quantitative structure-activity relationships (qsar) of trimedlure isomers

Journal of Chemical Ecology, Vol. 19, No. 7, 1993

QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS (QSAR) OF TRIMEDLURE ISOMERS

J .D. W A R T H E N , JR., I '* W . F . S C H M I D T , e R.T. C U N N I N G H A M , 3 A.B. D E M I L O , I and G.L. F R I T Z 1'4

~ USDA, ARS, Insect Chemical Ecology Laboratory, BARC-West

2USDA, ARS, Nonruminant Animal Nutrition Laboratory, BARC-East Beltsville, Maryland 20705

3USDA, ARS, Tropical Fruit & Vegetable Research Laboratory Hilo, Hawaii 96720

(Received October 13, 1992; accepted February 9, 1993)

Abstract--Trimedlure (tert-butyl 4- and 5-chloro-cis- and trans-2-methylcy- clohexane-l-carboxylate), a mixture of eight isomers, is used as an attractant for detecting and monitoring the male Mediterranean fruit fly. This paper reports the quantitative structure-activity relationship (QSAR), via CHEM- X, of the eight purified isomers (racemic mixtures) of trimedlure. The relationship between structure and attractiveness is demonstrated by utilizing male medfly field catch on day 0 of the individual isomers vs. several molecular descriptors: volume, surface area, a torsion angle, and an interatomic distance.

Key Words--Trimedlure, medfly, Ceratitus capitata, attractancy, quantitative structure-activity relationship, QSAR, CHEM-X, linear regression.

INTRODUCTION

Trimedlure (TML) , tert-butyl 4- and 5-chloro-cis- and t rans-2-methylcyclo-

hexane- l -carboxyla te , is a synthetic mixture of eight isomers (each of which is a racemic mixture) that is used as an attractant for detect ing and moni tor ing the

male medfiy, Ceratitis capitata (Wiedemann) . The medfly is a worldwide pest

o f fruits, nuts, and vegetables (Hagen et al . , 1981; Jackson and Lee, 1985). Commerc ia l T M L is prepared by a four-step procedure (Beroza et al . , 1961)

*To whom correspondence should be addressed. 4 Present address: Technical Resources Incorporated, 1000 6th Street #315, SW, Washington, D.C. 20024.

1323

0098-0331/93/0700-1323507.00/0 �9 1993 Plenum Publishing Corporation

1 3 2 4 WARTHEN ET AL.

that results in a preponderance (90-95 %) of four trans isomers (McGovern et al., 1986) where the trans designation refers to the diequatorial relationship between the vicinal 1-carboxylic ester group and the 2-methyl group (Figure 1). The four t r a n s - T M L isomers are arbitrarily designated A, B1, B2, and C (McGovern and Beroza, 1966) with the chlorine atom in the 4- or 5-position being either equatorial or axial (Warthen et al., 1988). The remaining 5-10% of commercial TML consists of four cis isomers (Figure 1), arbitrarily designated V, W, X, and Y (McGovern et al., 1986; Leonhardt et al., 1982); V, W, and X are shown with a 1-carboxyl-2-methyl axial-equatorial conformation (McGovern et al., 1986), and Y (McGovern et al., 1986; Warthen et al., 1987) is shown with a 1-carboxyl-2-methyl equatorial-axial conformation.

The gas chromatographic (GC) separation of these eight isomers (Leonhardt et al,, 1982; Warthen and McGovern, 1986a; Beroza and Sarmiento, 1964) and the stereochemical, structural assignments of each of the trans (McGovern and Beroza, 1966) and cis isomers (McGovern et al., 1986) have been reported. The semipreparative high-performance liquid chromatographic (HPLC) separation of the four t r a n s - T M L isomers (Sonnet et al., 1984) and the analytical HPLC separation of the four cis isomers (Warthen and McGovern, 1986b) preceded the subsequent semipreparative HPLC separation of all eight TML isomers (Warthen and McGovern, 1988). These separations made possible the isolation of sufficient quantities of all eight isomers of TML to determine relative attractiveness in the field (McGovern et al., 1990) (Figure 2). Although the most attractive trans isomer is TML-C (McGovern et al., 1966, 1987), or more

