标准差标准化方法修正的PBBs多效应3D-QSAR模型及其在环境友好性分子修饰中的应用

doi:10.7503/cjcu20190402

摘要/Abstract

摘要：

构建了标准差标准化方法修正的兼具多溴联苯(PBBs)分子红外振动强度、生物富集性和毒性3种效应的CoMFA模型, 分析了PBBs分子力场对其综合值的影响, 确定取代位点, 并进行兼具易红外光谱检出、低生物富集性和毒性特征的PBB分子修饰(以PBB-153为例). 研究结果表明, 构建的CoMFA模型对PBBs分子的红外振动强度、生物富集性和毒性3种效应综合值具有较好的预测和拟合能力, 且具有较好的稳定性, 静电场和立体场的贡献率分别为59.9%和40.1%. 根据模型三维等势图选择正电性高于Br原子的5种取代基团对目标分子PBB-153进行单、双取代, 筛选出6个3种效应综合值上升的PBB-153衍生物. PBBs衍生物分子单效应计算或预测结果验证表明所构建的兼具PBBs分子红外振动强度、生物富集性和毒性3种效应综合值的CoMFA模型可以有效应用于PBBs分子的修饰. 设计的PBB-153衍生物分子具有较好的稳定性, 同时阻燃性与目标分子相当, 环境持久性及迁移性方面优于目标分子. 2D-QSAR模型表明, PBBs分子的偶极矩、最负电荷及邻位Br原子数对其红外振动强度、生物富集性和毒性单效应和综合值影响趋势一致.

关键词: 生物富集性, 红外光谱, 毒性, 多溴联苯, 分子修饰

Abstract:

A CoMFA model of tri-effect comprehensive values of infrared vibration intensity, bioconcentration and toxicity of PBBs via standard deviation method was constructed. The influence of PBBs’ molecular force fields on comprehensive values were analyzed to determine substitution sites. And the modification for PBB-153 with easy infrared detection, low bioconcentration and toxicity was accomplished. The CoMFA model had a good fitting and predicting ability on PBBs comprehensive values of infrared vibration intensity, bioconcentration and toxicity and had a good stability, the influencing force fields were electrostatic fields(E, 59.9%) and steric fields(S, 40.1%), respectively. Five substituents with higher electropositivity than Br were selected for single and double substitution of the target molecule PBB-153 according to the contour maps of CoMFA model, and six PBB-153 derivatives with increased tri-effect comprehensive values were screened. Predicting or calculating results of single effect of PBB derivatives indicated that the constructed CoMFA model can be applied to the modification of PBBs molecules. In addition, the flame retardancy and environmental friendliness of designed derivatives was comparable to the target molecule and the stability of derivatives was well. The results of 2D-QSAR model showed that the influence trends of dipole moment, maximum negative charge and the number of ortho Br atomic on the three single effects and comprehensive values were consistent.

Key words: Bioconcentration, Infrared spectrum, Toxicity, Polybrominated biphenyl, Molecular modification

中图分类号:

TrendMD:

杨璐泽,刘淼. 标准差标准化方法修正的PBBs多效应3D-QSAR模型及其在环境友好性分子修饰中的应用. 高等学校化学学报, 2019, 40(12): 2471.

Luze YANG,Miao LIU. 3D-QSAR Model of Polybrominated Biphenyls Tri-effect Modified by Standard Deviation Standardization Method and Its Application in Environmental Friendly Molecular Modification ^†. Chem. J. Chinese Universities, 2019, 40(12): 2471.

图/表 9

Fig.1 Molecular structure of PBBs(R1, R1': C; R2—R6: H, Br; R2'—R6' : H, Br)

Table 1 Evaluation parameters of CoMFA model based on comprehensive values of highest infrared vibration intensity, bioconcentration and toxicity of PBBs

Model	q²	n	SEE	R²	F	$r pred 2$	SEP	Q²	cSDEP	dq²/dr²yy
CoMFA	0.51	8	0.18	0.94	28.38	0.63	0.35	0.18	0.64	1.19

Table 1 Evaluation parameters of CoMFA model based on comprehensive values of highest infrared vibration intensity, bioconcentration and toxicity of PBBs

Model	q²	n	SEE	R²	F	$r pred 2$	SEP	Q²	cSDEP	dq²/dr²yy
CoMFA	0.51	8	0.18	0.94	28.38	0.63	0.35	0.18	0.64	1.19

Fig.2 Contour maps of CoMFA model of steric(A) and electrostatic fields(B)

Table 2 CoMFA model’s prediction of the comprehensive values of highest infrared vibration intensity, bioconcentration and toxicity of PBB-153 derivatives

