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An Investigation of Novel Flourescent Antimetabolites As Potential Molecular Probes in Neoplastic Cells Jeffrey Samuel Barkin Yale University

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An Investigation of Novel Flourescent Antimetabolites As Potential Molecular Probes in Neoplastic Cells Jeffrey Samuel Barkin Yale University Yale University EliScholar – A Digital Platform for Scholarly Publishing at Yale Yale Medicine Thesis Digital Library School of Medicine 1987 An investigation of novel flourescent antimetabolites as potential molecular probes in neoplastic cells Jeffrey Samuel Barkin Yale University Follow this and additional works at: http://elischolar.library.yale.edu/ymtdl Recommended Citation Barkin, Jeffrey Samuel, "An investigation of novel flourescent antimetabolites as potential molecular probes in neoplastic cells" (1987). Yale Medicine Thesis Digital Library. 2378. http://elischolar.library.yale.edu/ymtdl/2378 This Open Access Thesis is brought to you for free and open access by the School of Medicine at EliScholar – A Digital Platform for Scholarly Publishing at Yale. It has been accepted for inclusion in Yale Medicine Thesis Digital Library by an authorized administrator of EliScholar – A Digital Platform for Scholarly Publishing at Yale. For more information, please contact [email protected]. TiI3 YALE MEDICAL LIBRARY +YI2 08627 8745 5404 YALE mmmll ll D* 0* , MEDICAL LIBRARV Permission for photocopying or microfilming of " /fn r ^y j f 0^ -_" for the purpose of individual scholarly consultation or reference is hereby granted by the author. This permission is not to be interpreted as affecting publication of this work, or otherwise placing it in the public domain, and the author reserves all rights of ownership guaranteed under ccanmon law protection of unpublished manuscripts. Signature of author) (Printed name) A (1^ (Date) Digitized by the Internet Archive in 2017 with funding from The National Endowment for the Humanities and the Arcadia Fund https://archive.org/details/investigationofnOObark L. i-'i .. ‘V IHR , -• . -rt ‘ ■A^1 ■!' '** * ■ - ^ 4it- .( t\ A t % m4 ! AN INVESTIGATION OF NOVEL FLOURESCENT ANTIMETABOLITES AS POTENTIAL MOLECULAR PROBES IN NEOPLASTIC CELLS A Thesis Submitted to the Yale University School of Medicine Department of Pharmacology In partial fulfdlment of the requirements for the degree of Doctor of Medicine by Jeffrey Samuel Barkin 1987 /V)e(-{ Liia ni3 Hx ABSTRACT An Investigation of Novel Rourescent Metabolites As Potential Molecular Probes in Neoplastic Cells Jeffrey Samuel Barkin 1987 Many 2,4-diamino-pteridines are potent inhibitors of dihydrofolate reductase; two novel trimethoxy-pteridines were synthesized. Rourescence characteristics of these two compounds were assessed, as were their ultraviolet and visible spectra. The first compound, l-(2,4-diamino-6-pteridinyl)-2-3,4,5-trimethoxyphenyl(ethylene) ('PKC-l'), was unable to inhibit dihydrofolate reductase (DHFR) derived from both a mammalian leukemic cell line and a bacterial source, Lactobacillus caseii. The compound 7,8-dihydro form (PKC-2') was unable to inhibit either form of DHFR as well. As neither compound was an inhibitor of DHFR in vitro , it was not surprising that they demonstrated no appreciable cytotoxicity against a leukemic cell line (CEM) or a human colon carcinoma derived solid tumor. The concentration necessary to reduce the number of cells growing in culture by half was greater than 1 X 10"“^ M. Both PKC-l and PKC-2 are flourescent. A compound which is flourescent and avidly binds to and inhibits an enzyme such as DHFR would be very useful in elucidating the intracellular pathways of reduced folates. Further understanding the pathways of folates would aid in the development of new anti-folates, which themselves may circumvent some drug-resistance mechanisms in cancer cells. 