R 4 Rsj_ ~ R3

R674 6 _ RT~, **''f~ R I

FIc. 1. The trans-(A, B1, B2, C) and cis- (V, W, X, Y) TML isomers (calculated lowest energy conformers). TML-A: R 2 = CO2t-Bu, R 3 = C H 3, R 8 = C I , R I = R 4 = R 5 = R 6 = R 7 = H ; T M L - B I : R 2 = C O 2 t - B u , R 3 = C H 3 , R 7 = CI , R j = R 4 = R 5 = R 6

= R 8 = H; TML-B2: R 2 = CO2t-Bu, R 3 = C H 3 , R 6 = C I , R 1 = R 4 = R 5 = R 7 =

R 8 = H ; T M L - C : R 2 = C O z t - B u , R 3 = C H 3, R 5 = C1, R I = R 4 = R 6 = R 7 = R 8 =

H; TML-V: R I = CO2t-Bu, R 3 = C H 3 , R 7 = C I , R 2 = R 4 = R 5 = R 6 = R 8 = H ;

T M L - W : R I = C O 2 t - B u , R 3 = C H 3 , R 5 = C1, R 2 = R 4 = R 6 = R 7 = R 8 = H ;

T M L - X : R j = C O 2 t - B u , R 3 = C H 3, R 6 = C I , R 2 = R 4 = R 5 = R 7 = R 8 = H ;

T M L - Y : R 2 = C O 2 t - B u , R 4 = C H 3, R 7 = CI , R ~ = R 3 = R 5 = R 6 = R 8 = H .

TRIMEDLURE ISOMERS 1 3 2 5

,o

N

121 C 0

o

O >,

02

200

100

0 C A Y B1 V X W B2

Trimedlure Isomers

Most active C A Y B1 Least active V X W B2 trans C A B 1 132

cis y V X W

1,2,4 C X W 82 1,2,5 A Y B1 V

FIG. 2. Field medfly catch on day 0 (means of six replicates) of TML isomers (racemic mixtures) (McGovern et al., 1990), and groupings of four TML isomers utilized in Table 4 data.

specifically the IS,2S,4R-TML-C enantiomer, followed by the trans enantiomers 1R,2R,5S-TML-A > 1R,2R,5R-TML-B1 (Sonnet et al., 1984; Doolittle et al., 1991), the individual cis enantiomers have not been biologically evaluated to complete the study on relative attractiveness of TML enantiomers.

Therefore, this paper reports the quantitative structure-activity relationships (QSAR) of only the eight TML isomers (racemic mixtures) rather than the 16 enantiomers and suggests a relationship between molecular descriptors of the isomers and medfly attractiveness.

METHODS AND MATERIALS

Lowest energy conformations of TML isomers were determined using molecular mechanics (Burkert and Allinger, 1982; Clark, 1985) with modified force-field parameters (including Gasteiger charges) of the computer program CHEM-X (January 1991 VAX version, Chemical Design Ltd., Oxford, Eng- land).

Conformational analyses were performed on the TML conformers begin-

1326 WARTHEN ET AL.

ning with the torsion angle (edfg) (Figure 3), then (bcde), and then (abcd) each with an angle interval of every 10 ~ The MM energy of the lowest energy conformer was optimized. Then the three torsion angles were each varied within the 10 ~ window in the same order; if a decrease in the MM energy was observed, iterations were performed to obtain a lower MM energy. This process was continued until a change of 0.5 ~ for any of the three torsion angles no longer

produced any decrease in the MM energy. Dipole moments, interatomic distances, molecular volumes, and surface areas were determined on the final energy-minimized conformers. Correlation analyses (Kilpatrick, 1987; Freund and Walpole, 1980; Hayslett, 1968) of these descriptors vs. medfly catch on day 0 for each isomer (McGovern et al., 1990) were performed for the six

groupings of four TML isomers (Figure 2) and the group of all eight TML

isomers to discover structure-activity relationships. The linear best fit for each analysis, by the method of least squares, was constructed and the R 2 (Kilpatrick, 1987) was calculated.

