Synthesis and -Antitumor Activity of 9- Substituted Nitrogen Alustard Derivatives of 6-Alkylthiopurines' '
The preparation of (i-alkylthio-0-i~-clil~)roetl~yl~p~iriiie~ and 6-alkyltliio-~-[bis(p-cl~loruetliyl)~1iiiii).ljpiuines was reported. Direct, alkylation of 6-( alky1thio)purines with ethylene bromohydrin or 2-bromoethyl chloride i i i dimethyl sulfoxide gave o j-9-(phydrosyethyl)pnriiies or &(alkylthio)-9-(p-chloroethyl)piirines, respectively, in good yield. mpouiids were identical Kith thoae prepared by nlteriinte :itid unambiguous syiithet,ic routes. *Ut ization of some -2-(d-chloroetli!-l:tmiilo)pyrimidiiies t o dihyt1t.oimidazolo [2,3-c]pyrimidines has been reported, the closely related ~-artiiiio-G-alkylthio-9-(p-chloroetl)pi1~i~i~~~ did not undergo similar type of cyclization. Several ~i-alkylthio-R-(@-hydroq-etliyl)-aiid -cJ-(~-ctiloroetliylJpurines possess antitumor activity against Adeiiocarc.irmm:L 755 system. 111 addition, significant activities i t i Friend virus leukemia (solid) aiid i n tissue cult,iire htudieq have also beeii observed in some 6-(aralkylttiio)-!)-idchloroethy1)pwiiies.
Since the discovery of the autitutiior activity of iimercaptopurine iri 1934,4 various striwtural 1iiodific.at ions haw beeti explored by tiiany investigatorh. Screening results indicated5a6 that iioiie of the piirinca ticrivatives substituted at positions 1, :3. arid 7 cxhibited
aiiy significant activity. Substitutioii at' positioii 8 gavc varied results, and aii nniiiio group a t positioti 2 of the purine ring often is the only substit,uent at this position which does not result in the loss of (wciriostatic effect. A riuiiiher of 6-substitut ed puriiics, tlspecially 6-S-substituted, h a v r bren showii t>oposscw significant activity. Substitution at the c3-posit8ioiihas rewarded cancer clieiiiotherapeutists with iiiariy en-
couraging results. For instatwe, although 2,Ci-diaiiiinoS-(p-tolyl)purine7 is the oiily active coiiipound among a nuriiber of S-aryl-substitut,cd purines, a Tvitle variety of S-alliyl-substii-utcd puriiws ~ e r cfound t o haw antituiiior activity equal to, or greater than. thcit, parent coinpound. This iriforiiiatiori clearly suggcstcd t>hat,with regard to antitauinoractivity, future irivest.'igat ion involving the purine ring ~ i i iiiiiglif well t)o reiiterc\d about tlic O-alliyl-(i-alliyltliiop~irities(aiitl t I i c rorrespoiiding derivatives of ti-thioguaiiiiw). Sitrogeii rtiustard and its derivatives have been used widt.ly as carcinostatic agciii s? A rccent publication ( 1 ) This investipation uas suprjorted i n par1 ti? the ('ancer ? h e i i i < ~ tlirrapy Sational Servirr Center. National Cancer Institute, National Institutes of Health, PiiAlic Health G e r \ - i c r . Contract 5.1-43-pii-3025; and in part 1,). research Grant Xo. CT-4008(C:I) friirn tlie Xational Caiic~v Institute. Sational Institrites of Health. ( 2 ) Presented in part hefore the LXvision of 1Iedirinal Chemistry, 1 i i t i i Nat,ional >Ieet,ing of tlrr American riirinii,al Societ,y, Philadelphia, Pa.. .\pril I M 4 . (.'i) Taken iii part froin tlie Master's 'l'liesis of James 11. \Yestoyer suliiiiitted t o t h e Department of Cheinistrj, .\rizona State I-nirersity, Temp?. . b i z . , 1961. (4) G. lr. Hitcliings and C:. 1'. Rliorirs, S. 1.. .Ir,ud. ,Sei., 60, 18:1 i19.5 a). i 5 ) T'iir a detailed disciission of the antitiimor activity and struetural rt-lationsliips of purine derix-atives. see R. K. Robins, J . M e d . Chem., 7 , 186 (lOR1),and references cited therein. ( 6 ) ia) Cilia Foundation Symposiuin o n tlie Ctiemisiry and Bidopy
