Cancer preventive agents 11. Novel analogs of dimethyl dicarboxylate biphenyl as potent cancer chemopreventive agents^†

Figures & data

Figure 1.  Structures of DDB and schizandrin C.

Figure 2.  Syntheses of DDB analogs.

Table 1.  DDB analogs and their EBV-EA inhibition ability.

cmpd No.		R^1	R^2	Percentage of EBV-EA positive cells concentration (mol ratio/TPA^b)				IC50^d
				1000	500	100	10
1		H		6.3 (70)^c	32.8	67.8	97.3	341
2		Br		14.6 (60)	40.2	76.0	100	403
3		Br		8.4 (60)	36.0	71.2	100	358
4		Br		7.9 (60)	35.8	68.2	98.6	349
5		Br		7.9 (60)	35.8	68.2	98.6	349
6		Br		11.5 (60)	38.6	75.5	100	389
7				13.1 (60)	37.0	71.3	100	390
8				12.0 (60)	35.9	70.0	100	381
9				11.2 (60)	37.0	72.0	100	380
10				10.3 (60)	37.4	71.7	100	379
11				15.6 (60)	41.0	76.9	100	426
12				3.1 (70)	27.0	54.9	93.4	278
13				1.7 (70)	23.5	51.6	90.3	260
14				2.9 (70)	25.1	53.7	91.7	269
15				2.1 (60)	24.8	52.6	91.5	265
16				4.1 (60)	28.6	57.4	96.6	287
17				9.5 (60)	36.0	71.0	100	372
18				8.9 (60)	35.7	71.5	100	369
19				0 (70)	21.6	50.3	89.1	252
20^a				1.9 (70)	24.6	52.9	91.6	263
curcumin				0 (60)	21.1	80.1	100	379

^aIn this structure, only one R² is the moiety shown above; the other R² is a hydrogen group.

^bTPA concentration is 32 pmol/mL.

^cValues in parentheses are viability percentages of Raji cells.

^dIC₅₀ in mol/ratio TPA.

Table 2.  In vivo inhibitory effects of 13, 15, and 19 on two-stage mouse carcinogenesis.

Week	Papilloma (%)				Papillomas/mouse
	Positive control^a	13^b	15^b	19^b	Positive control^a	13^b	15^b	19^b
1	0	0	0	0	0	0	0	0
2	0	0	0	0	0	0	0	0
3	0	0	0	0	0	0	0	0
4	0	0	0	0	0	0	0	0
5	0	0	0	0	0	0	0	0
6	6.6	0	0	0	0.4	0	0	0
7	20.0	0	0	0	0.9	0	0	0
8	40.0	6.6	13.3	6.6	1.8	0.7	0.9	0.6
9	73.3	13.3	26.6	13.3	2.4	1.6	2.0	1.4
10	86.6	26.6	33.3	26.6	3.5	2.0	2.2	1.8
11	100	33.3	40.0	33.3	3.9	2.4	2.6	2.0
12	100	40.0	53.3	40.0	4.3	2.6	2.9	2.4
13	100	53.3	66.6	53.3	5.2	3.3	3.6	3.1
14	100	66.6	73.3	66.6	5.9	4.3	4.5	4.0
15	100	73.3	73.3	66.6	6.3	4.6	5.1	4.4

^aThe positive control is DMBA (390 nmol) plus TPA (1.7 nmol).

^bThe concentration of compound is 85 nmol.

Figure 3.  Inhibitory effects of compounds 13, 15, and 19 on DMBA–TPA mouse skin carcinogenesis. Tumor formation in all mice was initiated with DMBA (390 nmol) and promoted with TPA (1.7 nmol) twice weekly beginning 1 week after initiation. (A) Papilloma percentage in mice. (B) Average number of papillomas/mouse. (♦) Control TPA alone; (▪) TPA + compound 13 (85 nmol); (×) TPA+ compound 15 (85 nmol); (▴) TPA +compound 19 (85 nmol). After 15 weeks of promotion, a significant difference in the number of papillomas/mouse between the treated groups and the control group was evident (p <0.05). In Figure 3A, the trace for compound 19 is superimposed with that for compound 13.