RESULTS AND DISCUSSION

Two possible conformers (inverted chairs) for each TML isomer were tar-

gets for QSAR. Based upon the MM energies obtained, those in Table 1 are

the calculated lowest energy conformers and the following are MM energies

TABLE 1. MOLECULAR DESCRIPTORS AND MEDFLY CATCH OF CALCULATED LOWEST ENERGY

MM MINIMIZED TML CONFORMERS

Torsion angles (o)1, Surface Medfly Isomer/ MM energy Dipole Mol. vol. area catch

conformation" (kcal/mot) (abcd), (bcde), (edfg) moment (D) (,~ 3), (~.3),. (on day 0) '/

1,2,4-Isomers C/e,e,a -2.712 + 178.94, +3.04, -8.45 0.98 186.39 190.00 143 X/a,e,e -2.755 -178.49 -3.56, +0.72 0.95 186.45 189.26 21 W/a,e,a -2.464 + 179.03, +2.54, +45.42 1.13 186.36 187.90 15 B2/e,e~e -3.139 + 178.94, +3.14, -5.35 1.09 186.15 191.65 11

1,2,5-Iomers A/e,e,a -4.284 - 179.14, -2.70 - 1.29 1.86 186.04 190.04 99 Y/e,a,e -3.097 + 179.3t, + 1.73, +27.00 0.88 186.30 191.22 78 B1/e,e,e -4.309 -179.42, -1.58, +5.88 1.22 186.60 191.81 49 V/a,e,e -4.377 -179.59, -1.49 +0.33 1.16 186.55 189.21 28

"Conformations of Co2/-Bu , CH3, and CI: e = equatorial, bSee Figure 3 for angle designations. "Molecular volume determined with 5 contours/,~, except aMeans from six replicates (McGovem et al., 1990).

a = axial.

for BI at 4.75 contours/,~,.

TRIMEDLURE ISOMERS 1327

(kilocalories per mole) of the calculated highest energy conformers: C/a,a,e -2 .087; X/e,a,a -0 .329; W/e,a,e -1 .946; B2/a,a,a -0 .978; A/a,a,e -3 .650; Y/a,e,a -2 .310; B1/a,a,a -2 .078; V/e,a,a -3 .118. The calculated lowest energy conformers in Table 1 agree with the proposed conformations in the literature (McGovern and Beroza, 1966; McGovern et al., 1986). Inconclusive data on the conformation of TML-W in solution via NMR was suggested by Warthen and McGovern (1988); for the present study, data for the calculated lowest energy conformer of TML-W was used since it represents the conformation in the vapor phase. The remaining calculated lowest energy TML conformers also represent those conformations of the molecule that would predominate in the vapor phase at room temperature in vacuo. This is particu- larly important since these same energy-minimized conformations in the vapor phase at approximately the same temperature would be impinging upon the male medfly antennae, in field tests (Keaau, Hawaii; McGovern et al., 1990); whether or not these minimized conformations would be modified (Liljefors et al., 1985) by the receptor to a higher energy state is unknown, but it seems unlikely due to the energy barrier to the higher energy stable chair conformation. Moreover, attractiveness to the receptor site should depend upon an existing minimal energy conformation in the vapor phase. Any one of many equally probable higher energy conformations are equally unlikely to exist in the vapor phase in abun- dance. Without additional experimental evidence, there is no rational basis for predicting which one of the many higher energy states should interact with the receptor. Since A and B 1 are liquids and B2 and C (the most attractive isomer; McGovem et al., 1990) are solids, volatility of the individual TML isomers was not considered because McGovern et al. (1966) indicated that the attractiveness of the t r a n s - T M L isomers is related more to their stereochemistry than to their volatilities. Volatilities of the c i s - T M L isomers have not been studied, but V is a liquid, Y is a semisolid, and W and X are solids (Warthen and McGovern, 1988); semisolid Y (the most active cis isomer) is more attractive than V (a liquid) (McGovern et al., 1990).

Correlation analyses of the data in Tables 1-3 and several averages of pairs of interatomic distances show some possible relationships concerning structure and attractiveness of TML isomers. Although we were familiar with the limi- tations of using field attractancy data (McGovern et al., 1990) over single cell EAG data (Liljefors et al., 1984), no techniques had been developed for obtain- ing single cell data. The field attractancy data in this paper are means that resulted from six replicates that were statistically analyzed. There are 14 linear correlations of R 2 > 0.905 (Table 4) between physical or molecular descriptors of TML isomers (TML groupings of 4, designated in Figure 2) and medfly attractiveness from 270 attempted correlations or observations. There are two correlations of R 2 > 0.5 [HPLC R t and cosine torsion (edfg); R 2 = 0.592 and 0.517, respectively] with all eight isomers from 45 attempted correlations or

