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Specific Estrogen Sulfotransferase (SULT1E1) Substrates and Molecular Imaging Probe Candidates

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Specific Estrogen Sulfotransferase (SULT1E1) Substrates and Molecular Imaging Probe Candidates Specific estrogen sulfotransferase (SULT1E1) substrates and molecular imaging probe candidates Graham B. Colea, Gyochang Keuma, Jie Liua, Gary W. Smallb, Nagichettiar Satyamurthya, Vladimir Kepea, and Jorge R. Barrioa,1 aDepartments of Molecular and Medical Pharmacology and bPsychiatry and Biobehavioral Sciences, David Geffen School of Medicine at University of California, Los Angeles, CA 90095-6948 Communicated by Michael E. Phelps, University of California, Los Angeles, Los Angeles, CA, December 28, 2009 (received for review July 24, 2009) This work focuses on the development of specific substrates for estrogen sulfotransferase (SULT1E1) to produce molecular imaging probes for this enzyme. SULT1E1 is a key enzyme in estrogen homeostasis, playing a central role in the prevention and develop- ment of human disease. In vitro sulfation assays showed alkyl and aryl substitutions to a fused heterocyclic system modeled after β- naphthol (βN), based on compounds that interact with the estrogen receptor, rendered several molecules with enhanced specificity for SULT1E1 over SULT1A1*1, SULT1A1*2, SULT1A3, and SULT2A1. Sev- eral 6-hydroxy-2-arylbenzothiazoles tested demonstrated excel- —V ∕K — K lent affinity max m ratios and specificity for SULT1E1. m values ranged from 0.12–2.36 μM. A strong correlation was ob- served between polarity of the 4′-sustituent on the 2-aryl moiety σ ðV ∕K Þ r ¼ 0 964 Fig. 1. (A) Interplay of estrogen sulfation and estrogen receptor (ER). Tissue (Hammett p) and the log max m ( . ). Substrate sensitiv- levels of E2 are regulated by SULT1E1 and STS, thus, modulating E2 interac- ity is influenced by the acidity of the 6-phenolic group tion with the estrogen receptor (ER). (B): Active site of human SULT1E1 with 1 δ demonstrated by correlating its H NMR chemical shift ( OH) with E2 (Green) bound in the active site. Amino acid residues that form the binding ðV ∕K Þ r ¼ 0 963 the log max m ( . ). Acidity is mediated by the electron pocket are show in Beige (oxygen, Red; nitrogen, Blue; sulfur, Red; and free withdrawing capacity of the 4′-substituent outlined by the correla- water molecures, Cyan) [Modified with permission from (25).© National 13 δ ðV ∕K Þ tion of the C-2 C NMR chemical shift ( C2) with the log max m Institute of Environmental Health Sciences, 2003]. (r ¼ 0.987). 2-[4-(Methylamino)phenyl]-6-hydroxybenzothiazole (2b) was radiolabeled with carbon-11 (11C-ð2bÞ) and used in vivo Three hSULTs can metabolize estrogens: SULT1A1 (EC2.8.2.1), for microPET scanning and tissue metabolite identification. High SULT1E1 (EC2.8.2.4), and SULT2A1 (EC2.8.2.2) (1), but only PET signal was paralleled with the presence of radiolabeled SULT1E1 possesses sufficient affinity for sulfoconjugation of 11 C-ð2bÞ-6-O-sulfate and the SULT1E1 protein detected by western 17β-estradiol (E2)[Km ¼ 5 nM (4)] to allow its inactivation at a blot. Because this and other members of this family presenting concentration range that competes with binding to estrogen specificity for SULT1E1 can be labeled with carbon-11 or fluorine-18, receptors(ER)[KD ¼ 1 nM (4)]. E2 is released from its inactive in vivo assays of SULT1E1 functional activity are now feasible in 3-O-sulfated (E2S) form by steroid sulfatase (STS) (Fig. 1A), an humans. enzyme also widely distributed throughout the body (3). E2 and other estrogens interact with target tissues (or immune molecular imaging probes ∣ positron emission tomography ∣ Pittsburgh cell types) primarily via estrogen receptors (ERα and ERβ). They Compound B ∣ PIB ∣ 18F-Flutemetamol have tissue dependent effects, for example, contributing to bone homeostasis (5), cardiovascular system protection (6), and regu- ytosolic sulfotransferases (SULT enzymes; EC 2.8.2) are lation of inflammation in autoimmune, neurodegenerative, and CPhase II metabolic enzymes that mediate sulfation from a do- other diseases (7). Therefore, estrogen sensitivity depends on nor (3′-phosphoadenosine 5′-phosphosulfate, PAPS) to a variety both the concentration of estrogen receptors as well as of endogenous and exogenous substrates containing aryl alcohol, SULT1E1/STS regulation of the free estrogen in these tissues alkyl alcohol, hydroxylamino, or amino groups (Fig 1A) (1, 2). (8, 9). This role of SULT1E1 (estrogen sulfotransferase or SULTs play an important role in the homeostasis of the body EST) as a “molecular switch” (8) is evident in estrogen sensitive in two ways. First, by sulfoconjugating drugs and xenobiotic com- cancers such as breast and endometrial cancer. In hormone re- pounds for their removal via hepatobilliary and urinary systems; sponsive cancers, an increase in E2 (10), in part resulting from second, by sulfoconjugating and deactivating endogenous active down regulation or loss of SULT1E1, potently stimulates tumor substances [e.g., dopamine (DA), thyroid hormones, and estro- growth. Alternatively, presence of SULT1E1 in the absence of gens], therefore, participating in their regulation both systemically STS leads to lower recurrence rate and longer survival (10–13). and locally in different organs. In mammalian species, SULTs are Several high-impact neurodegenerative diseases are also being found throughout the body in the gut, liver, kidneys, adrenal and examined for interactions with E2 and other estrogen analogs thyroid glands, lungs, reproductive organs, breast tissue, brain, and based on the assumed interaction of the estrogens with the blood (1, 3). More than 65 distinct SULT enzymes, spanning 33 isoforms, have been identified and characterized, 11 of which Author contributions: G.B.C., V.K., and J.R.B. designed research; G.B.C., G.K., J.L., N.S., are human sulfotransferases (hSULTs) (2) found in three families: and V.K. performed research; G.B.C., N.S., V.K., and J.R.B. analyzed data; and G.B.C., SULT1, SULT2, and SULT4. Although human SULTs sulfoconju- G.K., J.L., G.W.S., N.S., V.K., and J.R.B. wrote the paper. gate multiple classes of hydroxylated molecules, they show in- The authors declare no conflict of interest. creased affinity for specific endogenous substrates, for example, 1To whom correspondence should be addressed. E-mail: [email protected]. SULT1A3 for DA, SULT1B1 for thyroid hormones, SULT1E1 This article contains supporting information online at www.pnas.org/cgi/content/full/ for estrogens, and SULT2A and SULT2B for hydroxysteroids. 0914904107/DCSupplemental. 6222–6227 ∣ PNAS ∣ April 6, 2010 ∣ vol. 107 ∣ no. 14 www.pnas.org/cgi/doi/10.1073/pnas.0914904107 Downloaded by guest on October 1, 2021 ER (14, 15), however, estrogen sulfating enzymes (e.g., (Km ¼ 0.03 μMand0.17μM, resp.) all benzothiazoles, SULT1E1) are rarely, if ever, invoked in these experiments. benzoxazole 1e and benzimidazole 1f showed one to two orders In this work a family of SULT1E1 substrates were synthesized of magnitude higher Km values (0.42–2.75 μM and 2.08–19.3 μM, and investigated for sensitivity and specificity by examining their resp.). Methyl (1g) or phenyl substitution (2a) at carbon-2 of the ability to act as substrates with four other common sulfotrans- 6-hydroxybenzothiazole ring lead to 7- and 60-fold increases in ferases: SULT1A1*1, SULT1A1*2, SULT1A3, and SULT2A1. affinity (lower Km) for SULT1E1, resp., over the parent com- It is of great interest to assess the in vivo status of SULT1E1 pound 1d. However, these compounds have parallel Km effects in estrogen target tissues and to determine changes in SULT1E1 with both SULT1A1 isoforms detracting from any possible spec- expression as a result of inflammation, cancer, and neurodegen- ificity trend. eration. Molecular imaging with PET using optimum SULT1E1 specific substrates radiolabeled with a short-lived positron emit- 2-Aryl 6-(and 5-)hydroxybenzothiazoles. The effect of 4′-substitution ting radioisotope such as carbon-11 (t1∕2 ¼ 20.4 min) or fluorine- was examined in enzyme assays with 2-phenyl-6-(and 5-) 18 (t1∕2 ¼ 109.8 min) would offer a sensitive tool for this assess- hydroxybenzothiazoles (Scheme 1, Table 1) against SULT1E1, ment. Identification of patient populations in which SULT1E1 SULT1A1*1, SULT1A1*2, SULT1A3, and SULT2A1 enzymes. expression is elevated or absent would help define unique adju- With the 6-hydroxybenzothiazole derivatives (2a–2d, 2f–2l), there vant cancer therapies symbiotic to estrogen therapies currently in was a correlation between the polarity of the 4′-substitution on use. Considering the antiinflammatory role of estrogen and the the 2-phenyl ring (Hammett σp) and SULT1E1 substrate sensitiv- role of SULT1E1 in regulating estrogen levels (7), it can also V ∕K A ity ( max m) (Fig. 2 ) (17). This is due to the electron-donating be anticipated that identification of SULT1E1 in patients with or withdrawing effects of the 4′-substituents on the acidity of the neurodegenerative diseases would have significant diagnostic 6-arylhydroxyl moiety. To corroborate this interpretation, the 1H value and potential therapeutic connotations. δ NMR chemical shift of the hydroxyl group ( OH) is also tightly ðV ∕K Þ C correlated with the log max m kinetic parameter (Fig. 2 ). Results Furthermore, there is an analogous correlation of the 13C Enzyme Assay Validation. Control reactions were used to confirm δ NMR chemical shift of C-2 ( C2) in these benzothiazoles with the activity and identity of the commercially purchased enzymes. ðV ∕K Þ B the log max m (Fig 2 ). Exceptions to these correlations p-Nitrophenol (PNP) and SULT1A1*1 or SULT1A1*2, E2 and included compounds with large 4′-substituents, such as sulfone SULT1E1, dehydroepiandrosterone (DHEA) and SULT2A1, V ∕K (2k)oracetamide(2g), which have lower max m values and DA and SULT1A3 gave Km values of 0.1 μM, 0.8 μM, (Table 1) than expected from their electronic character. 0.006 μM, 0.8 μM, and 2.1 μM, respectively, in agreement with All 4′-substituted 6-hydroxybenzothiazoles 2b-n, had no previously published values (4, 16).
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