5-flouro-2'-deoxyuridine-ethyl(7-methoxy)coumarin (FdUrd-MmC) is a strongly flourescent analog of deoxyuridine. After this compound was synthesized, its flourescence characterisitics were obtained, as were ultraviolet and visible spectra. FdUrd-MmC was unable to passively enter cells, as assessed by flourescence microscopy. It had no appreciable cytotoxic effect against either a leukemic cell line (CEM) or a solid tumor. FdUrd-MmC was forced to enter cells using electroporation, a technique which enables the introduction of otherwise impermeable compounds. Once introduced into CEM cells, FdUrd-MmC was not cytotoxic. As measured by a tritium release assay, FdUrd-Mmc transiently decreased DNA synthesis by ninety per-cent. Electroporation alone was also noted to decrease DNA synthesis. Rourescent nucleotide analogs may help elucidate molecular pathways of DNA synthesis by allowing direct visualization of cells under a flourescence microscope. This would be particularly useful in defining differences between neoplastic and normal cells. :■■:■■/'v'V'' ■ "“'1. 1 , K ' ' eg ■ ' ' :. Q), ' 'I: . , '■■'^'^ ■« ' ■ ',, ‘ 'ij ' E;„‘ ' ' '' '4 t^;> ■ m ft fjini.anrt fifio ff lUc'! -■. ti ..,„. , ' **■ •' ■’ -•' . Wfflrvv-^ v-m md) Jon>m*> »* .,UJv„r>’ >’^'H<if:>o .ajJdku/; ui bfiuwM iRWisAtn ,«A ^|HO''t0 ■' ttfnfxK;Itwjfd.l ■ . ^,^4 «■ :<3fa;*fvjv^rJ 3(diife(cw ' '**i'’’ ^ ,!9VUTm'i)’i ifcAlw a’BO TSi. i^'^t(|0*a-sKat» 'vrff ■’3<l!Wl : [■y:: .. ■'‘■»' ' M- #■ . ' ,' t,. - " Jit,; ' , , ‘,, I ■ ' 2'-*' I ' , l., vd’ ^kiHC-^'r:! i?A 'it/iw IO'4''4<:'^*J»(^,iulu:>3ann,t ,^.'i^M;)yvi^jt 2»^ . ' ■ X ■ ,„- ' i5E,;j{> 4a 'm iiSiJ' ■ •.'•.VA' ■■„ ' m'- " ACKNOWLEDGEMENTS: This thesis was made possible by the help, kindness, knowledge and patience of many people. Dr. Joe Bertino, my thesis advisor, whose laboratory all of this work was conducted in, provided guidance, encouragement, ideas, warmth and humor. Arlene Cashmore patiently taught me many technical processes, provided the illustrations contained herein, and was an abundant source of overall support. Dr. Pauline Chang synthesized FdUrd-MmC and the PKC 'series' of compounds, which bear her initials. Barbara A. Moroson guided me through the tissue culture lab and never hesitated to help me out when problems arose. Margaret Jastreboff, and Ramaswamy Narayanan patiently discussed new ideas and taught me the technique of electroporation. Dawne Newcombe helped with many references and always kept my spirits up. I am and honored to have worked with this group of people. Finally, I am grateful to my family and all of my friends who encouraged me throughout not only this thesis, but all of medical school. * U7. >' ‘ V T'.. .lip., ■' ff-*. ' !.'•'■ ■, .»! ,pl<|«;ti.i v/awn IjO asfi-.iuu’f bms: (Ki fX'-K ^('t; ’jtaii «w ifearii ?-irfr ..a-iiilvivii ^r-hiv^w; ,ffi m'n 4 m' >j/U fa>4lE .'nrii.wml _inv!