Synthesis, Biological Activities, and Quantitative Structure–Activity Relationship (QSAR) Study of Novel Camptothecin Analogues

In continuation of our program aimed at the development of natural product-based pesticidal agents, three series of novel camptothecin derivatives were designed, synthesized, and evaluated for their biological activities against T. Cinnabarinus, B. brassicae, and B. xylophilus. All of the derivatives showed good-to-excellent activity against three insect species tested, with LC50 values ranging from 0.00761 to 0.35496 mmol/L. Remarkably, all of the compounds were more potent than CPT against T. Cinnabarinus, and compounds 4d and 4c displayed superior activity (LC50 0.00761 mmol/L and 0.00942 mmol/L, respectively) compared with CPT (LC50 0.19719 mmol/L) against T. Cinnabarinus. Based on the observed bioactivities, preliminary structure–activity relationship (SAR) correlations were also discussed. Furthermore, a three-dimensional quantitative structure–activity relationship (3D-QSAR) model using comparative molecular field analysis (CoMFA) was built. The model gave statistically significant results with the cross-validated q2 values of 0.580 and correlation coefficient r2 of 0.991 and rpred2 of 0.993. The QSAR analysis indicated that the size of the substituents play an important in the activity of 7-modified camptothecin derivatives. These findings will pave the way for further design, structural optimization, and development of camptothecin-derived compounds as pesticidal agents.

[1]  Gang Feng,et al.  Evaluation of insecticidal activity of camptothecin analogs against Brontispa longissima , 2014, Medicinal Chemistry Research.

[2]  Jin-Ying Tian,et al.  Design, synthesis and potent cytotoxic activity of novel podophyllotoxin derivatives. , 2013, Bioorganic & medicinal chemistry.

[3]  Yanning Zhang,et al.  Characterization of DNA Topoisomerase-1 in Spodoptera exigua for Toxicity Evaluation of Camptothecin and Hydoxy-Camptothecin , 2013, PloS one.

[4]  Wen-Qun Li,et al.  Antifeedant Activity of Camptothecin and its Semisynthetic Derivatives Against Spodoptera litura (Fabricius) (Lepidoptera: Noctuidae) Larvae , 2012 .

[5]  Zhongshan Cheng,et al.  The Utility of Camptothecin as a Synergist of Bacillus thuringiensis var. kurstaki and Nucleopolyhedroviruses Against Trichoplusia ni and Spodoptera exigua , 2012, Journal of economic entomology.

[6]  Li-xia Xiong,et al.  Synthesis and insecticidal activities of novel anthranilic diamides containing acylthiourea and acylurea. , 2012, Journal of agricultural and food chemistry.

[7]  Charles L Cantrell,et al.  Natural products as sources for new pesticides. , 2012, Journal of natural products.

[8]  A. Kamel,et al.  Insecticide residues in pollen and nectar of a cucurbit crop and their potential exposure to pollinators. , 2012, Journal of agricultural and food chemistry.

[9]  Yanning Zhang,et al.  Effects of camptothecin and hydroxycamptothecin on insect cell lines Sf21 and IOZCAS-Spex-II. , 2012, Pest management science.

[10]  D. Hollomon.  Do we have the tools to manage resistance in the future? , 2012, Pest management science.

[11]  Ying-Qian Liu and.  Synthesis and Insecticidal Activities of Novel Spin-Labeled Derivatives of Camptothecin. , 2012 .

[12]  Zhang Li-qin.  Nematocidal activity against pine wood nematode (Bursaphelenchus xylophilus) of 7-C-substituted 20-(S)-camptothecins , 2011 .

[13]  Wang Wenxiang,et al.  Induced apoptosis of camptothecin in Spodoptera frugiperda Sf9 cells. , 2011 .

[14]  Zhan‐qian Song,et al.  Synthesis and antitumor activities of unsymmetrically disubstituted acylthioureas fused with hydrophenanthrene structure , 2011, Medicinal Chemistry Research.

[15]  Ying-Qian Liu,et al.  Synthesis of novel derivatives of camptothecin as potential insecticides , 2010 .

[16]  Liqin Zhang,et al.  Insecticidal Activity of Camptothecin Against Nilaparvata lugens, Brevicoryne brassicae, and Chilo suppressalis , 2010, Journal of economic entomology.

[17]  Li-xia Xiong,et al.  Design, synthesis and insecticidal activity of novel phenylpyrazoles containing a 2,2,2-trichloro-1-alkoxyethyl moiety. , 2010, Journal of agricultural and food chemistry.

[18]  D. Stanley,et al.  Natural compounds for pest and weed control. , 2009, Journal of agricultural and food chemistry.

[19]  Charles L Cantrell,et al.  Natural products in crop protection. , 2009, Bioorganic & medicinal chemistry.

[20]  Zhang Liqin,et al.  Insecticidal effect of camptothecin against Nilaparvata Lugens, Brevicoryne Brassicae and Chilosuppressalis Walker. , 2009 .

[21]  Qingshan Li,et al.  Design, synthesis, bioactivity, and structure-activity relationship (SAR) studies of novel benzoylphenylureas containing oxime ether group. , 2008, Journal of agricultural and food chemistry.

[22]  K. Togashi,et al.  The nematocidal activity and the structure–activity relationships of stilbenes , 2007, Natural product research.

[23]  S. Sukumar,et al.  Benzoylphenylurea sulfur analogues with potent antitumor activity. , 2006, Journal of medicinal chemistry.

[24]  Hai Huang,et al.  A novel class of potent influenza virus inhibitors: polysubstituted acylthiourea and its fused heterocycle derivatives. , 2006, Bioorganic & medicinal chemistry letters.

[25]  Y. Kuai.  Toxicities of Novel Insecticide Chlorfenpyr Against Several Insects in Lab , 2006 .

[26]  Lisa G. Neven,et al.  BOTANICAL INSECTICIDES , DETERRENTS , AND REPELLENTS IN MODERN AGRICULTURE AND AN INCREASINGLY REGULATED WORLD , 2005 .

[27]  F. Zunino,et al.  Current status and perspectives in the development of camptothecins. , 2002, Current pharmaceutical design.

[28]  R. G. Hall,et al.  Synthesis and structure-activity relationships of benzophenone hydrazone derivatives with insecticidal activity. , 2001, Pest management science.

[29]  L. Crombie.  Natural product chemistry and its part in the defence against insects and fungi in agriculture , 1999 .

[30]  A. Terry,et al.  Natural products as a source of agrochemicals and leads for chemical synthesis , 1993 .

[31]  S. Sawada,et al.  Chemical modification of an antitumor alkaloid camptothecin: synthesis and antitumor activity of 7-C-substituted camptothecins. , 1991, Chemical & pharmaceutical bulletin.

[32]  W. S. Abbott,et al.  A method of computing the effectiveness of an insecticide. 1925. , 1925, Journal of the American Mosquito Control Association.

[33]  J. Hollingshaus.  Inhibition of mitochondrial electron transport by hydramethylnon: a new amidinohydrazone insecticide , 1987 .

[34]  A. Bořkovec.  Control and management of insect populations by chemosterilants. , 1976, Environmental health perspectives.

[35]  A. Demilo,et al.  Camptothecin, a potent chemosterilant against the house fly. , 1974, Journal of economic entomology.

[36]  A. McPhail,et al.  Plant Antitumor Agents. I. The Isolation and Structure of Camptothecin, a Novel Alkaloidal Leukemia and Tumor Inhibitor from Camptotheca acuminata1,2 , 1966 .