Quantitative structure-activity relationship study of novel rhinacanthins and related naphthoquinone esters as anticancer agents

Figures & data

Figure 1 Structures of rhinacanthin–M (1), –N (14), –Q (15) and related naphthoquinone esters (2–13, 16–42).

Table I.  Observed, calculated and predicted cytotoxicities of rhinacanthins and naphthoquinone esters (Figure 1) against human carcinoma cell lines (KB, HeLa and HepG2).

							pIC50 (M)^b
							KB
								Cald	Cald	Prctd	HeLa	HepG2
S. No.	R1	R2	R3	R4	R5	X^a	Obsd	F.B.	Eq.(6)		Obsd	Obsd
1^c	Me	Me	H	H	OH	–	5.82	5.51	5.59	5.55	5.52	5.31
2	Me	Me	OMe	H	OH	–	5.73	5.83	5.90	5.93	5.39	5.33
3	Me	Me	OH	H	OH	–	5.33	5.77	5.90	5.98	5.36	5.26
4	Me	Me	OMe	OMe	OH	–	5.47	5.86	5.86	5.91	5.49	5.45
5	Me	Me	OH	OMe	OH	–	5.93	5.81	5.86	5.86	5.48	5.79
6	Me	Me	OH	OH	OH	–	4.19	4.56	4.57	5.01	4.34	4.32
7	Me	H	H	H	OH	–	5.34	5.15	5.04	4.96	5.32	5.07
8	Me	H	OMe	H	OH	–	5.79	5.46	5.34	5.29	5.39	5.39
9	Me	H	OH	H	OH	–	5.33	5.41	5.34	5.35	4.99	4.93
10	Me	H	OMe	OMe	OH	–	4.43^d	5.50	4.82	–	4.38	4.28
11	Me	H	OH	OMe	OH	–	5.39	5.45	5.30	5.29	5.34	5.30
12	Me	Me	H	H	OMe	–	4.37	4.17	4.26	4.23	4.39	4.33
13	Me	Me	OMe	OMe	OMe	–	4.83	4.52	4.53	4.46	4.41	4.39
14^e	Me	Me	OH	OMe	OH	Ar	6.66	6.26	6.29	6.24	6.52	6.42
15^f	Me	Me	OMe	OMe	OH	Ar	6.46	6.31	6.29	6.27	5.96	6.01
16	Me	Me	H	H	OH	Ar	5.80	5.96	6.02	6.07	5.93	5.89
17	Me	Me	OMe	H	OH	Ar	6.66	6.27	6.33	6.29	6.64	6.62
18	Me	Me	OH	H	OH	Ar	6.64	6.22	6.33	6.29	6.64	6.49
19	Me	Me	OH	OH	OH	Ar	5.37	5.01	5.00	4.57	4.91	4.89
20	Me	H	H	H	OH	Ar	5.45	5.60	5.46	5.46	5.37	5.43
21	Me	H	OMe	H	OH	Ar	6.18	5.91	5.77	5.74	6.42	5.98
22	Me	H	OH	H	OH	Ar	5.97	5.86	5.77	5.76	5.40	6.00
23	Me	H	OMe	OMe	OH	Ar	5.45	5.95	5.73	5.75	5.42	5.44
24	Me	H	OH	OMe	OH	Ar	5.67	5.90	5.73	5.73	5.55	5.50
25	H	H	H	H	OH	Ar	4.84	4.76	4.90	4.92	4.80	4.81
26	H	H	OMe	H	OH	Ar	4.47	5.08	5.21	5.30	4.37	4.34
27	H	H	OH	H	OH	Ar	4.91	5.03	5.21	5.25	4.82	4.79
28	H	H	OMe	OMe	OH	Ar	4.89	5.12	5.17	5.20	4.49	4.45
29	H	H	OH	OMe	OH	Ar	5.39	5.07	5.17	5.14	5.37	5.37
30	Me	Me	H	H	H	Ar	4.49	4.64	4.64	4.68	4.38	4.34
31	Me	Me	OMe	H	H	Ar	4.90	4.95	4.95	4.96	4.43	4.84
32	Me	Me	OH	H	H	Ar	4.42	4.90	4.95	5.03	4.34	4.32
33	Me	H	H	H	H	Ar	4.54	4.28	4.08	4.00	4.42	4.56
34	Me	H	OMe	H	H	Ar	4.58	4.59	4.39	4.38	4.40	4.40
35	Me	H	OH	H	H	Ar	4.41	4.54	4.39	4.39	4.33	4.38
36	H	H	H	H	H	Ar	4.86^d	3.45	3.04	–	4.89	4.99
37	H	H	OMe	H	H	Ar	4.30	3.76	3.83	3.76	4.32	4.27
38	H	H	OH	H	H	Ar	3.59	3.70	3.83	3.87	3.59	3.59
39	H	H	OMe	OMe	H	Ar	3.63	3.80	3.79	3.82	3.63	3.63
40	H	H	OH	OMe	H	Ar	4.03	3.74	3.79	3.75	4.34	4.19
41	Me	Me	H	H	OMe	Ar	4.04	4.61	4.68	4.82	4.35	3.90
42	Me	Me	OMe	H	OMe	Ar	5.00	4.93	4.99	4.99	5.02	4.94

^aSubstituent X indicates either no ring or an aromatic ring fused with phenyl moiety

^bIC₅₀ represents the concentration of a compound required to exhibit 50% cytotoxicitiy against KB, HeLa and HepG2 cell lines

^cRhinacanthin–M

^dThe ‘outlier'compound of present study

^eRhinacanthin–N

^fRhinacanthin–Q.

Table II.  QSAR parameters for the substituents of varying positions of the title compounds.

R1	R2	MW1+2	R3	HA3	R4	π4	R5	π5
H	H	0.02	H	0	H	0.00	H	0.00
H	Me	0.16	OH	1	OH	–0.67	OH	–0.67
Me	Me	0.30	OMe	1	OMe	–0.02	OMe	–0.02

Table III.  Fujita-Ban contribution of substituents and parent compound (7) to the cytotoxicity against human carcinoma KB cell lines of the title compounds.

		Contribution to pIC50(KB)
Position	Substitution	n = 42	n = 40
R1, R2	H, H	–0.64( ± 0.34)	–0.83( ± 0.28)
	Me, Me	0.44( ± 0.29)	0.36( ± 0.24)
R3	OH	0.15( ± 0.34)	0.26( ± 0.28)
	OMe	0.14( ± 0.33)	0.31( ± 0.27)
R4	OH	–1.21( ± 0.61)	–1.21( ± 0.49)
	OMe	–0.03( ± 0.29)	0.04( ± 0.23)
R5	H	–1.23( ± 0.30)	–1.32( ± 0.24)
	OMe	–1.35( ± 0.45)	–1.35( ± 0.36)
Ar	–(CH = CH)2–	0.49( ± 0.29)	0.45( ± 0.23)
Parent	μ	5.16( ± 0.35)	5.15( ± 0.29)

Table IV.  Intercorrelation matrix^a amongst the predictor variables of Equation (6).

	HA3	π4	π5	MW1+2	IAr
HA3	1.00	0.15	0.10	0.13	0.04
π4		1.00	0.18	0.21	0.10
π5			1.00	0.04	0.26
MW1 + 2				1.00	0.34
IAr					1.00

^aMatrix elements are the r-values.

Table

R1, R2	R3	R4	R5	Ar
Me, Me	OH	OMe	–	–(CH = CH)2–
	OMe

Figure 2 Plot of observed versus calculated pIC₅₀ values.