.289
OJW6-5	1.160±0.113	2.061±0.234	1.098±0.176	1.045±0.09	2.062±0.059
OJW7-1	2.413±0.065	4.268±0.174	1.687±0.181	3.407±0.689	6.863±0.297
OJW7-2	2.796±0.106	5.067±0.502	1.142±0.071	1.926±0.023	4.269±0.487
OJW7-3	1.839±0.145	2.556±0.110	1.601±0.101	2.258±0.310	4.085±0.180
OJW8-1	1.255±0.157	2.692±0.257	0.905±0.113	1.771±0.058	3.028±0.098
OJW8-2	1.183±0.071	3.153±0.255	1.348±0.212	1.886±0.300	3.097±0.424
OJW8-3	1.283±0.050	2.486±0.329	1.088±0.129	2.220±0.363	3.698±0.487
OJW8-4	1.013±0.038	2.967±0.017	0.708±0.073	2.350±0.025	2.767±0.112
OJW8-5	2.468±0.326	5.283±0.164	1.765±0.169	4.476±0.287	6.688±0.771
OJW8-6	0.667±0.081	2.653±0.208	0.938±0.005	1.471±0.318	3.265±0.290
OJW8-7	1.281±0.034	1.974±0.219	1.669±0.042	2.174±0.215	6.629±0.715
OJW8-8	1.701±0.124	2.501±0.174	1.871±0.040	2.265±0.066	7.854±0.098
OJW8-9	0.804±0.013	1.452±0.126	0.478±0.109	1.097±0.125	1.864±0.073
OJW8-10	2.309±0.056	2.777±0.280	1.557±0.223	2.196±0.263	9.159±1.309
OJW8-11	1.263±0.140	1.523±0.251	0.858±0.119	2.040±0.130	3.729±0.090
OJW9-1	2.101±0.131	5.364±0.416	1.130±0.166	1.887±0.135	4.322±0.323
OJW9-2	2.449±0.135	3.578±0.362	1.989±0.016	1.648±0.243	5.210±0.271
OJW9-3	1.957±0.022	3.444±0.101	1.152±0.197	2.187±0.143	3.664±0.425
OJW10-1	0.886±0.015	1.746±0.107	0.726±0.053	0.963±0.179	0.970±0.055
OJW10-2	1.506±0.179	3.137±0.191	0.936±0.019	1.908±0.225	5.179±0.509
OJW11	1.267±0.074	3.568±0.365	0.974±0.064	1.983±0.260	3.135±0.251

济源冬凌草甲素衍生物作为潜在抗肿瘤药物的合成及药理学活性研究