Antimitotic agents: ring analogues and derivatives of ethyl [(S)-5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b]pyrazin-7- yl]carbamate.
The synthesis of ring analogues and derivatives of the S isomer of ethyl [5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b]pyrazin-7 - yl[carbamate, (S)-1, a potent antimitotic agent with anticancer activity, was directed toward the determination of the contribution of several structural features of this compound to biological activity. Replacement of the 5-amino with a 5(6H)-oxo group and either transposing the 6-ring nitrogen to or incorporation of a ring nitrogen at the 8-position caused a significant decrease in in vitro activity and destroyed in vivo activity. Although in vivo cytotoxicity was reduced, in vitro activity at higher doses relative to (S)-1 was retained by replacement of the 5-amino group with hydrogen and by expansion of the 1,2-dihydropyrazine to give a dihydro-1,4-diazepine ring.
Temple
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Organic Chemistry Research Laboratories, Southern Research Institute, Birmingham, Alabama 35255-5305.
Rener
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D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D007939:Leukemia L1210 / Q000188:drug therapy; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014520:Urethane / Q000031:analogs & derivatives*
D000970:Antineoplastic Agents; D011719:Pyrazines; D014520:Urethane