Chem. Res. Toxicol. 1994, 7, 68-72
68
Estrogen Quinones: Reaction with Propylamine Dipti Khasnis and Yusuf J. Abul-Hajj* Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455 Received August 13, 1993”
Reaction of propylamine with 2,3-estrone o-quinone (2,3-EQ) and 3,4-estrone o-quinone (3,4EQ) gave a complex mixture of mostly unidentifiable products. Several reaction products were isolated and identified using spectroscopic techniques. With 3,4-EQ, both 1,2- and 1,6-Michael addition reactions were observed in which 4-hydroxyestradiol, an estrogen oxazole, and a violet compound identified as the iminoquinone adduct that was obtained by condensation of one molecule of an estrogen o-aminophenol with the 1,6-Michael addition product of propylamine to 3,4-EQ were identified. Unlike reactions of 3,4-EQ, only 1,2-Michael addition reactions were observed with 2,3-EQ leading to the formation of 2-hydroxyestradiol, two monoiminoquinone compounds, and a bisiminoquinone product.
Introduction Most chemical carcinogens exert their activity either through covalent interaction of a reactive metabolite with DNA in the target organ (1)or by modulating one or more of a variety of biochemical and biological steps related to the process of tumor formation. Carcinogenic hormones are widely believed to belong to the latter group of chemicals because of their proliferative effect on target cells. Estrogens have been shown to induce mammary, pituitary, cervical, and uterine tumors in rats, mice, and guinea pigs (2). Estradiol and other estrogens induce renal carcinoma in 80-100% of Syrian hamsters within 6-8 months (3). Although the exact mechanism for carcinogenesis induced by estrogenic compounds is not fully understood, it is generally believed that metabolic activation of estradiol leading to the formation of catechol estrogens is a prerequisite for its genotoxic activity (4). It has been proposed that the steroid estrogens may generate reactive intermediates, particularly arene oxides (5-8) and quinones/semiquinones, during their metabolism in analogy to the metabolism of aromatic polycyclichydrocarbons which are known to be implicated in carcinogenesis (9). The estrogen o-quinones produced by the oxidation of catechol estrogens by phenol oxidase (IO),prostaglandin H synthetase (II),and cytochrome P-450oxidase (12)have the potential to be cytotoxic and genotoxic. These compounds can undergo one electron redox cycling resulting in the formation of semiquinone, superoxide anion, and hydroxyl radical. Furthermore, they are Michael acceptors and may alkylate cellular nucleophiles as well as macromolecules. Studies from this laboratory have shown that the major pathway for the irreversible binding of estrogens to proteins involves the estrogen o-quinones1 semiquinones and not the estrogen arene oxides (13). Reactions of glutathione and cysteine with the estrogen o-quinones led to the formation of thioether estrogen conjugates (14, 15). More recently, we showed that 3,4estrone o-quinone (3,4-EQ)was capable of inducing specific DNA damage in a human breast cancer cell line (16). Although our knowledge of conjugation of estrogen o-quinones with thiol nucleophiles is well documented,
* Author to whom correspondence should be addressed. e Abstract published in Aduance
ACS Abstracts, December 15,1993.
very little is known about the reactions of amine nucleophiles with estrogen quinones. Recent findings by Kalyanaraman e t al. (17) showed indirect evidence for selective removal of 3,4-estrogen o-quinones through reaction with amino acids and proteins, which led these workers to propose the addition of nucleophiles to the estrogen o-quinone. Several groups studied the reaction “Corey’sReagent”, of 3,5-di-tert-butyl-l,2-benzoquinone, as a synthetic reagent for oxidative deamination of aliphatic amines (18, 19). While these studies provide some information on 1,2-Michaeladdition chemistry, these results do not provide adequate information about the reaction of amines with estrogen o-quinones. To further understand the conjugation chemistry of estrogen o-quinones with amine nucleophiles, we carried out studies on the reactions of 2,3- and 3,4-estrogen o-quinones with propylamine, which is intended as a model compound for lysine, which has been strongly implicated in protein-quinone coupling reactions.
