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Structure-Activity Relationships of Isothiocyanates

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Structure-Activity Relationships of Isothiocyanates [CANCER RESEARCH 54, 4327-4333, August 15, 1994] Structure-Activity Relationships of Isothiocyanates as Mechanism-based Inhibitors of 4-(Methy Initrosamino) -1-(3-py ridy 1)-1-butanone-induced Lung Tumorigenesis in A/J Mice1 Ding Jiao, Karin I. Eklind, Chang-In Choi, Dhimant H. Desai, Shantu G. Amin, and Fung-Lung Chung2 Division of Chemical Carcinogcnesis, Naylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, New York 10595 ABSTRACT duced tumor development in the lung and forestomach and N-nitroso- diethylamine-induced neoplasms in the forestomach in A/J mice (1, A structure-activity relationship study was carried out to identify struc 2). PEITC showed significant inhibitory effects against lung tumor tural features in arylalkyl and alkyl isothiocyanates that are associated with the inhibitory potency of these compounds against lung tumorigen- induction by NNK in both F344 rats and A/J mice (3, 4). PEITC also esis induced in A/J mice by the tobacco-specific nitrosamine 4-(methylni- effectively inhibited W-nitrosobenzylmethylamine-induced esopha- trosamino)-l-(3-pyridyl)-l-butanone (NNK). These features include the geal carcinogenesis in rats (5). However, PEITC showed no effect on alkyl chain length, phenyl substitution, and secondary isothiocyanates. lung tumorigenesis induced by B(a)P in A/J mice (6). Since both The naturally occurring ally! isothiocyanate, phenethyl ¡sothiocyanate, NNK and B(a)P are important tobacco carcinogens and lung cancer is and the synthetic analogues such as 6-phenylhexyl isothiocyanate, 8-phe- attributed to tobacco usage (7), further development of more effective nyloctyl isothiocyanate, 10-phenyldecyl isothiocyanate, 1,2-diphenylethyl isothiocyanate, 2,2-diphenylethyl isothiocyanate, and alkyl isothiocyanates chemopreventive agents in the isothiocyanate family is warranted for (with 1-hexyl, 2-hexyl, and 1-dodecyl as alkyl moieties) were assayed in the prevention of lung cancers (8-11). mice for their tumor inhibitory potential. The isothiocyanates were given We have previously shown that synthetic analogues of PEITC with in corn oil by gavage at doses of either 0.04, 0.1, and 0.2 juniol or 1 and 5 a longer alkyl chain length, up to 6 carbons as in PHITC, possess /imol 2 h prior to a single i.p. injection of 10 jumol NNK. Mice were greater inhibitory activity against NNK-induced lung tumors in A/J sacrificed 16 weeks later and lung adenomas were counted. At 0.2 /¿mol, mice (12). These natural and synthetic isothiocyanates are potent 8-phenyloctyl isothiocyanate and 10-phenyldecyl isothiocyanate were competitive inhibitors of cytochrome P-450 isozymes in mouse lung stronger inhibitors than the previously tested 6-phenylhexyl isothiocya microsomes that are responsible for the metabolic activation of NNK nate, but the difference in potency was not obvious at the lower doses. At to methylating and pyridyloxobutylating species (13-15). Inhibition both 1 and 5 /xmol, ally! isothiocyanate was inactive, while the other five of the metabolic activation of NNK reduces the formation of O6- synthetic isothiocyanates were considerably more potent than phenethyl isothiocyanate. In the alkyl isothiocyanate series, 2-hexyl isothiocyanate methylguanine and consequently decreases the number of neoplasms was more potent than 1-hexyl isothiocyanate, while 1-dodecyl isothiocya in the lungs of NNK-treated A/J mice (3, 12). The greater inhibitions nate was the most potent at 1 itmol, reducing tumor multiplicity in the by arylalkyl isothiocyanates with a longer alkyl chain are qualitatively group treated with NNK alone from 11.1 to the background level. Also, correlated with the decreasing level of O6-methylguanine in the DNA 1,2-diphenylethyl isothiocyanate appeared to be a stronger inhibitor than of lung tissues (12). Consistent with these observations, in vitro 2,2-diphenylethyl isothiocyanate. In this study we have shown that the studies have shown that increasing the alkyl chain length enhanced the phenyl moiety is not essential for the inhibitory activity since alkyl iso binding affinity of isothiocyanates to cytochrome P-450 isozymes, thiocyanates exhibit strong inhibitory effects against lung tumorigenesis. We have also shown that secondary isothiocyanates possess a higher which resulted in greater inhibition of NNK metabolism (15). It has potency than their structural isomers bearing a primary isothiocyanate. been suggested that the increased lipophilicity of the longer chain From results of this study and of seven previously studied isothiocyanates, analogues enhances the binding affinity of the isothiocyanates to we conclude that the observed inhibitory potency of isothiocyanates in the cytochrome P-450 isozymes (12). Factors such as chemical stability, A/J mouse lung tumor model is correlated with their partition coefficients metabolism, absorption, and molecular geometry