No.	Compound	Comprehensive value of three properties	Change rate(%)
0	PBB-153	1.15	—
1	R₂-(CH₂)₃NO₂-PBB-153	1.38	20.71
2	R₂-C₂H₅-R₄-CH₂NO₂-PBB-153	1.26	9.63
3	R₂-C₂H₅-R₄-(CH₂)₂NO₂-PBB-153	1.95	69.81
4	R₂-(CH₂)₂NO₂-R₄-C₂H₅-PBB-153	1.52	32.3
5	R₂-(CH₂)₂NO₂-R₄-(CH₂)₃NO₂-PBB-153	1.38	20.18
6	R₂-(CH₂)₂NO₂-R₄-(CH₂)₄NO₂-PBB-153	1.84	60.65

Table 3 Highest infrared vibration intensity, BCF, lgLC50 value and change rate of PBB-153 derivatives

Compound	Highest infrared vibration intensity	Change rate(%)	BCF	Change rate(%)	lgLC₅₀	Change rate(%)
PBB-153	688.69	—	4814	—	-3.66	—
R₂-(CH₂)₃NO₂-PBB-153	777.68	12.92	1619	66.37	-3.45	5.78
R₂-C₂H₅-R₄-CH₂NO₂-PBB-153	983.34	42.78	4147	13.86	-2.76	24.70
R₂-C₂H₅-R₄-(CH₂)₂NO₂-PBB-153	855.31	24.19	2383	50.50	-3.19	12.92
R₂-(CH₂)₂NO₂-R₄-C₂H₅-PBB-153	794.56	15.37	2383	50.50	-3.19	12.92
R₂-(CH₂)₂NO₂-R₄-(CH₂)₃NO₂-PBB-153	1523.49	121.22	3651	24.16	-2.81	23.34
R₂-(CH₂)₂NO₂-R₄-(CH₂)₄NO₂-PBB-153	1581.47	129.63	2098	56.42	-3.24	11.59

Fig.3 Infrared vibration intensity of PBB-153 and PBB-153 derivatives

Table 4 Long distance transport and environmental persistence of PBB-153 derivatives

Compound	lgt_1/2(air)	Change rate(%)	lgt_1/2(river)	Change rate(%)
PBB-153	1.92	—	2.82	—
R₂-(CH₂)₃NO₂-PBB-153	1.64	14.64	2.38	15.71
R₂-C₂H₅-R₄-CH₂NO₂-PBB-153	1.35	29.64	2.14	23.97
R₂-C₂H₅-R₄-(CH₂)₂NO₂-PBB-153	1.12	41.93	1.80	36.28
R₂-(CH₂)₂NO₂-R₄-C₂H₅-PBB-153	1.33	30.57	1.93	31.60
R₂-(CH₂)₂NO₂-R₄-(CH₂)₃NO₂-PBB-153	1.26	34.32	1.86	34.11
R₂-(CH₂)₂NO₂-R₄-(CH₂)₄NO₂-PBB-153	1.31	31.56	1.91	32.27

Table 5 Stability and functional parameters of PBB-153 derivatives

Compound	Frequency/cm^-1	Energy gap/a.u.	Change rate (%)	Dissociation enthalpy/ (kJ·mol^-1)	Change rate(%)
PBB-153	20.27	0.192	—	348.49	—
R₂-(CH₂)₃NO₂-PBB-153	12.72	0.186	-3.33	358.02	2.73
R₂-C₂H₅-R₄-CH₂NO₂-PBB-153	18.60	0.188	-1.98	357.68	2.64
R₂-C₂H₅-R₄-(CH₂)₂NO₂-PBB-153	17.91	0.185	-3.77	351.96	0.99
R₂-(CH₂)₂NO₂-R₄-C₂H₅-PBB-153	14.34	0.186	-3.23	359.31	3.10
R₂-(CH₂)₂NO₂-R₄-(CH₂)₃NO₂-PBB-153	12.96	0.189	-1.89	359.31	3.11
R₂-(CH₂)₂NO₂-R₄-(CH₂)₄NO₂-PBB-153	12.78	0.189	-1.87	359.15	3.06

Table 6 Sensitivity coefficient of each parameter of the 2D-QSAR models

Eq.	SC_i	Freq.	a	μ	q⁺	q^-	qH⁺	E_HOMO	E_LUMO	lgP	V	N₂
(3)	y	-50.94	319.73	-130.4	-13.91	-45.23	23.28	-2686.7	82.77	-79.15	429.63	-31.34
(4)	lgIR	0.02	0	-0.05	-0.01	-0.03	-0.04	-0.97	0.05	-0.05	0.31	-0.003
(5)	-lgBCF	-0.14	0	-0.03	0.04	-0.01	0.2	0.07	-0.02	0.04	0	-0.05
(6)	lgLC50	-0.02	0	-0.02	-0.02	-0.004	-0.11	-0.38	0.18	0.02	-0.88	-0.01

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