Novel pyrrolo[2,3-d]pyrimidine antifolates: synthesis and antitumor activities.
New antifolates, characterized by a 6-5 fused ring system, a pyrrolo[2,3-d]pyrimidine ring, and a trimethylene bridge at position 5 (12a,b and 13a,b) were designed and efficiently synthesized. The synthetic method included (1) construction of the key intermediary acyclic skeleton, 5-[4-(tert-butoxycarbonyl)phenyl]- 2-(dicyanomethyl)pentanoates (6a,b), (2) cyclization with guanidine, followed by reduction to the pyrrolo[2,3-d]pyrimidine derivatives (8a,b and 9a,b), and (3) subsequent glutamate coupling and saponification. These antifolates were more growth-inhibitory by about 1 order of magnitude than methotrexate (MTX) against KB human epidermoid carcinoma cells and A549 human nonsmall cell lung carcinoma cells in in vitro culture. Growth inhibitory IC50 values for N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5- yl)propyl]benzoyl]-L-glutamic acid (12a) against KB and A549 were 0.27 and 4.5 ng/mL, while those for MTX were 5.0 and 35 ng/mL, respectively. Other members of this class of antifolates, 12b and 13a,b, showed good activities nearly equal to that of 12a.
Miwa
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Research & Development Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
Hitaka
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Akimoto
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Nomura
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D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D002460:Cell Line; D055598:Chemical Phenomena; D002621:Chemistry; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000627:therapeutic use; D011758:Pyrroles / Q000138:chemical synthesis* / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D011743:Pyrimidines; D011758:Pyrroles