Synthesis analogues of milbemycin and their bioactivity evaluation

Article abstract of DOI:10.1016/j.cclet.2010.06.035

Eight new 13-O-aminocarbonylivermectin aglycones and 4′-O-aminocarbonylivermectin monosaccharide were synthesized from ivermectin aglycone and ivermectin monosaccharide by the selective protection of C₅-OH group. Their bioactivities were evalua

Full text of DOI:10.1016/j.cclet.2010.06.035

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 1391–1394
www.elsevier.com/locate/cclet
Synthesis analogues of milbemycin and their bioactivity evaluation
Jin Hao Zhao a, Ming Hua Ji a,b, Xu Hui Xu a, Jing Li Cheng a, Guo Nian Zhu a,*
a College of Agriculture and Biotechnology, Zhejiang University, Hangzhou 310029, China
b Zhejiang NHU Ltd., Shaoxing 312500, China
Received 12 April 2010
Abstract
Eight new 13-O-aminocarbonylivermectin aglycones and 40-O-aminocarbonylivermectin monosaccharide were synthesized
from ivermectin aglycone and ivermectin monosaccharide by the selective protection of C5-OH group. Their bioactivities were
evaluated against spider mites (Tetranychus cinnabarinus), aphid (Aphis fabae) and orlental armyworm (Mythimma sepatara).
1
Their structures were confirmed by H NMR, MS.
# 2010 Guo Nian Zhu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: 13-O-Aminocarbonylivermectin aglycone; 40-O-Aminocarbonylivermectin monosaccharide; Synthesis; Insecticidal and acaricidal
activities
Recently, macrocyclic lactones play a great role in the pharmaceutical and pesticides [1,2]. Milbemycin, a 16-
membered macrocyclic lactone produced by Streptomyces hygroscopius, are potent miticidal, insecticidal and
anthelmintic compounds [3]. Milbemycin were both environmentally friendly and having efficient and wide biological
activity features. The high intrinsic potency, remarkable biological activity and unique molecular architecture have
attracted the attention of research groups concerning with chemical modification. Generally modification of
milbemycin C13-position group includes: alkylation, acylation, amination and sulfonylation, etc. [4–8]. However,
there have been no reports on N-substituted-13-O-aminocarbonylmilbemycin. Worth noting that, milbemycin and
acylivermectin aglycone have similar structure (Scheme 1). In order to explore this void field, eight novel analogues of
milbemycin have been synthesized (Scheme 2) from 5-O-TBDMS-ivermectin aglycone and 5-O-TBDMS-ivermectin
monosaccharide. Their bioactivity data against spider mites (Tetranychus cinnabarinus), aphid (Aphis fabae) and
orlental armyworm (Mythimma sepatara) were obtained herein for the first time.
As shown in Scheme 2, the key intermediates 2 and 20 were formed by selective protective reaction of C5-OH group
with tert-butyl dimethyl chlorosilane in 82.3% and 83.6% yields, respectively [9,10]. Compounds 1 and 10 were
obtained in the literature method [11,12].
The typical process of synthesis of novel analogues of milbemycin 4a–4d0 was shown as following: the key
intermediate (2, 0.351 g, 0.5 mmol) and triethylamine (0.051 g, 0.5 mmol) were dissolved in dry dichloromethane
(20 mL). And substituted isocyanate (R-NCO) (0.8 mmol) was added dropwise to the mixture at 0–5 8C. The mixture
was stirred at 20–25 8C for 8 h, and quenched with 1% aqueous HCl. The organic layer was washed to neutral with
* Corresponding author.
E-mail address: zhugn@zju.edu.cn (G.N. Zhu).
1001-8417/$ – see front matter # 2010 Guo Nian Zhu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.06.035