1328 WARTHEN ET AL.

TABLE 2. MOLECULAR, HPLC, R,, AND G L C R t DESCRIPTORS OF CALCULATED LOWEST ENERGY

MM MINIMIZED TML CONFORMERS

Interatomic distance (~.2) GC R~ (min) Isomer/ t Area HPLC R,(min)

conformation" C1-2CHs CI- / O \ ~' / O \ -2CH3 (~x2) '' (silica) J DMS" Supelcowax d

1,2,4-Isomers C/e,e,a 4.552 4.753 3.451 7.443 22.1 17.4 50.7 X/a,e~e 5.220 4.274 3.544 7.540 13.2 17.1 48.6 W/a,e,a 4.553 5.235 3.009 6.824 13.8 17.4 46.7 B2/e,e,e 5.203 6.485 3.525 9.148 18.5 16.6 45.9

1,2,5-1somers A/e,e,a 4.838 5.466 3.592 8.539 20.1 16.7 44.9 Y/e,a,e 4.990 5.382 3.127 7.670 16.7 19.8 56.5 Bl/e,e,e 6.059 5.561 3.494 9.582 14.1 16.6 45.8 V/a,e,e 6.062 4.543 3.543 7.999 12.0 17.1 44.5

"Conformations of CO2t-Bu, CH 3, and CI: e = equatorial, a = axial. ~' / O \ = alcohol oxygen. 'A = 1/2c{b2-[(c 2 + b 2 - a2)/2c] 2} ~/2; interatomic distances in the previous column were used for the scalene triangle.

aWarthen and McGovem (1988). "Warthen and McGovern (1986a).

observations. Thir teen correlations in Table 4 would be expected by random selection with at least an R 2 = 0.905, N = 4 (two for each group of four in Figure 2). Two correlations would be expected with at least an R 2 = 0.5, N =

8. Thus, al though some of the correlations found would occur purely by chance, the majori ty of them are well above their m i n i m u m R 2 for random correlation.

These difficulties are in part due to the reasonably small number of stereoisomers

that have been synthesized. Nevertheless, the results do aid in more complicated and significant correlations.

It was necessary to consider combinat ions of descriptors that influence the

relationship between the structure of all eight T M L isomers and medfly attrac- t iveness. The use of the molecular vo lume-molecu l a r surface area ratio as a descriptor versus medfly attractiveness showed R 2 > 0.905 for groupings of four t r a n s isomers, four c i s isomers, and the most active isomers (CAYB1) (Table 4); even six (four c i s + 1,2,5-A and -B1) of the eight isomers would correlate ( R 2 ~-- 0.682). Inc luding the cosine torsion (abcd) as a modula t ing factor ( f l ) to the molecular vo lume-molecu l a r surface area ratio added more 1 ,2 ,5-numerical weight (Table 4; AYB1V, R 2 = 0.925) to the relationship and

al lowed seven of the eight T M L isomers (all but T M L - W ) to be correlated (R 2 = o.858).

It was found necessary to include an average interatomic distance, [( tCH3- 6C) + (C1-2C__H3)] /2 , tCH3 = atom " a " in Figure 3, as a modula t ing factor


TABLE 3. INTERATOMIC DESCRIPTORS OF CALCULATED LOWEST ENERGY MM MINIMIZED T M L

CONFORMERS

Interatomic TML-C TML-B2 TML-X TML-W TML-A TML-Y TML-B 1 TML-V distance (,~)a (e,e,a)b (e,e,e) (a,e,e) (a,e,a) (e,e,a) (e,a,e) (e,e,e) (a,e,a)

= O - - C I 5.954 6.912 6.170 5.881 4.986 6.242 5.973 5.713 =C--C1 4.816 6.018 4.968 4.947 4.512 5.222 5.171 4.709 =C--3C(aH) 4.150 2.798 2.816 4.173 4.149 4.128 4.152 2.823 C1-- 1C (H_H_H_H_H_H_H_H_H_H) 4.535 4.730 5.608 4.466 2.743 4.379 4.405 4.832 C1--6C(aH) 2.760 4.423 2.753 4.398 3.674 2.863 2.861 2.837 tCH3--6C 5.223 5.169 5.188 5.638 5.105 4.966 5.180 5.178 tCH3--2C 5.034 5.039 5.146 4.895 5.126 5.455 5.064 5.185 tCH3--2CH 3 5.274 5.371 5.388 4.712 5.473 4~847 5.352 5.409 tCH3--6C(aH) 4.636 6.222 6.599 4.545 4.481 4.418 4.577 6.221 / O \ "--6C 3.069 3.028 3.051 3.432 2.978 2.865 3.042 3.048 / O \ --2C 2.955 2.963 3.062 2.835 3.028 3.277 2.971 3.073

