Conformational Analysis of Lipophilic Antifolates: Crystal and Molecular Structures of 6-Substituted 5-Adamantyl-2,4-diaminopyrimidines by X-ray Analysis and Molecular Mechanics Calculations

Vivian Cody, Paul A. Sutton, William J. Welsh

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

The results of crystal structure determinations and molecular mechanics force field calculations on a series of four 6-substituted 5-adamantyl-2,4-diaminopyrimidine antifolates show that the pyrimidine ring and its substituents become more distorted from planarity as the size of the 6-substituent increases. These distortions are caused by the steric interference of the adamantyl hydrogen atoms with those of the 4,6-pyrimidine ring substituents. This series of antifolates shows a 500-fold increase in their cytotoxic activity against mammalian dihydrofolate reductase when the 6-substituent is increased from hydrogen to methyl to ethyl but drops at propyl. Full relaxation MM2P conformational energy profiles for rotation about the pyrimidine—adamantyl bond show that the maximum energy barrier (~6 kcal/mol) is located at 60° within the 0-120° unique conformational space studied. The structurally observed conformations of the 6-H and 6-methyl analogues are located at energy minima, whereas the most active antifolate 6-ethyl and 6-propyl analogues are observed in high energy conformations. The crystal structure of the 6-ethyl antifolate also reveals a (67/33% occupancy) disorder in the methylene carbon of the ethyl side chain which makes several short intramolecular H⃛H contacts with the adamantyl hydrogen atoms. This conformation may be stabilized in the crystal by intermolecular interactions not considered in the present force field calculations. Such stabilization could also be operative at the enzyme binding site and thus contribute to the 6-ethyl analogue's high potency.

Original languageEnglish (US)
Pages (from-to)4053-4057
Number of pages5
JournalJournal of the American Chemical Society
Volume109
Issue number13
DOIs
StatePublished - Jun 1 1987
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry
  • Catalysis
  • Colloid and Surface Chemistry

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