Experimental Procedures Chemicals. Estrone was purchased from Steraloids (Wilton, NH), and all other reagents were obtained from Aldrich Chemical Co. (Milwaukee, WI). The synthesis of the catechol estrogens was carried out as described by Stubenrauch and Knuppen (20). The estrogen o-quinones were synthesized by the oxidation of the catechol estrogens by activated MnOz as described previously in our laboratory (21). The estrogen o-quinones are potentially hazardous and were handled in accordance withNIH Guidelines for the Laboratory Use of Chemical Carcinogens (22). Characterization of Compounds. All of the compoundswere characterized by nuclear magnetic resonance (NMR), UV, and mass spectrometry (MS). Melting points (uncorrected) were taken on a Fisher-Johns apparatus. lH NMR spectra were obtained with a GE-300 MHz NMR spectrometer, and the chemical shift data are reported in parts per million (6) downfield from tetramethylsilane as an internal standard. The IR spectra were obtained on a Nicolet 5DXC FT-IR spectrometer. Ultraviolet spectra were obtained using a Beckman DU-70. Mass spectral data were determined on an AEI MS-30, a VG 7070 E-HF, and a Finnigan MAT 95. Reaction of 3,4-Estrogen +Quinone (1) with n-Propylamine (Figure 1). n-Propylamine (64pL,0.77 mmol) was added to a red-colored quinone (1) solution in CHzClz (5 mL), which instantaneously turned to a dark violet color. The quinone was totally consumed within 5 min, after which evaporation of CH2-
0893-228~/94/2707-OO68$0~.50/0 0 1994 American Chemical Society
Chem. Res. Toxicol., Vol. 7, No. 1, 1994 69
Estrogen Quinones: Reaction with Propylamine
n-propylamine
1
&H,CH,
3
5
2
t
+
t+z&
o 0 &
OH
0
~
6
.t&
.so 4
-0
Figure 1. Products from the reaction of 3,4-estrogeno-quinone with n-propylamine. Cl2 left a solid that showed several spots on TLC that were separated on a silica gel column. Elution of the column with 5 % EtOAc in hexane yielded 2'-ethylestrogenoxazole 3 (15 mg), mp 138-140 OC. Rf = 0.60 in 25% EtOAc in benzene. UV (nm) 242, 272, 281. IR (CHCl3): cm-' 3568, (methanol): A, 3025,1725,1600,1540,1500. 'H-NMR (CDCl3) 6 7.49 (lH, d, J = 8.6 Hz, 2-H), 7.30 (lH, d, J = 8.6 Hz, 1-HI, 3.20-1.50 (15H, m, methylene and methine protons), 2.99 (2H, q, J = 7.9 Hz, -CH2CH3), 1.47 (3H, t, J = 7.9 Hz, -CH2-CH3), 0.95 (3H, 8, 18-CH3). MS mlz: 323.2 (100, M), in agreement with CzlH25N02;294.2 (M - C2H5); 266.2 (M - CsH50); 238.1 (M - C5H9O); 225.1 (M C,J+~O);210.1(M-CTH~~O); 199.1(M-CBHI~O).Further elution of the column with 10%EtOAc in hexane gave 4-hydroxyestrone (2, 25 mg), mp 263-265 "C dec [lit. mp 260-265 "C (20)], Rf = 0.58 in 25% EtOAc in benzene. Elution with 15% EtOAc in hexane furnished a violet compound (4, 15 mg), Rf = 0.74 in 25% EtOAc in benzene. UV (methanol): ,A, (nm) 243.0,315.8, 319.8, and 531.3. IR (KBr): cm-' 3400, 2992, 2952, 2888, 2860, 1735, 1638, 1624, 1586. 