Chapter 22
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Three-Dimensional Quantitative Structure—Activity Analysis of Steroidal and Dibenzoylhydrazine-Type Ecdysone Agonists 1
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Yoshiaki Nakagawa , Bun-ichi Shimizu , Nobuhiro Oikawa , Miki Akamatsu , Keiichiro Nishimura , Norio Kurihara , Tamio Ueno , and Toshio Fujita 1
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Department of Agricultural Chemistry andRadioisotopeResearch Center, Kyoto University, Kyoto 606-01, Japan Comparative molecular field analysis (CoMFA) was utilized to examine the relationship between structure and insect molting hormone activity of substituted N-t-butyl-N,N'-dibenzoylhydrazines. The CoMFA features well reproduced the structure-activity inferences deduced from a traditional QSAR previously studied. A set of compounds combining dibenzoylhydrazines and structurally different steroidal molting hormones such as 20-hydroxyecdysone was then submitted to the C o M F A . Among a number of superimposition procedures with which the molecular field descriptors are evaluated, the most probable candidates to give reasonable qualities for the structure-activity relationship were selected. This study is regarded to be a preliminary work from which to look for the next direction for the syntheses of better molting-hormone-active compounds.
Steroidal molting hormone, 20-hydroxyecdysone (I), regulates insect metamorphoses. However, the external administration of an excessive amount of the molting hormone-active compounds causes the premature molting of larvae leading to their death (7). Recently, structurally very different dibenzoylhydrazines (II) have been disclosed to be agonists of the molting hormone (2, 3), and tebufenozide (II: X = 3,5Me2, Y = 4-Et) has been commercialized as a selective insecticide, especially against lepidopteran pest insect larvae (4). We have measured the potency of these two types of compounds to promote the incorporation of N-acetylglucosamine into cultured integument fragments from the rice stem borers, Chilo suppresssalis Walker (5-7). For 20-hydroxyecdysone and its steroidal analogs, the potency measured by this procedure has been shown to parallel that measured in terms of the evagination of imaginai discs of Drosophila melanogaster (7), a conventional procedure to estimate the insect molting hormone activity (8\ Because these two types of compounds are believed to share common receptor sites from experimental observations using the receptor preparation from the 3
Current address: EMIL Project, Fujitsu Kansai Systems Laboratory, 2-2-6 Shiromi, Chuo-ku, Osaka 540, Japan 0097-6156/95/0606-0288S12.00/0 © 1995 American Chemical Society In Classical and Three-Dimensional QSAR in Agrochemistry; Hansch, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1995.
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NAKAGAWA ET AL.
Steroidal and Ecdysone Agonists
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i-Bu
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CONNHCO
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HO' H
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ο (D W Figure 1. 20-Hydroxyecdysone (I) and Dibenzoylhydrazines (II). Drosophila Kc cells (3), we have been interested in elucidating the structural factors required for the molting hormone activity which are common to two series of compounds. Previously, we have analyzed quantitatively the index of the molting hormone activity measured using the rice stem borer integument system for a number of dibenzoylhydrazines carrying substituents on the two benzene rings in terms of physicochemical substituent effects (with the traditional QSAR procedure) (6). We have also examined qualitatively the structure-activity relationship of 20hydroxyecdysone and its analogs, in which the structure of the side chain at position 17 of the steroidal skeleton is varied (7). Because these two sets of compounds belong to "entirely" different structural series, it is impossible to combine them as a single set for the traditional QSAR. Moreover, the number of compounds included in the two series is not well balanced. Some forty "systematically" substituted compounds are included in the dibenzoylhydrazines, whereas there are only five steroidal hormones the potency value of which has been measurable. In this chapter, procedures which we took under these circumstances for the structure-activity analyses will be described. We used the comparative molecular field analysis (CoMFA) (9), a variation of the QSAR which enables us to deal with a combined set of structurally different series of compounds. First, we applied the C o M F A procedure to the set of dibenzoylhydrazines. We compared the C o M F A result with that previously obtained from the traditional QSAR, and examined as to whether they are conformable with each other. Then, we attempted to select superimposition procedures of the skeletal structure of dibenzoylhydrazines and the steroidal structure of 20-hydroxyecdysone and its analogs on the basis of intuitive and three-dimensional structural "similarities" as well as the structure-activity information for each series of compounds. The most probable superimposition procedures would be those with which the structural requirements of the combined set of compounds for the molting hormone activity could be elucidated by common patterns of molecular fields surrounding the entire molecule three-dimensionally. Because the C o M F A procedure was not practical to apply to only five steroidal ecdysone agonists, we examined how far the patterns of the molecular fields for dibenzoylhydrazines alone were affected after the steroidal compounds were superimposed. The less affected the molecular field patterns after the superimposition of steroidal agonists, the more "reliable" would be the prediction of the molting hormone activity of dibenzoyl hydrazines and, in turn, that of the combined set of compounds including steroidal ecdysones. Methods Compounds. Dibenzoylhydrazines (II) and 20-hydroxyecdysone (I) and their analogs dealt with in this article are shown in Table I. Substituted dibenzoylhydrazines are classified into two groups, in one of which the monosubstitution is made on the Α-ring and in the other of which the A-ring substituent is fixed as the 2-C1 but the B-ring is mono-substituted. The structure of steroidal molting hormones is indicated in Table II. In addition, we have synthesized a compound in which the carbonyl group adjacent to the r-Bu-amino moiety in In Classical and Three-Dimensional QSAR in Agrochemistry; Hansch, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1995.
CLASSICAL AND THREE-DIMENSIONAL QSAR IN AGROCHEMISTRY
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Table I. Molting Hormone Activity of Dibenzoylhydrazines and Ecdysones p E C (M) Correlation 9 6 6.58 6.48 6.90 6.92 6.74 7.06 6.82 6.65 7.19 7.53 6.80 6.71 6.52 6.33 6.99 7.01 6.24 6.28 5.61 5.58 5.62 5.72 6.94 6.89 6.81 6.68 6.38 6.39 6.19 5.97 4.97 5.18 5.24 5.05 5.95 5.99 5.23 5.25 6.92 7.14 6.60 6.60 6.64 6.77 6.06 6.02 7.00 7.04 5.80 5.71 7.00 7.04 6.76 6.93 6.06 6.24 5.46 5.84 6.85 6.66 7.27 7.38 7.24 7.41 7.46 7.58 6.82 7.02 6.47 6.47 6.56 6.28 7.30 7.24 6.79 6.95 7.43 e 6.64 e 6.39 e 6.36 e 5.55 e 7.11 e 4.78 e 5 0
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Structure II No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45
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H H H 2-C1 H 2-N0 H 2-CH3 H 2-C H 2-OCH3 H 3-F H H 3-C1 H 3-CF3 H 3-NO2 3-CN H H 3-CH3 3-OCH3 H H 4-C1 4-1 H H 4-NO2 4-CN H H 4-CH3 4-OCH3 H 2'-F 2-C1 2-C1 2'-Cl 2'-Br 2-C1 2-C1 2'-CF 2-C1 2'-CH 2-C1 2-OCH3 2-C1 3'-Cl 2-C1 3'-I 2-C1 3'-CF 2-C1 3-NO2 2-C1 3'-CH 2-C1 4'-Cl 4'-Br 2-C1 4'-I 2-C1 2-C1 4'-CF 2-C1 4'-N0 4'-CN 2-C1 4'-CH 2-C1 2-C1 4'-OCH Ponasterone A 20-Hydroxyecdysone Cyasterone Inokosterone Makisterone A Ecdysone Benzyl derivative 2
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Obsd. 6.40 7.51 6.80 6.49
