Molecular modifications of 2-arylidene-1-indanones leading to increased cytotoxic potencies

Figures & data

Figure 1 Structures of series 1-3. The aryl substituents are as follows: a: R¹ = R² = H; b: R¹ = 4-Cl, R² = H; c: R¹ = 3-Cl, R² = 4-Cl; d: R¹ = 4-CH₃, R² = H; e: R¹ = 4-OCH₃, R² = H; f: R¹ = 4-F, R² = H; g: R¹ = 4-Br, R² = H; h: R¹ = 2-NO₂, R² = H; i: R¹ = 3-NO₂, R² = H; j: R¹ = 4-NO₂, R² = H.

Table I.  Examination of 2a-j, 3a-j and melphalan against human Molt 4/C8 and CEM T-lymphocytes as well as murine L1210 cells

	Molt 4/C8		CEM		L1210
Compound	IC50(μM)	RP^a	IC50(μM)	RP^a	IC50(μM)	RP^a
2a	34.6 ± 1.6	1.22	31.2 ± 5.1	1.32	28.3 ± 0.6	3.96
2b	8.70 ± 0.12	>57.5	9.41 ± 0.97	30.2	42.5 ± 1.5	1.27
2c	166 ± 4	>3.01	144 ± 11	2.76	233 ± 1	> 2.15
2d	35.9 ± 0.2	>13.9	26.4 ± 6.3	2.54	29.3 ± 1.3	2.02
2e	72.6 ± 10.2	3.11	69.6 ± 7.6	0.47	170 ± 6	0.27
2f	43.9 ± 0.6	1.37	42.5 ± 4.2	0.99^b	184 ± 28	0.48
2 g	45.2 ± 0.3	>11.1	46.0 ± 0.8	6.50	184 ± 4	0.35
2 h	8.71 ± 0.11	0.29	25.4 ± 2.7	0.14	44.9 ± 1.0	0.17
2i	33.3 ± 6.3	>15.0	23.6 ± 10.2	9.41	233 ± 7	1.10^b
2j	13.2 ± 1.8	>37.9	10.1 ± 3.5	>49.5	80.4 ± 26.2	>6.22
3a	7.94 ± 0.32	5.33	11.1 ± 3.1	3.72	49.4 ± 0.4	2.27
3b	9.00 ± 0.53	>55.6	8.06 ± 0.29	35.2	39.3 ± 6.7	1.38
3c	8.67 ± 0.74	>57.7	7.44 ± 1.27	53.4	46.8 ± 6.2	>10.7
3d	7.80 ± 0.47	>64.1	12.9 ± 1.1	5.20	43.5 ± 1.4	1.36
3e	20.6 ± 11.5	11.0	28.4 ± 11.6	1.15^b	42.8 ± 2.0	1.07
3f	8.23 ± 0.11	7.29	5.80 ± 3.46	7.28	44.0 ± 3.7	2.02
3 g	8.41 ± 1.48	>59.5	8.54 ± 0.52	35.0	78.2 ± 13.5	0.83^b
3 h	7.95 ± 0.57	0.32	8.55 ± 0.30	0.41	31.8 ± 0.4	0.24
3i	7.88 ± 0.08	>63.5	7.49 ± 1.23	29.6	47.0 ± 1.3	5.45
3j	8.21 ± 0.23	>60.9	9.06 ± 1.32	>55.2	52.8 ± 4.0	>9.47
melphalan	3.24 ± 0.79	—	2.47 ± 0.30	—	2.13 ± 0.03	—

^aThe letters RP indicate relative potency, i.e., the quotients obtained by dividing the IC₅₀ value of the indanone 1 by the IC₅₀ value of the corresponding 1,3-indandione 2 or chalcone 3 which had identical aryl substituents

^bThere is not a statistically significant difference between the IC₅₀ values used in calculating the RP figures.

Table II.  A comparison of the relative potency (RP) values of series 1-3^a

RP values compared	Molt 4/C8	CEM	L1210	TOTAL
2>1	9/10	7/10	5/10	21/30 (70%)
3>1	9/10	8/10	8/10	25/30 (83%)
3>2	8/10	10/10	8/10	26/30 (87%)

^aComparisons were made between the potencies of two series of compounds in which the aryl substituents were identical. The figures out of ten indicate the number of comparisons in which greater potencies were displayed by both series 2 and 3 than 1 and also between 3a-j and 2a-j.

Figure 2 Models of 1c, 2c and 3c in which ring A is overlapped. (see colour online)

Figure 3 Interatomic distances (d₁, d₂) and bond angles (Ψ₁, Ψ₂) measured in order to determine the location of ring B and the C* atom in relation to ring A in 1c, 2c and 3c.

Table III.  Various interatomic distances (d₁, d₂), bond angles (ψ₁, ψ₂) and a torsion angle (θ₁) in 1c, 2c and 3c determined by molecular modeling

Compound	d1 (Å)	d2 (Å)	ψ1 (°)	ψ2 (°)	θ1 (°)
1c	6.992	4.803	72.37	90.63	46.10
2c	7.130	4.813	74.70	91.08	34.05
3c	7.436	5.077	91.99	105.05	21.05

Table IV.  Charge densities of the olefinic carbon atoms adjacent to aryl ring B

	Charge densities (esu)
Charge	1b	2b	1c	2c	1 h	2 h	1j	2j
Electrostatic	− 0.277	0.028	− 0.290	0.022	− 0.352	− 0.009	− 0.277	− 0.035
Mulliken	− 0.051	0.043	− 0.056	0.038	− 0.092	0.029	− 0.074	0.019