'H-NMR (acetone-& 6 6.86 (lH, d, J = 8.7 Hz, 2'-ArH), 6.79 (lH, d, J = 8.7 Hz, 1'-ArH), 5.97 (lH, s, 1-ArH), 3.01-1.38 (35H, m, methylene and methine protons and NH), 2.85 (lH, s, -OH), 0.92 (3H, s, 18-CH3),0.90 (3H, s, 18'CH3), 0.89 (3H, t, J = 8.0 Hz, -CH2-CH3). NH4+ CI MS gave unequivocal data for 4, in agreement with C39HaH204, showing [M + H+] peak at 609 with other fragments at 396, 328 (loo), 323 (13), 303 (13), 286 (701, 272 (8), 270 (6), and 146 (15). Reaction of 2,j-Estrogen *Quinone (5) with n-Propylamine (Figure 2). To a solution of quinone 5 (0.4 g, 1.4 mmol) in CHzCl2 (10 mL), n-propylamine (127 pL, 1.5 mmol) was added at room temp. After 5 min, there was no quinone left (checked by TLC), and the reaction mixture was concentrated under vacuum. Theresidue was dissolvedinmethanol (20mL),acidified with 0.6 N HC1 (2 mL), and stirred at room temperature for 5 min. It was then diluted with water (100 mL) and extracted successively with hexane (3 X 50 mL), ether (2 X 50 mL), and CHzCl2 (2 x 50 mL); dried (Na2S04);and concentrated on a rotor evaporator. The residues from hexane and ether were found to be identical and were mixed prior to separation on a column of silica gel. Elution of the column with 5 % EtOAc in hexane yielded an orange colored solid, [2,3-bis(propylimino)-l(10),4(5),6(7)estratrien-17-oneI(9,5mg), mp 215-217 "C. Rf = 0.62 in 25% EtOAc in benzene. UV (methanol): A,, (nm) 216 (e, 2394), 280 (e, 23841, 398 (c, 388), 432 (e, 393). IR (KBr): cm-l 3300, 2960, 2925, 2854, 1741, 1670, 1615, 1576, 1560. 'H-NMR (CDC13) 6 8.18(1H,d, J - 10.7Hz,6-H),8.08 (lH, d, J =8.3Hz, 1-H), 7.42 (lH,d,J=7.7Hz,4-H),6.72 (lH,d,J =11e0Hz,7-H),3.12(4H, dd, J = 7.8 Hz, -N-CH2), 3.23-1.77 (11H, m, methylene and methine protons), 1.72 (4H, q, J = 8.2 Hz, -CHz-CH3), 1.02 (6H,
&d
Y" CH3
9
Figure 2. Products from the reaction of 2,3-estrogen o-quinone with n-propylamine.
t, J = 8.3 Hz, -CH2-CH3),0.77 (3H, s, 18-CH3). MS mlz: 364.2 (11.1,M), in agreement with CsH32N20;335.1 (M - C2H5); 321.1 (M - C3H7);307.1 (M - C3H50);278.1 (M - C5HeO). Elution of colum with 10% EtOAc in hexane gave impure gum, which was further purified by preparative TLC in 35% EtOAc in benzene to yield pure orange-colored solid, [2-hydroxy-N-propyl-6,7didehydroestrone 3-imineI (8, 10 mg), mp 101-103 "C. Rf = 0.49 in 25% EtOAc in benzene. UV (methanol): A, (nm) 214 (6,29611,256 (e, 26651,360 (e, 16681,492 (e, 437). IR (KBr): cm-' 3400,2960,2927,2a72, i742,i6ia,i602,i575,i509.'H-NMR (CDCl3) 6 6.93 (lH, d, J = 10.7 Hz, 6-H), 6.68 (lH, d, J = 10.7 Hz, 7-H), 6.26 (lH, 8, 4-H), 6.21 (lH, 8, l-H), 4.95 (OH, bs), 3.03 (lH, dd, J = 7.6 Hz, -N=CH), 2.85-1.50 ( l l H ,m, methylene and methine protons), 1.68 (2H, q, J = 7.6 Hz, -CH2-CHa), 1.06 (3H, s, 18-CH3),1.00 (3H, t, J = 8.3 Hz, -CH2-CH3).MS mlz: 323.0 (73.0, MI, in agreement with CzlH%N02: 308.0 (M- CH3); 294.0 (M - C2H5); 266.0 (M- CsH50). Continued elution of the column with 10%EtOAc in hexane gave thecatechol, 2-hydroxyestrone (6, 20 mg), mp 191-193 "C [lit. mp 192-193 "C (20)l. Further elution of the column with 15% EtOAc in hexane gave an impure solid, which was also purified by preparative TLC by running the plate three times in 10% EtOAc in benzene to yield pure pale orange-colored solid, [3-propylimino-l(10),4(5),6(7)-estratrien2,17-dione] (7,5 mg), mp 220-222 "C. Rf = 0.57 in 25% EtOAc (nm) 224 (e, 1836),254 (e, 3407), in benzene. UV (methanol): A, 338 (c, 401). IR (KBr): cm-l3409,3372,2959,2930,2872,1735, 1720,1538,1533,1522. 