Conjugates of steroids and anti-cancer agents. III. The synthesis of estrynamine and certain derivatives.
Propargyl amine was protected by condensing it with 2,5-hexane-dione to give 2,5-dimethyl-N-(2'-propyn-1'-yl)pyrrole (2). The latter was converted to the corresponding Grignard reagent with ethylmagnesium bromide, and then condensed with estrone tetrahydropyranyl ether to give 17 alpha-[3'-(2'',5''-dimethyl-1''-pyrryl)-1'-propyn-1'-yl)-1,3 ,5( 10)- estratriene-3,17 beta-diol 3-tetrahydropyranyl ether (3), in 85% yield. Acetic acid and methanol cleaved the tetrahydropyranyl ether group, and hydroxylamine and sodium bicarbonate cleaved the pyrrole ring to give 17 alpha-(3'-amino-1'-propyn-1'-yl)-1,3,5(10)-estratriene-3,17 beta-diol (1), estrynamine. Several derivatives and analogs of 1 were also synthesized. Estrynamine binds to estrogen receptor with an RBA of 0.0045 (estradiol = 1.0). Several of the compounds, including estrynamine, are weak estrogens (stimulation of prolactin synthesis).
Blickenstaff
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Veterans Administration Medical Center, Department of Biochemistry, Indianapolis, IN 46202.
Foster
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Gerzon
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Young
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D000818:Animals; D000970:Antineoplastic Agents; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002621:Chemistry; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D045166:Estradiol Congeners; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism; D011388:Prolactin / Q000096:biosynthesis; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism; D013256:Steroids
D000970:Antineoplastic Agents; D045166:Estradiol Congeners; D011960:Receptors, Estrogen; D013256:Steroids; C055391:estrynamine; D004958:Estradiol; D011388:Prolactin