of these isothiocya (log /') and the pseudo first order rate constants for the reaction of nates may also play a role in the relative inhibitory potency of these isothiocyanates toward glutathione (A,,,,J. These results reveal that both compounds. Since the major metabolic pathway of isothiocyanates in high lipophilicity and low reactivity of isothiocyanates are important for rodents and humans proceeds via conjugation with GSH (16-18), inhibitory activity toward NNK-induced lung tumorigenesis. These obser vations provide a structural basis for the discovery of more effective their chemical reactivity toward GSH would seem to be important for chemopreventive agents. in vivo potency. The identification of the structural features of iso thiocyanates is important to explain their inhibitory efficacy and to guide the design of more effective chemopreventive agents. Our goals INTRODUCTION in this study were: (a) to determine the optimal chain length for Naturally occurring isothiocyanates of cruciferous origin have been maximal tumor inhibition by testing synthetic arylalkyl isothiocya shown to protect against tumorigenesis induced by environmental nates with longer alkyl chain lengths than those previously assayed; carcinogens such as polycyclic aromatic hydrocarbons and nitro- (b) to examine other structural features that are critical to the inhib samines in rodents (1-3). For example, BITC3 inhibited B(o)P-in- itory activities by replacing the aromatic moiety with allyl and alkyl groups, by increasing the number of aromatic rings, or by including Received 3/25/94; accepted 6/6/94. secondary isothiocyanates; (c) to correlate lipophilicity and chemical The costs of publication of this article were defrayed in part by the payment of page reactivity of isothiocyanates with their relative inhibitory potency in charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1This work was supported by Grant CA 46535 from the National Cancer Institute. cyanate, PHITC, 6-phenylhexyl isolhiocyanate; POITC, 8-phenyloctyl isothiocyanate; This is Paper 19 in the series. "Dietary Inhibitors of Chemical Carcinogenesis." PDITC, 10-phenyldecyl isothiocyanate; OPBITC, 4-oxo-4-(3-pyridyl)bulyl isothiocya 2 To whom requests for reprints should be addressed. nate; HITC, 1-hexyl isothiocyanate; 2HITC, 2-hexyl isothiocyanate; DDITC, 1-dodecyl ' The abbreviations used are: BITC, benzyl isothiocyanale; NNK, 4-(methylnitro- isothiocyanate; 12DPEITC, 1,2-diphenylelhyl isothiocyanate; 22DPEITC, 2,2-diphenyl samino)-l-(3-pyridyl)-l-butanone; B(a)P, benzo(a)pyrene; AITC, allyl isothiocyanate; ethyl isothiocyanate; GSH. glutathione; HPLC. high performance liquid chromalography; PITC, phenyl isothiocyanate; PEITC, phenethyl isothiocyanate; PPITC, 3-phenylpropyl DCI, desorption chemical ionization; NMR, nuclear magnetic resonance; m, multiplet; t, isothiocyanate; PBITC, 4-phenylbutyl ¡solhiocyanate; PPelTC, 5-phenylpentyl isothio- triplet. 4327 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1994 American Association for Cancer Research. CHEMOPREVENTIVE ACTIVITIES. LIPOPIIIIJCITY. AND REACTIVITY order to establish a convenient guide for predicting their inhibitory which is consistent with the M+ 1 of the molecular formula C|5H,|NS (cal activities against lung tumorigenesis (Figure 1). culated, 247.405). 'H-NMR (360 MHz, CDCI,, 6 in ppm, tetramethylsilane as internal reference): 0 1.30-1.45 (m, 8H), 1.55 - 1.75 (m, 4H), 2.60 (t, J = 7.6 Hz, 2H), 3.50 (t, J = 6.6 Hz, 2H), 7.18-7.32 (m, 5H). "C-NMR (92.52 MHz, MATERIALS AND METHODS CDCI,, S in ppm, tetramethylsilane as internal reference): 8 26.51, 28.70, Animals. Female A/J mice were obtained from The Jackson Laboratory 29.11, 29.22, 29.93, 31.39, 35.92, 45.03, 125.59, 128.23, 128.38, 129.61 (Bar Harbor, ME). The mice were fed the semipurified diet AIN-76A with 5% (-NCS), 142.75. The DCI-mass spectrometry of PDITC showed a base peak at corn oil (Dyets, Bethlehem, PA) and were maintained under the following mie 276, which is consistent with the M + l of the molecular formula standard conditions: 20 ±2°C(SD), 50 ±10% relative humidity, and a 12-h C^H^NS (calculated, 275.4ft). 'H-NMR: «1.30-1.45 (m, 12H), 1.55-1.75 light. 12-h dark cycle. Animals were used in bioassay at 7 weeks of age after (m, 8H), 2.70 (t, J = 7.6, 2H), 3.5 (t, J = 6.6, 2H), 7.18-7.32 (m, 5H). 13C-NMR: 26.54, 28.77, 29.27, 29.35, 29.40, 29.40, 29.94, 31.49, 35.96, 45.05, 2 weeks of quarantine. Instrumentation. A HPLC system equipped with an automatic gradient 125.56, 128.21, 128.38, 129.59 (-NCS), 142.87. controller, two Model 501 pumps, and a Waters 990 photodiode array detector Pulmonary Adenoma Bioassay in the A/J Mouse. The single-dose model in conjunction with a 4.6 x 250-mm Partisi! 5 ODS-3 reverse-phase C|K for NNK lung tumor induction in the A/J mouse was used in this study (21). analytical column (Whatman, Clifton, NJ) was used in the determination of the As an extension of the previous bioassay with PHITC, POITC, and PDITC capacity factor k' of isothiocyanates.
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