/ O \ -- 1C(HH _) 3.344 3.347 3.344 3.242 3.347 3.305 3.347 3.342 tC--6C 4.360 4.330 4.371 4.568 4.299 4.252 4.333 4.354 tC--2C 4.269 4.265 4.347 4.251 4.312 4.471 4.287 4.370 tC--2CH3 4.449 4.509 4.499 4.256 4.548 4.215 4.500 4.508 tC-- IC(H_) 4.453 4.460 4.454 4.393 4.457 4.423 4.459 4.449 2CH3--6C(aH ) 4.178 4.187 4.160 4.205 4.180 2.798 4.184 4.203

atCH3 = atom a in Figure 3; tC = atom b in Figure 3. hConformations of CO2t-Bu, CH 3 and CI: e = equatorial, a = axial. ' / 0 \ = alcohol oxygen.

(f2) to the molecular volume-molecular surface area ratio x (fl) to add more 1,2,4-numerical weight (CB2XW, R 2 = 0.879) for TML-W to the relationship. This resulted in a correlation of the grouping of all eight TML isomers. The constants in f l and 12, which represent the average cosine torsion (abcd) and the average of two interatomic distances, [(tCH3-6C) + (C1-2C__H3)]/2, were optimized. This resulted in an equation of the form Z = AX2y 2, where A = the volume-surface area ratio, X 2 = f l , and i12 = t2. The equation is more specifically designated as

Medfly catch = (molecular volume/molecular surface area)

x [cos abcd + 0.895] 2 x {[(tCH3-6C)+(C1-2CH3)/2]

- 5.221} 2

When the index or independent variable (~3 ) of the eight TML isomers, determined by the right-hand side of this equation, and the dependent variable (medfly catch on day 0 of the eight TML isomers) are analyzed for simple linear regression (Kilpatrick, 1987; Freund and Walpole, 1980; Hayslett, 1968), a regression line is obtained (R 2 = 0.939) with P < 0.01 (Figure 4). Logical input of

1330 WARTHEN ET AL.

TABLE 4. CORRELATION ANALYSES OF MOLECULAR/PHYSICAL DESCRIPTORS OF M M MINIMIZED

T M L CONFORMERS VERSUS MEDFLY CATCH ON DAY 0 OF T M L GROUPING (R 2 IN DESCENDING

ORDER)

TML grouping Descriptor" (isomers) I' R 2 Equation

N = 4, R z > 0.905 from 270 observations, P = 0.05 HPLC R, (silica) Average interatomic [(tC--6C) + (tCH3--2C)]/2 Interatomic / O \ ' - - 1CH Average interatomic [(tC_H3--6C )

+ (tC--2C_H3)]/2 Molecular volume/surface area

Interatomic / O ", --6C HPLC R, (silica) Average interatomic [(tC--6C)

+ (tC--2CH3)]/2 Cosine torsion (abcd)

GLC R,(DMS)

Average interatomic [(tCH3--6C) + (= C--C1)]/2 Molecular volume/surface area Molecular volume/surface area Average interatomic [(tCH3--6C)

+ (CI -- / 3'0 \ )]/2 N = 8, R 2 > 0.5 from 45 observations, P = 0.05

HPLC R,(silica)

Cosine torsion (edfg)

1,2,5 (AYBIV) 0.983 Y = -76.213 + 8.8848X cis (YVXW) 0.981 Y = 2555.4 + 542.23X cis (YVXW) 0.972 Y = 4828.3 - 1437.3X cis (YVXW) 0.962 Y = 930.71 - 186.2X

trans (CAB1B2) 0.961 Y = -1.1695 • 104 + 1.2060 • 104X

cis (YVXW) 0.957 Y = 982.52 - 315.88X MA (CAYB1) 0.943 Y = -105.7 + 10.812X cis (YVXW) 0.928 Y = 1291.8 - 286.97X

