In the search for new anticancer drugs. XXIII: Exploration of a predictive design for anticancer drugs of carbohydrates containing N-nitrosochloroethylamino, N-nitrosomethyl, and N-nitrosoaminoxyl components.
The spin-labeled glucose nitrosoureas 13-16, streptozotocin (18), chlorozotocin (31), streptozotocin analogues of galactosyl 24 and mannosyl 28, and their tetra-O-acetyl derivatives 25 and 29, MCNU (Cymerin, 34), and glucamine (21) were synthesized and evaluated in vivo for their anticancer activities against the murine lymphocytic leukemia P388. Compounds 13-16, 18, 24, 28, 31, and 34 possessed activities ranging from 33 to 603% increase in life span (%ILS), whereas 21, 25, and 29 were inactive (%ILS = 9 to 10). All CD2F1 male mice treated with the most active compounds (13, 14, and 34) at 20 mg/kg were alive after 30 days, whereas all mice treated with the clinical drug streptozotocin (18) and clinically tested chlorozotocin (31) succumbed. Compounds 13-16, 18, 31, and 34 were further evaluated for their antineoplastic activity against lymphoid leukemia L1210. Compounds 13 and 34 on day 60 exhibited %ILS values of 557 and 713, respectively, as compared with %ILS values of 646 and 713 for CCNU (1) and the spin-labeled SLCNU (3), respectively. The lipophilicities of 13-16, 18, 21, 24, 25, 28, 29, 31, and 34 were determined using EPR and/or UV methods. A predictive design pattern was observed, with the most active drug (34) possessing some hydrophobic property (log P = 1.24), followed by 13 (log P = 1.87) and 14 (log P = 1.81) as the more active drugs with higher hydrophobicity than 34. The clinical drugs streptozotocin (18) and chlorozotocin (31) were distinctly hydrophilic and less active. Finally, it was concluded that various scattered results of anticancer activity in the literature can be explained by a linear correlation of activities with lipophilicities.
Sosnovsky
G
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Department of Chemistry, University of Wisconsin-Milwaukee 53201.
Rao
N U
NU
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D002241:Carbohydrates / Q000138:chemical synthesis* / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D015195:Drug Design; D004578:Electron Spin Resonance Spectroscopy; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D009607:Nitrosourea Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D013056:Spectrophotometry, Ultraviolet
D000970:Antineoplastic Agents; D002241:Carbohydrates; D009607:Nitrosourea Compounds