4-Isoxazoly1-1,4-dihydropyridines: Biological, Theoretical, and Structural Studies

N. R. Natale, Robert B. Palmer, Barbara J. Lefler, W. Daniel Edwards, David J. Triggle

Research output: Contribution to journalArticlepeer-review

Abstract

Biological activity was determined for a series of seven isoxazolyldihydropyridines (IDHPs). The highest biological activity was observed for 5-alkyl-3-phenyl-IDHP (1), for which the O-endo conformation at the ring juncture between the heterocyclic rings is known in the solid state. The 3,5-dialkyl-IDHPs were intermediate in overall activity. A theoretical study of rotation about this ring juncture was performed to estimate the relative energy and barrier to rotation for the different conformers as a function of both the ring juncture between the heterocyclic rings and the esters in the 3- and 5-position of the dihydropyridine. Molecular mechanics predicts the minimum energy conformer to be\O-exo-ap,ap, while quantum mechanical calculations predict 0-exo-sp, sp as the minimum-energy conformer. Both methods indicate that the barrier to rotation about the heterocyclic ring juncture should be relative low, but both methods appear to overestimate the difficulty of ester rotation. A single-crystal X-ray diffractometry study of the (3,5-dimethylisoxazolyl)dihydropyridine 2 was carried out, and shows the O-endo ring juncture and sp, sp ester conformation. 2D NOESY NMR spectroscopy indicates the presence of both conformations about the ring juncture, at room temperature, as evidenced by correlations for both alkyl groups on the isoxazole with the C-2 methyl on the DHP moiety. The ap ester conformer was also evidenced by NOESY, indicating that ester interconversion must take place. Several 1,2,2-tris(sulfonyl)hydrazines, conceived as prodrugs of 1,2-bis(sulfonyl)hydrazines, were synthesized and evaluated for antineoplastic and trypanocidal activities in mice. 1-Methyl-1,2,2-tris(methylsulfonyl)hydrazine emerged as an extremely efficacious antitrypanosomal agent, whereas 1-(2-chloroethyl)-1,2,2-tris(methylsulfonyl)hydrazine was inactive. In contrast, 1-(2-chloroethyl)-l,2,2-tris(methylsulfonyl)hydrazine displayed potent antineoplastic activity, producing several 60-day “cures” of mice bearing leukemia L1210, leukemia P388, or Sarcoma 180. Furthermore, the fact that the tris(sulfonyl) derivatives will not generate isocyanates, which contribute to the host toxicity of nitrosoureas like 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), makes them agents of significant promise in trypanosomal and cancer chemotherapy.

Original languageEnglish
Pages (from-to)2255-2259
Number of pages5
JournalJournal of Medicinal Chemistry
Volume33
Issue number8
DOIs
StatePublished - 1990

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