1,2,5 (AYBIV) 0.925 Y = -444.66 - 538.17X

cis (YVXW) 0.919 Y = -339.94 + 21.074X

LA (VXWB2) 0.919 Y = 149.72 - 25.058X cis (YVXW) 0.916 Y = 3747.6 - 3771.3X MA (CAYB1) 0.910 Y = -9473.0 + 9792.8X trans (CAB1B2) 0.909 Y = 924.81 - 158.22X

(CAYBIVXWB2) 0.592 Y = -107.97 + 10.021X

(CAYB1VXWB2) 0.517 Y = 76.525 - 60.738X

"Data from Tables 1-3; tC = atom b in Figure 3; tCH3 = atom a in Figure 3. ~'TML grouping from Figure 2; MA = most active; LA = least active (McGovem et al., 1990). ' / O \ = alcohol oxygen.

d e s c r i p t o r s b a s e d o n c h e m i s t r y w a s u t i l i z e d to d e t e r m i n e t h e i n d e x o r i n d e p e n -

d e n t v a r i a b l e f o r t h e x a x i s , r e s u l t i n g in a t y p e o f p r i n c i p a l c o m p o n e n t s a n a l y s i s .

T h e r e f o r e , s i n c e s t e p w i s e m u l t i p l e r e g r e s s i o n ( T o p l i s s a n d E d w a r d s , 1979 ; D u n n

e t a l . , 1984) w a s n o t s p e c i f i c a l l y u s e d , it is n o t p o s s i b l e ( H a n s c h , 1991) to

e v a l u a t e t h e p r o b a b i l i t y f o r t h e c h a n c e f i t t ing o f t h e f inal e q u a t i o n e v e n t h o u g h

t h e s i m p l e c o r r e l a t i o n s d i d p l a y s o m e ro le in t h e s e l e c t i o n o f t h e d e s c r i p t o r s to

b e u s e d . W e b e l i e v e t h a t t h e o b s e r v e d i n c r e a s e o f R 2 f r o m 0 . 5 9 2 to 0 . 9 3 9 is

m u c h g r e a t e r t h a n w h a t w o u l d b e e x p e c t e d b y c h a n c e a l o n e .

T h e a b o v e e q u a t i o n r e l a t e s m o l e c u l a r d e s c r i p t o r s ( ~ 3 ) w i t h m e d f l y c a t c h

o f t h e e i g h t T M L i s o m e r s ( r a c e m i c m i x t u r e s ) . T h e s t r u c t u r e - a c t i v i t y r e l a t i o n s h i p


TML-C (trans-l,2,4)

axC l~ . �82 "~ a

mos t a t t r a c t i v e

TML-A (trans-l,2,5)

TML-Y (cis.1,2,5)

ax 0 !

TML-B1 (trans-l,2,5)

�9 e i g

FI~. 3. Calculated lowest energy MM minimized TML conformers with rotated space-

filled equivalents; attractiveness to male medfly is C > A > Y > B1 > V > X > W > B2, (McGovem et al., 1990).

1332 WARTHEN ET AL.

TML-V (cjs-1,2,5)

TML-X (cis-1,2,4)

!

TML-W (cis.1,2,4) ~ axCI

la x g

TML-B2 (trans.1,2,4)

least attractive

. J

FIG. 3. Continued

T R I M E D L U R E I S O M E R S 1333

200 -. ~ ]

180- Y 12"804+1"2897x105 X

S " ~, 140

s 120 - E: 0 100-

o u ~ 80 ~ m o ~ . 60

"1~ 4O

~ x 213 - - JR 2 * W

0.0 0.2 0.4 0.6 0.8 1.0 1.2 ~3 -3

A ( x l 0 ) (Mo lecu la r Vo lume /Sur face Area) x f l x f2

FIG. 4. Linear regression (R 2 = 0.939, N = 8, P < 0.01) of medfly catch on day 0 (means of six replicates) of eight TML isomers (racemic mixtures) (McGovem et al., 1990) versus [(molecular volume/molecular surface area) x fl x f2] (~3) of calculated lowest energy MM minimized TML conformers, fl = [cos abcd + 0.895]2; t'2 = { [(tC H3-6C) + (C1-2C H3)/2] - 5.221 } 2.

of this series of compounds follows: The molecular volume-surface area of this series of compounds represents a molecular size-shape ratio, which, when varied > or <0 .981 , in combination with fl and f2, no longer will impinge the medfly antennae correctly for attractancy. The term fl (cos torsion abcd) and the first distance of f2 (tC_ H3-6C) define the orientation of the tert-butyl ester with respect to the C = O moiety and the cyclohexane ring, while the second distance of f2 (C1-2CH3) limits the spatial relationship requirement of these substituents that is necessary for medfly attractancy. These distance descriptors differ for each racemic T M L isomer mixture, but the two enantiomers of that mixture have equivalent distance descriptors.

