Disposition Release Form for RPT Organotellurium Compounds of Biological Interest - Unique Properties of the N-Chlorosuccinimide Oxidation Proct of 9-Telluraheptadecanoic Acid (Att: Report; Form)

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TITLE Organo tellurium Compounds of Biolo ica Unique Properties of the N-Chlorosuccinirnfde Oxidation Pro- - In sui fo cent PatentS u jn if i can ce - Prevtousir Released _ a Released By DOE S IS POSITION ---*elease Approved - Use Cautbon Label Over

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(Allow 3 - 5 Days For Clearance) Submit capies 1-7 of form, properly executed to Laboratory Records Department w i t h (a) repraduciblesor ( b ) 3 x x copies of document i f 1. REQUEST: 13 Classification and Patent Release 3 Declassification OF THE ATTACHED a Abstract a Paper2. TITLE: (Show in full unless classified) 26)7 3 Orqanotell urium Comaounds of Biological Interest - Unique bowrties o f the N-Chlorosucclnhf de 3. AUTHOR: (List Ali Authors; i f not an ORNL employee, indicate address on a separate line) Wniversfty o f Metz, Pletz, France 4. PURPOSE: DO NOT ABBREVIATE Titles of Meetings, Journals, Universities (a) Oral Presentation (Give name, place, andexact dates of meeting) T o be published i n program, 6ookiet, brochure, ctc. Yes Copies of t h i s document w i l l be distributed 0 before, 0 after, 0 during the meeting, or i-J no distribution w i l l be made. 0 No 0 Not Known (b) Publication (Proceedings of a meeting, give place and dates; Journal, give publication date; Book, give editor and publisher) To beissued as a report a No 0 Yes (Number) To be condensed and published in open litemture No 0 Yes (Where?) 5. INVENTIONS: ( L i s t Page No. of any item appearing t o have significant novelty; indicate if none.) 6. PREV\OUSLY CLEARED DOCUMENT: (Paper, abstract, progress report, etc., containing similar information; indicate if classified.) Associate Laboratory Dlrector Review Required 0 Yes a No - Determined Division Director Prolect Director ram Director ynyy= Classification Off icer Date Date Potent Office bate Associate Laboratory Director Distribution of Documents 1. Classification Office File 2. Potent Office File (if requested) Dirtrlbution of Form 1. C loss if ica tim Office File 2. P a t 8 n t Office File 7. DOE - Technicol Information Center 3. Keypunch 8. Suspense copy - Division File. 3. DOE - TIC (if speech) 4.. Approvod, Return to Division Office 5. Laboratory Records Dept. - Reprints 6, Public Information Office

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Organotell uri urn Compounds o f B i 01 ogi cal Interest - Uni que Troperties o f the N-Chl orosucci nimi de Oxi dation Product o f Nuclear Medicine Group Health and Safety Research Division Oak R i dge National Laboratory Oak Ridge, Tennessee 37830, U.S.A., Health and Safety Research Division, Building 3047, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830. Research sponsored by the Office o f Health and Environmental Research, U.S. Department of Energy under contract A-7405-eng-25 w i t h the Union Science, Yniversite de Mett, Metz, 5700, France. Laboratoi r e de Chernie Organique, Facul t e de B y acceptance of this article, the pubtishe? or recipient acknowladprr license in and t o any copyright

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The product formed by N-chl orosucci nimde (NCS) oxidation of 9-telluraheptadecanoic acid (9-THDA) i s insoluble in organic solvents and appears t o have an oligomeric or polymeric structure. i s solubilized in dilute base t o the sodium salt of the monomer, the Te( fV) geminal diol of 9-THDA. While the insoluble oxidation product cannot be analyzed directly, ithas been converted t o products of treatnent with acetic anhydride forms the Te(1V) geminal diacetate o f dioctyl telluride in each case gives the Te(IV) geminal diols that exhibit normal sol ubi1 i t y i n organic sol vents and the expected physical properties. In contrast, NCS oxidation of 9-selenaheptadecanoic acid (9-SYDA) gives a selenoxide (Se=O) which is readily so?uble in organic solvents. oxi 3ati on products o f 9-THDA and 9-SHDA correlate directly with the heart specificity and degree of retention in the heart muscle a f t e r i ntravenous admi ni s t r a t i on of the radi ol abel ed compounds (9-[l 23mTe]- THDA and 9-L7%elSHDA) t o experimental animals. The radiolabeled tellurium f a t t y acid shows pronounced heart uptake and prolonged retention ( " trapping " ) and represents a new type o f imaging agcnt for the potential clinical evaluation of heart disease. The present studies suggest that the "trapping" o f tellurium fatty acids i n the heart may result from the formation o f an insoluble oxidation product after entry into the cells of the heart muscle. Treatment with HBr gives the dibroinide of 9-THDA and Similar NCS oxidation of the methyl ester of 9-THDA or The contrasting properties of the