'H-NMR (CDCls) 6 7.51 (lH, d, J = 9.6 Hz, 6-H), 7.12 (lH, s, 1-H), 7.10 (lH, d, J = 9.6 Hz, 7-H), 6.85 (lH, s, 4-H), 3.21 (2H, t, J = 8.3 Hz, -N-CH2), 3.25-1.80 (llH, m, methylene and methine protons), 1.76 (2H, q, J = 8.3 Hz, -CH2-CH3),1.06 (3H, t, J = 8.3 Hz, -CH2-CH3),0.80 (3H, s, 18CH3). MS mlz: 323.0 (82.7, M), in agreement with C21HzN02; ; 294.0 (M - C2H5); 280.0 (M - c~H,); 266.0 (M - c ~ H ~ o )238.0 (M - CsHgO).
Results and Discussion The reactions of 2,3-EQ and 3,4-EQ with propylamine in methylene chloride were complete within 5 min (as determined by loss of quinone) and resulted in a very
70 Chem. Res. Toxicol., Vol. 7, No. 1, 1994
Khasnis and Abul-Hajj
3
(I)
CH$H
I
i
Me
j
2
CH,CH,
3
10
+
12
1 * n-propylamine
13
A
10
2
Figure 3. Proposed pathway for the formation of products from the reaction of n-propylamine with 3,4-estrogen o-quinone (1). complex mixture. TLC indicated the formation of over 15 compounds with 3,4-EQ and about 10 compounds with 2,3-EQ, the majority in less than 1%yield as well as considerable amounts of polymerized products. As a consequence, only the major products were isolated and characterized by a combination of UV, IR, NMR, and mass spectral data. In the reaction of 3,4-EQ with propylamine, three major products were isolated and purified using a combination of column chromatography and preparative TLC. 2 was found to be identical to a standard sample of 4-hydroxyestrone. The UV spectrum of 3 showed three maxima at 242, 272, and 281 nm. Infrared spectra showed a characteristic absorbance at 3568 cm-' indicating a secondary amine group (23). Proton NMR showed an AB doublet at 6 7.49 and 7.30 (J = 8.6 Hz) corresponding to C-1H and C-2H, a quartet at 2.99, and a triplet at 1.47 assigned to the CH2 and CH3 groups of the ethyl side chain. Mass spectral data showed an M+ ion at mlz of 323 and characteristic fragmentation peaks of steroid nucleus (24) corresponding to (M - C2H5), (M - CSH~O), (M - C~HIOO), and (M-C&20) of mlz 292,238,225and 199,respectively, are due to the fragmentation initiated by benzylic cleavage, whereas (M - C3H5O) and (M - C~H130)of mlz 266 and 210, respectively, are due to the fragmentation initiated by ionization of the carbonyl group. These data support the structure of an oxazole 3, which is consistent with earlier studies obtained from reaction of o-quinones with amines (18,27). The characteristic violet-colored compound suggested that 4 has an iminoquinone chromophore in ita structure. lH-NMR showed the presence of a typical AB doublet at 6 6.86 and 6.79 and a singlet at 5.97 in the aromatic region. The singlets at 6 0.92 (3H) and 0.90 (3H) were assigned to the (2-18and (2-18' methyl protons, whereas the singlet a t 2.85 (lH), which exchanged with D20, was assigned to the phenolic OH. Several methylene and methine protons were observed between 6 3.01 and 1.38, and a triplet at 0.89 (3H) was assigned to the side-chain methyl group.