Observation of the rotated space-filled structures in Figure 3 reveals that the axial position of the 4-C1, the equatorial position of the 2-CH 3, and the 1-equatorial tert-butyl formate are extremely important for medfly attraction. When the C1 is no longer axial or in the 4 position as in TML-B1, activity decreases (Figure 4), and as the tert-butyl formate becomes axial as in TML-V, TML-X, and TML-W (even with an axial C1), medfly attraction decreases even further (Figure 4). TML-B2 is least attractive, probably due to the absence of the axial 4-C1 even though a 1-equatorial tert-butyl formate and an equatorial 2-CH3 are present. These visual observations are closely linked to the descriptors of the eight T M L isomers (Tables 1-3), which appear in the

1334 WARTHEN ET AL.

equation used to calculate the index or independent variable (2~x 3) in the simple linear regression analysis.

CONCLUSIONS

QSAR, via CHEM-X, of TML isomers and examination of data resulted in an equation for the relationship between medfly catch on day 0 and four

molecular descriptors of the eight TML isomers (racemic mixtures). The equation is used to determine the index or independent variable of distance for simple linear regression analysis with the dependent variable of medfly catch; a linear best-fit line results (R 2 = 0.939, P < 0.01). Essentially, medfly catch in the

eight-isomer TML series of compounds is determined by the ratio of molecular volume to surface area with modulation of the molecular surface area by a torsion

angle and an average of two interatomic distances. Future QSAR correlations will involve single-cell studies with racemic TML isomers and enantiomers (when the cis enantiomers become available). These future studies will help to

confirm the present work and lead to a more refined independent variable in our equation with descriptors that will address the asymmetry of the enantiomers.

Acknowledgments--The authors thank Mr. C. Roeder (Computer Specialist, Systems Research Laboratory, Natural Resources Institute), for demonstrated expertise as system manager of the DEC VAX computers that were utilized with the CHEM-X software, Dr. K. Thorpe (Research Ento- mologist, Insect Biocontrol Laboratory, Plant Sciences Institute) and Dr. L.W. Douglass, Depart- ment of Animal Sciences Biometrics Program, University of Maryland/USDA, ARS, Statistical Consulting and Analysis Services for helpful discussions on correlation, regression, and statistics.

REFERENCES

BEROZA, M., and SARMIENTO, R. 1964. Gas chromatographic analysis of insect attractants: Tri- medlure, medlure, siglure, butyl sorbate, cue-lure, methyleugenol. J. Assoc. Off. Agr. Chem. 47:838-841.

BEROZA, M., GREEN, N., GERTLER, S.I., STEINER, L.F., and MIYASHITA, D.M. 196l. New attractants for the Mediterranean fruit fly. J. Agric. Food Chem. 9:361-365.

BURKERT, U., and ALLINGER, N.L. 1982. Molecular Mechanics. ACS Monograph 177. American Chemical Society, Washington, D.C., p. 339.

CLARK, T. 1985~ Computational Chemistry, A Practical Guide to Chemical Structure and Energy Calculations. John Wiley & Sons, New York, p. 332.

DOOL1TTLE, R.E., CUNNINGHAM, R.T., McGOVERN, T.P., and SONNET, P.E. 1991. Trimedlure enantiomers: Differences in attraction for Mediterranean fruit fly, Ceratitus capitata (Wied.) (Diptera: Tephritidae). J. Chem. Ecol. 17:475-484.

DUNN, W.J., III, WOLD, S., EDLUND, U., HELLBERG, S., and GASTEIGER, J. 1984. Multivariate structure-activity relationships between data from a battery of biological tests and an ensemble of structure descriptors: The PLS method. Quant. Struct. Act. Relat. 3:131-137.

FREUND, J.E., and WALPOLE, R.E. 1980. Mathematical Statistics, 3rd ed., Prentice-Hall, Engle- wood Cliffs, New Jersey, p. 419.