1[(Schme_1)TD$FIG] 392
J.H. Zhao et al. / Chinese Chemical Letters 21 (2010) 1391–1394
Scheme 1. Structures of milbemycin and ivermectin aglycone.
water and dried over Na2SO4. After filtration and concentration, the organic residue was purified by silica gel column-
chromatography (ethyl acetate/petroleum ether, 1:2.5, v/v) to give gum (in 70–80% yield). Their structures were
shown in Table 1 (n = 0, compounds: 4a, 4b, 4c, 4d; n = 1, compounds: 40a, 40b, 40c, 40d).
The bioactivity of novel compounds against spider mites (T. cinnabarinus), aphid (A. fabae) and orlental
armyworm (M. sepatara) were evaluated according to the standard method (dipping method in insecticide general
screen) [13]. The biological data were listed in Table 1. As shown in Table 1, the compounds 40a–40d show better
bioactivity than 4a–4d against spider mites (T. cinnabarinus). Interestingly, the compounds 4a–4d show better
bioactivity than 40a–40d against aphid (A. fabae) and orlental armyworm (M. sepatara). Exhilaratingly, the preliminary
[(Schme_2)TD$FIG]
Scheme 2. (a) TBDMS-Cl, imidazole, CH2Cl2/RT; (b) R–N
C O, DMAP, CH2Cl2/RT; (c) PTSA, CH3OH (2%)/RT.

J.H. Zhao et al. / Chinese Chemical Letters 21 (2010) 1391–1394
1393
Table 1
The structures and biological data of new compounds.
Compd.
n
R
Inhibitory rate (0.006 mg/L)
Inhibitory rate (200 mg/L)
Tetranychus cinnabarinus
Aphis fabae
Mythimma sepatara
Ivermectin
–
0
–
57.9
45.2
100
100
100
4a
97.6
[DT$LINE]
4b
4c
0
0
29.8
30.6
77.9
79.1
90.3
100
[DT$LINE]
[DT$LINE]
4d
0
49.2
100
100
[DT$LINE]
40a
40b
40c
1
1
1
55.2
30.8
31.5
89.2
67.8
65.4
97.1
88.5
91.2
[DT$LINE]
[DT$LINE]
[DT$LINE]
40d
1
56.6
100
100
[DT$LINE]
Spiromesifen
Pymetrozine
–
–
–
–
41.0
23.0
98.6
85.0
96.5
88.0
bioassay indicated that the compounds 4d and 40d given an inhibition rate up to 100% against aphid (A. fabae) and
orlental armyworm (M. sepatara) as same as ivermectin. Although the biological activities of these compounds are
near or the same as lead compound, they are higher than pymetrozine and spiromesifen [14], which were the
commercial varieties. Further toxicity evaluation of 4d, 40a, 40d, structural optimization and insecticidal activity about
all of these compounds are well under way.
Acknowledgments
This work is financially supported by National Natural Science Foundation of China (No. 30700532) and the
Science and Technology Project of Zhejiang province (No. 2008C02007-3).
References
[1] P. Sarasola, D.A. Jernigan, D.K. Walker, J. Vet. Pharmacol. Therap. 25 (2002) 265.
[2] E. Rodrigue, S. Peiru, J.R. Carney, Microbiology 152 (2006) 667.
[3] G.H. Baker, S.E. Blanchflower, J.J. Roderich, J. Antibiot. 49 (1996) 272.

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J.H. Zhao et al. / Chinese Chemical Letters 21 (2010) 1391–1394
[4] S. Naito, T. Nanba, Y. Owatari, J. Antibiot. 47 (1994) 233.
[5] P. Ina, S. Anderew, J. Roderick, Tetrahedron Lett. 37 (1996) 4811.
[6] G.H. Baker, J.J. Roderich, N. Hussian, Tetrahedron Lett. 35 (1994) 2381.
[7] K. Sato, T. Tsukiyama, M. Suzuki, WO 9961447 1999-12-2.
[8] N.V. Derek, WO 9522552 1995-8-24.
[9] H. Mrozik, P. Eskola, M.H. Fisher, J. Med. Chem. 25 (1982) 658.
[10] T.A. Blizzard, G.M. Margiatto, H. Mrozik, J. Med. Chem. 35 (1992) 3873.
[11] J.C. Chabala, H. Mrozik, R.L. Tolman, J. Med. Chem. 23 (1980) 1134.
[12] H. Mrozik, P. Eskola, B.H. Arison, J. Org. Chem. 47 (1982) 489.
[13] J.L. Cheng, F.L. Wei, L. Zhu, Chin. J. Org. Chem. 28 (2008) 622.
[14] J.H. Zhao, M.H. Ji, X.X. Hui, et al. Chin. Chem. Lett. 20 (2009) 1307.