Mass spectral studies showed an (M + H)+ a t 609.6. The data support the structure of 4. Reaction of 2,3-EQ (5) with propylamine was instantaneous and showed the formation of several products on TLC, four of which were isolated and characterized to be (7), 2-hy3-propylimho-1(10),4(5),6(7)-estratrien-2,17-dione droxy-N-propyl-6,7-didehydroestrone3-imine (8),2,3-bis(propy1imino)-l(10),4(5),6(7)-estratrien-17-one (9), and 2-hydroxyestrone (6). The spectral data are consistent with the structures of 7-9. Figure 3 shows the proposed pathway for formation of 2-4. We assume that the 18-addition of propylamine takes place at the C-3 carbonyl to give 10. A 1,5-proton shift followed by the aromatization of the isomeric Schiff base (11) has now been definitively documented for several o-quinones (19,25,26),which can undergo rearrangement and oxidation by 3,4-EQ resulting in the formation of the oxazole (3) and the catechol (2). While we do not have conclusive evidence that the 1,2-addition of propylamine takes place at the C-3 carbonyl and not at the C-4 carbonyl of 3,4-EQ, we were able to isolate in minute quantities an aminophenol that was not identical to a standard sample of 4-aminoestrone, thus proposing the formation of 13. Figure 3 shows the formation of catechol (2) by either route a or b. The fact that the oxazole (3) was isolated in only 7.5% yield while the catechol (2) was obtained in 18% yield suggests that pathway b may also be an important route for the formation of catechol. Furthermore, this is supported by studies which showed the release of ammonia during the reaction of 3,4-EQ with propylamine. Although several attempts to isolate 14 were not successful, it is proposed as an intermediate based on the isolation and identification of 4. While it is quite conceivable that the Michael addition of propylamine to 3,4-EQcould proceed by either 1,4-or 1,badditionleading to substitution at C-1 or C-2 of 3,4-EQ, respectively, in general, conjugate addition favors the most extended position. Recent studies by Murty and Penning (28)
Estrogen Quinones: Reaction with Propylamine
5
+
n-PrNH2
Me
Me 16 Quinone-methide
15
1,bpmton shift
8
r?’ Me
1
n-PrNHn
9
Figure 4. Proposed pathway for the products from the reaction of n-propylamine with 2,3-estrogen o-quinone (5).