HAGEN, K.S., ALLEN, W.W., and TASSAN, R.L. 1981. Mediterranean fruit fly: The worst may be yet to come. Calif. Agric. 35:5-7.

HANSCH, C. 1991. New perspectives in QSAR. Pharmacochem. Libr. 16:3-10. HAYSLETT, H.T., JR. 1968. Statistics Made Simple. Doubleday, Garden City, New York, p. 107. JACKSON, D.S., and LEE, B.B. 1985. Medfly in California 1980-1982. Bull. EntomoL Soc. Am.

31:29-37. KILPATRICK, N. 1987. Business Statistics Using Lotus 1-2-3. John Wiley & Sons, New York,

p. 259. LEONHARDT, B.A., McGOVERN, T.P., and PLIMMER, J.R. 1982. Capillary GC analysis of trimed-

lure, the attractant for the medfly. J. High ResoL Chromatogr. Chromatogr. Commun. 5:430- 431.

LILJEFORS, T., THELIN, B., and VAN DER PERS, J.N.C. 1984. Structure-activity relationships between stimulus molecule and response of a pheromone receptor cell in turnip moth. J. Chem. Ecol. 10:1661-1675.

LILJEFORS, T., THELIN, B., and VAN DER PERS, J.N.C., and LC3FSTEDT, C. 1985. Chain-elongated analogues of a pheromone component of the turnip moth, Agrotis segetum. A structure-activity study using molecular mechanics. J. Chem. Soc. Perkin Trans. 2:1957-1962.

McGOVERN, T.P., and BEROZA, M. 1966. Structure of the four isomers of the insect attractant trimedlure. J. Org. Chem. 31:1472-1477.

McGOVERN, T.P., BEROZA, M., OHINATA, K., MIYASHITA, D., and STEINER, L.F. 1966. Volatility and attractiveness to the Mediterranean fruit fly of trimedlure and its isomers, and a comparison of its volatility with that of seven other insect attractants. J. Econ. Entomol. 59:1450-1455.

McGOVERN, T.P., CUNNINGHAM, R.T., and LEONHARDT, B.A. 1986. cis-Trimedlure: Attraction for the Mediterranean fruit fly (Diptera: Tephritidae) and isomeric structural assignments. J. Econ. Entomol. 79:98-102.

McGOVERN, T.P., CUNN1NGHAM, R.T., and LEONHARDT, B.A. 1987. Attractiveness of trans-trimedlure and its four isomers in field tests with the Mediterranean fruit fly (Diptera: Tephritidae). J. Econ. Entomol. 80:617-620.

McGOVERN, T.P., WARTHEN, J.D., JR., and CUNNINGHAM, R.T. 1990. Relative attraction of the Mediterranean fruit fly (Diptera: Tephritidae) to the eight isomers of trimedlure. J. Econ. Entomol. 83:1350-1354.

SONNET, P.E., McGOVERN, T.P., and CUNNINGHAM, R.T. 1984. Enantiomers of the biologically active components of the insect attractant trimedlure. J. Org. Chem. 49:4639-4643.

TOPLISS, J.G., and EDWARDS, R.P. 1979. Chance factors in studies of quantitative structure-activity relationships. J. Med. Chem. 22:1238-1244.

WARTHEN, J.D., JR., and McGOVERN, T.P. 1986a. GC/FTIR analyses of trimedlure isomers and related esters. J. Chromatogr. Sci. 24:451-457.

WARTHEN, J.D., JR., and McGOVERN, T.P. 1986b. Purification of cis-trimedlure isomers by high- performance liquid chromatography. Chromatographia 21:651-654.

WARTHEN, J.D., JR., and McGOVERN, T.P. 1988. Semi-preparative high-performance liquid chromatographic separation of trimedlure isomers. Chromatographia 25:811-814.

WARTHEN, J.D., JR., WATERS, R.M., and McGOVERN, T.P. 1987. ~3C and nH chemical shift assignments and conformation confirmation of trimedlure-Y via 2-D NMR. Spectrochim. Acta 43:895-899.

WARTHEN, J.D., JR., WATERS, R.M., and McGOVERN, T.P. 1988. ~H/t3C chemical shift correlations in the complex proton pattern of trans-trimedlure isomers. Spectrochim. Acta 44:175- 178.

quantitative structure-activity relationships (qsar) of trimedlure isomers

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