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The f i e l d of organotellurium chemistry1 has grown rapidly over the last few years as a result o f the development o f tellurium "reagents" that have unique and subtle applications i n organic synthesis. One exanple i s dianisyltelluroxide, which is amild oxidizing agent.2 addition, a variety of new organotelluriurn compounds of biological interest have been synthesized and evaluated because of interest in the potential use of the lZ3Te-labeled agents f o r diagnostic applications i n clinical nuclear medicine.3 radi oi sotope i s produced by neutron irradiation of isotopi cal ly enriched tel lurium-122 and has attractive radionucl i d i c properties for determining the tissue distribution of 123qe-labeled tissue-specific radi opharmaceutizal s by external scanning or imaging techniques. A variety of structurally modified steroids labeled i n the sidechain w i t h 1 2 3 * T e have been prepared and evaluated4 and two o f these adrenal uptake i n experimental animals. These agents show promise as a means t o localize unilateral adrenal disease. Model tellurium amino acid7 have also been prepared. 123?e-labeled barbiturates substituted a t the C-5 position have been evaluated and show significant brain uptake i n experimental animal s.8 These agents may be useful for the evaluation o f regional cerebral More recently, a series of

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The radi ol abel ed tellurium fatty acids have been mre extensively studied because of their potential applications for the detection and evaluation of heart disease. We have prepared a series of long-chain fatty acids in which divalent Te(I1) has been inserted between two methylene units i n the alkyl chain.9 reinarkable specificity for the heart msc le (myocardium) and the uptake is dependent upon total chain length.10 myocardial uptali? similar to natural fatty acids like palmitic and s tea ric acids which are normally concentrated by the heart from the blood.ll This agent i s being extensively eva lua k d in laboratory azirnals for pot g nti al clinical applications.11,12 The unique feature exhibited by 9-THDA i s the prolonged myocardial rz tent ion. After a rzpid peak uptake, the myocardial radioactivity is very slowly lost or Some of these agents show "washed-out" from the heart ti ssue. In contrast to tellurium fatty acids like 9-THDA, the selenium analog, 9-sel enaheptadecanoi c acid (9-SI-IDA; F i gure 1), shows marginal heart uptake, slow blood clearance, and a rapid loss from the the Te and Se fatty acid analogs were unanticipated and could not be These major differences in the biological behavior o f

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fully rationalized by a comparison of the relative physical properties, such as differences in the carbon-heteroatom bond lengths, carbonh eteroatom-carbon bond angl es, o r heteroatom pol ari zabi 1it y , el ectro - negativity, etc. Since tissue distribution studies in rats with [10-1'C]-9-THDA appeared to indicate that the intact 9-THDA molecule was retained in the myocardium14, we proposed that an oxidative nadi fi cation of the tellurium i n the 9-THDA mlecule may lead to a product that could be "trapped" i n the myocardium by an unknown mechanism. The facile oxidation o f diorganyl tellurides in comparison t o the sel eni oxidation of the tellurium compounds can often be avoided by working analogs i s we1 1 documentedl. The photochemical Only recently have the properties of Te oxidation products of Ciorganyl tell d rides been investigated in detail .I6 prcqerties o f the t?llurium fatty acids "trapped" i n the heart may be very important for the development of new agents for the evaluation of Because the unusual heart disease, our goal inth2 present studies was to carefully ex mine tire chemical oxidation products o f 9-THDA. I n our early studies we observed thata heavy rhite preci itt incandescent room lights. When such solutions were protected from light and stored at 4"C, however, only minimal decomposition was observed by thin-1 ayer chromatographic (TLC)analysis over i! period of

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several weeks. These results suggested that 9-THDA underwent a rapid, photochemical l y induced oxi dative decomposition in ether solution to an insoluble material of unknown composition. The white precipitate was insoluble in water and the usual organic solvents that were tested,but readily dissolved i n dilute alkali at room temperature. These rzsults suggested that the carboxyl moiety was involved i n the structure o f the unknown material and that the framework o f this material was disrupted upon conversion t o the sodium salt. The exi sten ce of an 0: i gomeri c or polymeric structure i nvol ving interaction of the carboxyl group was postulated and further indicated since the oxi dati on products of methyl - 9 - t ~ l luraheptadecanoate (M2-9-THDA) and cii octyl telluride showed the expected sol ubi1 ityin organic sol vents ivi de infra). Because o f the unusual insolubility property,the autoxidation product " X " could not be analyzed directly by the usual physical methods, such as proton nuclear mg ne tic resonance (NHR) and mass spectrometry ! %I,but required convcrsion t o compounds of known structure that could be obtained directly from the parent compound, 9-TH3,4, by we1 1es i abl ished procedures. Thus, the inherent structure of " X " re quir s dc on vw sion to smaller components of known structure as directly by treatinent of 9-THDA with Br2 i n CC14.

