Gliotoxin analogues as inhibitors of reverse transcriptase. 2. Resolution and X-ray crystal structure determination.
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.
D000900:Anti-Bacterial Agents / Q000031:analogs & derivatives / Q000494:pharmacology; D002942:Circular Dichroism; D005912:Gliotoxin / Q000031:analogs & derivatives / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D018894:Reverse Transcriptase Inhibitors; D013237:Stereoisomerism; D014961:X-Ray Diffraction
D000900:Anti-Bacterial Agents; D018894:Reverse Transcriptase Inhibitors; D005912:Gliotoxin