Design and synthesis of novel oridonin analogues as potent anticancer agents

Figures & data

Figure 1. The structure of oridonin, costunolide, compound 3, 4, 5 and the design of target compound 2a–2y.

Scheme 1. Heck reaction of oridonin with aryl iodides.

Table 1. Antiproliferative efficacy of oridonin derivatives of 2a–2y in six human cancer cell lines^b.

	IC50 values (μM)^a
Compound	AGS	MGC803	Bel7402	HCT116	A549	Hela
2a	>100	9.13 ± 0.82	4.97 ± 0.56	47.12 ± 4.32	>100	>100
2b	13.86 ± 1.50	23.63 ± 1.48	>100	36.55 ± 2.43	47.43 ± 3.49	>100
2c	14.35 ± 2.43	>100	12.60 ± 1.05	10.25 ± 1.12	59.58 ± 4.75	>100
2d	14.13 ± 1.65	2.13 ± 0.13	16.94 ± 1.30	19.78 ± 3.19	12.73 ± 1.56	15.19 ± 1.47
2e	15.35 ± 1.78	7.27 ± 0.74	9.66 ± 1.15	13.95 ± 1.94	23.08 ± 3.63	>100
2f	>100	22.77 ± 1.25	>100	59.03 ± 3.37	>100	>100
2g	10.83 ± 2.39	17.65 ± 1.13	24.22 ± 2.27	14.16 ± 1.31	66.89 ± 5.29	22.32 ± 1.92
2h	5.26 ± 1.09	27.20 ± 2.38	11.29 ± 0.98	10.10 ± 1.39	18.04 ± 1.49	28.74 ± 2.13
2i	4.79 ± 0.94	11.51 ± 1.05	8.62 ± 0.78	8.03 ± 1.09	>100	14.33 ± 1.16
2j	2.87 ± 0.58	10.4 ± 1.29	3.56 ± 0.52	5.48 ± 0.64	7.89 ± 0.99	24.72 ± 2.08
2k	2.91 ± 0.42	2.79 ± 0.38	4.52 ± 0.46	2.99 ± 0.32	16.79 ± 2.51	68.81 ± 5.32
2l	5.85 ± 1.55	3.49 ± 0.44	2.41 ± 0.37	2.28 ± 0.54	5.12 ± 0.49	14.29 ± 2.04
2m	17.64 ± 2.32	17.68 ± 1.67	3.15 ± 0.64	11.07 ± 1.83	13.60 ± 1.89	30.66 ± 2.90
2n	17.30 ± 2.41	27.96 ± 1.73	14.56 ± 1.21	18.64 ± 1.78	15.78 ± 1.47	8.89 ± 0.94
2o	10.01 ± 1.88	10.86 ± 1.39	6.54 ± 0.94	3.09 ± 0.41	15.29 ± 1.31	8.21 ± 1.20
2p	4.09 ± 0.65	4.54 ± 0.94	3.21 ± 0.58	1.05 ± 0.23	5.90 ± 0.52	6.33 ± 0.96
2q	3.10 ± 0.41	9.10 ± 1.72	8.62 ± 1.12	7.63 ± 0.81	4.66 ± 0.30	5.43 ± 0.85
2r	13.7 ± 2.63	6.86 ± 1.24	8.45 ± 1.32	2.39 ± 0.19	4.16 ± 0.45	9.85 ± 2.03
2s	51.03 ± 3.34	53.22 ± 4.05	7.00 ± 1.05	10.04 ± 1.13	99.8 ± 7.45	>100
2t	22.05 ± 1.04	10.04 ± 0.84	14.56 ± 1.66	47.9 ± 3.91	97.1 ± 5.93	>100
2u	12.03 ± 1.99	12.22 ± 0.94	7.35 ± 1.28	4.02 ± 0.33	21.48 ± 1.88	9.79 ± 1.08
2v	30.28 ± 2.24	32.86 ± 2.31	60.32 ± 4.14	28.17 ± 2.67	>100	>100
2w	>100	>100	>100	22.14 ± 3.28	>100	>100
2x	>100	>100	>100	30.12 ± 3.57	>100	>100
2y	55.04 ± 4.43	20.96 ± 1.24	51.21 ± 5.43	17.46 ± 1.44	12.6 ± 1.39	26.02 ± 1.48
Oridonin	8.35 ± 0.41	9.18 ± 1.01	9.59 ± 1.19	6.84 ± 0.98	24.66 ± 2.11	15.03 ± 2.01
5-FU	29.61 ± 3.40	30.52 ± 4.42	21.3 ± 2.43	24.80 ± 2.08	23.65 ± 3.14	34.61 ± 3.14

^a IC₅₀: concentration that inhibits 50% of cell growth.

^b MTT methods; cells were incubated with indicated compounds for 48 h (means ± SD, n = 3).

Table 2. In vitro antiproliferative activities of compounds 2l and 2p against normal cell line (L02).

	(IC50, μM)^a	Selectivity index^b
Compound	L02	AGS	MGC803	Bel7402	HCT116	A549	Hela
2l	7.15 ± 1.36	1.22	2.05	2.97	3.14	1.40	0.44
2p	6.88 ± 1.12	3.28	0.75	0.72	6.55	1.17	1.09
Oridonin	6.97 ± 0.98	0.83	0.76	0.73	1.02	0.28	0.46
5-FU	19.12 ± 1.01	0.65	0.63	0.90	0.65	0.81	0.55

^a IC₅₀: concentration that inhibits 50% of cell growth.

^b SI: selective index (IC₅₀ on normal cells/IC₅₀ on tumour cells).

Figure 2. Flow cytometry analyses of cell cycle distribution of HCT116 cancer cell after treatment of compound 2p (5.00 μM), oridonin (5.00 μM) and no treatment (Ctrl) as a reference control for 48 h.

Figure 3. Apoptosis induction in HCT116 cancer cell after treatment with 2p (5.00 μM), oridonin (5.00 μM) and no treatment (Ctrl) as a reference control for 48 h.