Potential Anticancer Agents VI: 5-Substituted Pyrimidine-6-carboxaldehydes

• Published in: Journal of pharmaceutical sciences 1970-11, Vol.59 (11), p.1637-1645
• Main Authors: Hong, Chung Il, Piantadosi, Claude, Logan Irvin, J.
• Format: Article
• Language: English
• Subjects: 5-substituted-synthesis; Aldehydes - chemical synthesis; Aldehydes - metabolism; Aldehydes - therapeutic use; Animals; Anticancer activity-5-substituted pyrimidine-6-carboxaldehydes; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - metabolism; Antineoplastic Agents - therapeutic use; Carbon Isotopes; Carcinoma, Ehrlich Tumor - drug therapy; Chemical Phenomena; Chemistry; DNA, Neoplasm - biosynthesis; Fluorouracil - therapeutic use; Formates - antagonists & inhibitors; Mice; Nucleic acid synthesis inhibition-5-substituted pyrimidine-6-carboxaldehydes; Orotic Acid - antagonists & inhibitors; Phenylalanine - antagonists & inhibitors; Protein Biosynthesis; Protein synthesis inhibition-5-substituted pyrimidine-6-carboxaldehydes; Pyrimidine-6-carboxaldehydes; Pyrimidine-6-carboxaldehydes, 5-substituted—synthesis; Pyrimidines - chemical synthesis; Pyrimidines - metabolism; Pyrimidines - therapeutic use; RNA, Neoplasm - biosynthesis; Thymidine - antagonists & inhibitors; Tritium; Tumor aerobic respiration inhibition-5-substituted pyrimidine-6-carboxaldehydes
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.2600591120

A series of 5-substituted pyrimidine-6-carboxaldehydes and their derivatives were synthesized and tested for inhibition of growth of the Ehrlich ascites carcinoma and Ehrlich carcinoma. Further studies included inhibition of incorporation of L-phenylalanine-1-14C and formate-14C into proteins, and orotic acid -5-3H, thymidine-2-14C, and formate-14C into nucleic acids of the ascitic tumor cells in vitro. The following compounds were found to be particularly active as inhibitors: 2-mercapto-4-hydroxy-5-(3-phenylpropyl)pyrimidine-6-carboxaldehyde (VIII-2), 2-mercapto-4-hydroxy-5-(4-phenylbenzyl)pyrimidine-6-carboxaldehyde (VIII-3), and 2-mercapto-4-hydroxy-5-(α-naphthylmethyl)pyrimidine-6-carboxaldehyde (Ic). The best compounds of this series are equally as effective as 5-fluorouracil and 2-mercapto-4-hydroxy-5-(4-chlorobenzyl)pyrimidine-6-carboxaldehyde (Ib) in inhibiting formate incorporation into DNA and growth of the ascitic tumor. They are more effective than 5-fluorouracil in inhibiting incorporation of formate and orotic acid into RNA, thymidine into DNA, and phenylalanine into proteins. The active compounds also showed a strong inhibitory activity against respiration of the ascitic tumor. Compounds VIII-2 and VIII-3 also inhibited growth of the Ehrlich carcinoma as a solid tumor after subcutaneous transplantation, but in these tests the drugs were more toxic to the host when injected intraperitoneally since the drugs were not preferentially absorbed by the tumor cells in contrast to the tests versus the ascites form of the carcinoma.