«f afc^ xm Uf>no<<3«^ y“3in y<«: !iv5 ,V nutd bn^' il/iTii.Ar .ijwivi ><n-'^4BTtKrx» (iBwvri aoiuo*. m-il''!rj>;a nit vujw bfl^ ,iu5rjHl han.!unoo 88*r-*i«4wrf!j oH) fc^aiji. ivf .wvi*ftaov.l »#»| 'u»ri .4»wuio.|faa'> lo ’«iw^ ')>fM WIwki #;•?>«'{« •Jmjhwrti .t<I juo^wi^jtort u» !vi»cit.>;j!4 ovoT l<’i» <t{4 t&MiT>.<{;) 'w^ii ’idf dmuiU orf* n^bi^ia .A m;'.**-»»>'» .■JitiJW IjCft fift L Vf ui W’ .^.i/'a’J!) ^iusilas; ''-i' w- ,,:x;M umrA fwdk ai^ Ai .rjJoi <fiKm njiv hWTf'nfjiij^jinupHjsia u»'yjpwdaw <SilJ otti ,jk|^*q >f/ >irtJl *^'-'*r bt^tvti f<vi;n tA lsu^>n*>d U:» fm * .(JW iihw;>' '01 Hjai y{<iw jn iijc.if;/w>e?lj rr.m h/x^tu'j>n, od<A ^ '(nn Ia U« hs.v. x'h*^ i,’- *“ mu i .viHrtt i ' .lc>o<'a» '-i;.r34br):a 'to !ir, itfd Rid! .1 Table of contents page Introduction 1 Materials and Methods 19 Results 24 Discussion 39 Bibliography 43 LIST OF FIGURES Page Figure 1: Intracellular interconversions of folates. 4 Figure 2; Structure of classical anti-folates. 5 Figure 3: Mechanism of MTX cytotoxicity. 6 Figure 4: Structure of non-classical anti-folates. 10 Figure 5: Structures of PKC-1 and PKC-2. 14 Figure 6: Structure of flourescein-labelled MTX. 15 Figure 7: Structure of FdUrd-MmC. 16 Figure 8: UV and visible spectra of PKC-1 and PKC-2. 25 Figure 9: Hourescence spectra of PKC-1. 26 Figure 10: UV and visible spectra of FdUrd-MmC. 30 Figure 11: Mass spectroscopy of FdUrd-MmC. 31 Figure 12: Hourescence spectra of FdUrd-MmC. 32 'r.'.'ol M aw^ .l*!J> J l-U<;t; .C.4r;flZ ’t< ’"(J'. '(/U-'* •X • KTV V> >1 i»'' -jfcioW ;E * ii(.iP. a. ..:r" 'Miu tr jM.-j.‘>-i»*»»lV-a«<ri<nl.- ' tvwi i<» ^Tuu Jiiu? :4i -■r..* 'i4'nb>-'i''- '. I" .) mw'4,n OtotA \'fitut)mi'l :\ O'Uipn JOA’' ■' ■ *■*«(! 7U :8 Qiiflii H 1 ti; :»3i/! >■• 'JoH Vo W0O0ki i^ia VL Ot v-uJii’i ’jV..ir. Vyui .afpt tm usM il '/jagH XI y;‘'J*i LIST OF TABLES Table 1: Structure-activity relationships of various 2,4-diamino quinazolines. Table 2: ED5Q of various 2,4-diamino quinazolines in cell culture. Table 3: Tritium release from 3H-2'-deoxyuridine (DNA synthesis activity). !i' (!■ i V f • y.itv« (. - : f a(<?iiT acHnl« .Bni«p otv.fri^U if It! •wmwJi* t'.. /<nv.»^v Ki'^03 •1 oWtr ->UfflU9 U«> \)^f vT’-Mijif ', AyfC) y . ABBREVIATIONS DHFR Dihydrofolate Reductase DMSO Dimethyl Sulfoxide FACS Flourescence Activated Cell Sorting FdUrd 5-flouro-2'-deoxyuridine FdUrd-MmC 5-flouro-2'-deoxyuridine-ethyl(7-methoxy)coumarin FH2 dihydrofolate FH4 tetrahydrofolate FUDR 5-flouro-uridine HPLC High Pressure Liquid Chromatography MmC 4-bromoethyl-7-methoxycoumarin MTX Methotrexate PBS Phosphate Buffered Saline PKC-1 l-(2,4-diamino-6-pteridinyl)-2-3,4,5-trimethoxy- phenyl(ethylene) PKC-2 l-(2,4-diamino-6-pteridinyl)-2-3,4,5-trimethoxy- phenyl(ethane) S.C. Squamous Cell derived Solid Tumor TMQ Trimetrexate Tris tris(hydroxymethyl)aminomethane TZT Baker's antifolate "y ilrt; ^ ij-alJ.vr‘-,> .• y- «:)AH :>fi ilihu sf^ -o tuc ft ^ Z SiUbH ivitinys:i( i> ‘ ‘.->rri -i . • Hu* '•r'^bvirrt»l f,m * Hr).bu-<>itw>n‘*2 >iau*^' ' ‘11^ifflpu' '' I 'tJiil 1 ami ntiri :.'in>.3v >:(4!9tTi-V ^ 'y,y. l)jxiM >^VjX31K’i{'5!»iVl KPM zm 'Vruhi ii'fKi'ffir.iivk/.;■ i (0o:>i‘/m)iYn:i(i<i 1 '20:i^ ('3i!.iiiJd)l'{tD(iq 100,tuT ii5^h,'jo il‘/J ■Jtffcwuf-t.'pti .m f pMT OfaiOnTf'X y TST INTRODUCTION -2- Despite advances in cancer therapies, neoplastic disease still is the second leading cause of death in the United States, with approximately 5 million cases prevalent in the population in 1986 (Feldman, et al 1986).
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