Gliotoxin analogues as inhibitors of reverse transcriptase. 2. Resolution and X-ray crystal structure determination

J Med Chem. 1978 Aug;21(8):799-804. doi: 10.1021/jm00206a016.

Abstract

A novel, simple, and efficient method for the chemical resolution of epidithiodioxopiperazines is reported, which is based upon covalent formation of diastereomers. This method might be a general one for the resolution of chiral cyclic disulfides. Dithiol 5, prepared from 2 by reduction with NaBH4, was allowed to react with the disulfenyl chloride 8 to yield 9 and 10, which were separated by short-column chromatography on silica gel. From these, the optically pure enantiomers 11 and 12, respectively, were obtained by reduction with NaBH4, followed by reoxidation with I2-pyridine. In this way the precursor 7 of the resolving agent could also be recovered. The absolute configurations of 11 and 12 were derived from CD spectra. Kinetic asymmetric transformation of the gliotoxin analogue 2 with the diphosphine 6 gave a 19% enrichment in one enantiomer of the starting material. Surprisingly, both enantiomers were found to inhibit reverse transcriptase, the RNA-dependent DNA polymerase, to the same degree, indicating that there is no relation between this property of epidithiodioxopiperazines and their bridgehead configurations. From the X-ray crystal structure determination it can be seen that there is a considerable torsional and conformational strain in compound 2, which might enhance the ease of cleavage of the S-S bond. A possible relationship between this property and the biological activity of 2 is discussed.

MeSH terms

  • Anti-Bacterial Agents* / analogs & derivatives
  • Anti-Bacterial Agents* / pharmacology
  • Circular Dichroism
  • Gliotoxin* / analogs & derivatives
  • Gliotoxin* / pharmacology
  • Magnetic Resonance Spectroscopy
  • Molecular Conformation
  • Reverse Transcriptase Inhibitors*
  • Stereoisomerism
  • X-Ray Diffraction

Substances

  • Anti-Bacterial Agents
  • Reverse Transcriptase Inhibitors
  • Gliotoxin