showed that the addition of cysteine to naphthalene-1,2dione (NPQ) proceeds by 1,4-Michaeladdition. However, the NPQ system is significantly different from the 3,4-EQ system since there is no 1,g-extended conjugation in NPQ due to the presence of the aromatic system in ring B of NPQ. Further support for addition at C-2 is based on earlier studies by Jellinck (27) and us (15) in which thiols were found unequivocally to add at C-2 using specifically labeled [ 1-3HI- and [2-3H]-4-hydroxyestrogens.Thus, based on the above results and on the known addition chemistry of thiols to 3,4-EQ (15,27),it is proposed that a 1,6-Michael addition might occur at the C-2 of 3,4-EQ with the amino group of propylamine. Unfortunately, NMR analysis could not differentiate between C-1 and C-2 protons following the Michael addition of amine to 3,4-EQ. The formation of 4 is obtained from the reaction of aminophenol (13) and the addition product (14). Furthermore, the amino group of 13 is proposed to form an enamine with the C-3carbonyl and not the C-4 carbonyl group. This speculation is based on the earlier observation of formation of aminophenol(13) from the proposed Schiff base (ll),as well as the fact that the C-3 carbonyl group is sterically less hindered. Figure 4 shows the proposed pathway for the formation of compounds 7-9. A 1,2-addition of the propylamine to either the C-2 or the C-3 carbonyl results in the formation of a mono enamine. Since the C-3 carbonyl is less sterically hindered, it is proposed that the initial attack of the propylamine takes place at the C-3 carbonyl rather than a t the C-2 carbonyl, resultingin the formation of 15,which can tautomerize, leading to the formation of thep-quinone methide intermediate (16). Oxidation of the quinone methide intermediate by 2,3-EQ results in the formation of 7. While the oxidation of quinone methide intermediates by estrogen quinones has not been documented previously, the enzymatic oxidation of N-acetyldopamine quinone methide has been confirmed by Saul and Sugumaran (29). A 1,bproton shift followed by the aromatization of the Schiff base (7) results in the formation of 8. Further 1,2-addition of propylamine to 7 leads to the formation of 9. Even though we were not able to isolate and identify all the products from the reactions of 2,3-EQ and 3,4-EQwith propylamine, it is interesting to note some major differ-
Chem. Res. Toxicol., Vol. 7, No. 1, 1994 71
ences in conjugation chemistry between the two estrogen quinones. While only 1,2-addition products were isolated from 2,3-EQ, both 1,2- and 1,6-addition reactions were observed from reactions with 3,4-EQ based on the formation of 3 and 4. Furthermore, unlike the enamine (11) formed from the reaction of 3,4-EQ with propylamine (Figure 3), which undergoes rearrangement and oxidation to the oxazole (3), enamines 7-9 did not rearrange to form the corresponding oxazole. Studies by VanderZwan et al. (30)have shown that the formation of benzoxazoles, which requires a l,Zaddition, appears to be specific for 3,5-disubstituted o-quinones while unsubstituted quinones that undergo 1,Caddition remove the possibility for benzoxazole formation. Our studies have shown for the first time that 3,4-disubstituted o-quinones (such as 3,4-EQ)are also capable of benzoxazole formation. Furthermore, the fact that 1,Zaddition to o-quinones occurs does not, a priori, lead to the formation of benzoxazole as demonstrated in our results from the reaction of propylamine with 2,3-EQ. While we do not have a definitive reason for the lack of formation of benzoxazole for 1,2-addition reactions, it is quite possible that the proposed formation of the quinone methide intermediate (Figure 4) may prevent rearrangement of the enamines to the benzoxazole. The results obtained from this investigation clearly show that the estrogen o-quinones catalyze the oxidative deamination of propylamine by 1,2- or 1,6-addition, leading to the formation of a complex mixture of rearrangement products with the resultant release of ammonia. It is quite possible that the carcinogenicity/toxicityas well as the deotoxification of estrogen o-quinones may be, in part, due to their ability to react with proteins. It has been well-documented by us and others that thiols react with estrogen o-quinones by Michael addition, leading to the formation of thioether adducts. Furthermore, addition reactions between lysine and quinones have been implicated in several protein-quinone interactions. For example, the decrease in lysine content of casein following the incubation of caffeoquinone and chlorogenoquinone has been attributed to the addition of the e-amino group of lysine to respective quinone moieties (31, 32). Preliminary studies in our laboratory showed that estrogen o-quinones react with bovine serum albumin leading to the formation of the catechol, suggesting the 1,2-addition of amines followed by rearrangement as shown in Figure 3. Further studies on the reaction of amino acids and proteins with estrogen o-quinones are necessary and underway. Acknowledgment. This research was supported in part by the National Cancer Institute, Grant CA57615.
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