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transformation in obtaining insight into the structure of " X " was obtained by :ia33 treatment of 9-THDA dibromide (3). The MM8 spectrum of this solution was very similar to the spectrum o f an NaOD solution d i hromi de ( ?2-Te-Br2 )to the corresponding deuterated di hydroxy species (R2-Te-[OD]2), the similarity in the spectra of the two solutions suggested t h a t an oxidized product of 9-THDA was a major component of the material o f unknown structure "X". This mter i al probably also contains other minor components, such as the tell uri nic acids (R-TeOOH or HOO C - R I - TeOOH)that would be expected t o be formed by cleavage of

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A study of the chemical oxidation products of 9-THDA under carefully control led conditions was therefore ini t i a t z d (Scheme 11). We chose N-chl orosucci niini de (NCS) as the oxi 3i z i ng species since a recent study has reported the oxidation of a variety o f model diorganyl tellurides with this reagent.16 As expected, treatment o f 9-THDA with one equivalent o f NCS gave a gummy product that was insoluble i n organic solvents. The electron impact mass spectral fragmentation of this material did not exhibit a molecular ion that corresponded t o an oxygenated species, thus demonstrating facile deoxygenation. The el emental analyses, however, gave an empirical formula that was consistent with the structure of l-octylI ) . In a d d i t i o n , the diol ( 2 ) was converted to the diacetate ( 4 ) and ':he Further, the NMR spectrum o f a

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dibromide (3).The latter was converted to(4) by treatment with Ag(1)acetate, by the reactions described earlier. We were not able to obtain homogeneous oxidation products with n-butyl hypochlori te,16 and treatment of 9-THDA with this reagent gave a mixture o f products. Although the insolubility of the 9-THDA diol (2) precluded direct N MZ analysis or molecular weight determination by the usual methods, an examination of the NCS oxidation products of methyl - 9 - t e l l uraheptadecanoate (Y2-9-THDA) and d ioc tyl di telluride substantiated involvement of the carboxyl group inthe unique structure of the insoluble NCS product of 9-THDA. T h u s , YCS treatment of Me-9-TNA gave an oxidation product that was soluble in organic solvents and exhibited TLC mobility, elemental analysis and QlMR properties consistent with the expected In contrast to the formation of the unexpected insoluble oxygenated the sel eni urn anal og, 9-szl enaheptadecanoic aci d(g - SHDA), gave the expected sel snax i de, 9-selenaheptadecanoic acid oxide, mp 73.5OC. The elen en tal analysis, and infrared, mass spectral, and NMR spectral selenides form the expected selenoxi des while tell urides give products that analyze for dihydroxy o r hydrated tel lu r oxide species.16 Other workers have recently reported that diorganyl Dioctyl telluride was also treated with NCS and the oxidation product subjected t o the transformations described earlier for the XCS could be studied directly in a model compound. Thus, NCS oxidation of I n this manner, the effect of the carboxyl group

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dioctyl telluride (5; Scheme 111; R=H3C-(CH2)7-) gave dioctyl tellurium diol ( 6 ) which exhibited the expected solubility i n the usual organic solvents. Treatment o f the diol (6) with HBr gave the oily dibromide (7a),that was identical t o dioctyl tellurium dibromide ( 7 b ) formed by Qr2treatment o f the telluride (5). the diacetate ( 8 a ) prepared by Ac20 treatment o f the diol ( 6 ) was identical t:, the diacetate formed by A g ( 1 ) acetate trgatment o f o f the telluride (51, diol (61, dibromide (7b), and the N M R spectral properties o f the diacetates (8a and 8b) were consistent with the

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A1 though the structure of the insoluble aut oxidation product " X " and the NCS product (1) could not be elucidated by the usual physical methods, transformations of " X " t o known derivatives of 9-TYDA and the nornal behavfor o f the NCS oxidation products of Me-9-THDA and d ioc tyl telluride(Schme 1111, strongly suggest the structure of the i nsol uble 9-TYDA oxidation product invol ves interact i or? between the terminal carboxyl iiloiety and the geminal hydroxyl groups. This unexpected finding is consistent with the pro1 onged myocardi a1 ret m tion in eq eri mental animals that has been observed after intravenous admi nist ration of radi ol abel ed 9-THDA. In contrast, we have found that the analogous selenium fatty acids such as 9-selenaheptadecanoic acid (9-S:-1DA, Figure 11, do not suffer faci12 autoxi dati3nas observed wi t h 9-THDA. Cherni cal oxi dati on of seienides, B S dsscribed i n this study and more extensively elsewhere,l4 f orrn the exp ict edsel enoxi des. sel eni um d i ol …