Gliotoxin analogs as inhibitors of reverse transcriptase. 2. Resolution and x-ray crystal structure determination

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.

Mechanistic and Chiroptical Studies on the Desulfurization of Epidithiodioxopiperazines Reveal Universal Retention of Configuration at the Bridgehead Carbon Atoms

“…23 The ECD spectra were experimentally measured and computationally simulated for ( R , R )- 7 . Figure 3 compares the experimental ECD spectra obtained by us and those reported by Ottenheim et al 20 with the computationally simulated one. The two experimental spectra are analogous, with three negative Cotton effects around 230, 250, and 280 nm.…”

“…11 Ottenheijm and co-workers had assigned this stereoisomer to have ( R , R ) stereochemistry by qualitative comparison with the ECD spectra of the closely related gliotoxin. 20 Since correlative methods, which compare experimental chiroptical spectra of a given molecule to those acquired from related molecular frameworks, can lead to a significant chance of error 5,21 and ECD quantum-chemical simulations are generally less reliable than, for example, those for VCD and ROA, 22 we sought to confirm this assignment. The optical rotation of ( R , R )- 7 was calculated and compared to the experimental values.…”

The chemistry and biology of the immunomodulating agent gliotoxin and related epipolythiodioxopiperazines

“…In a related article, these authors also show the equivalence of activity of the two enantiomers of (21). Murdock26a has shown, using a series of modified acetyl aranotins that the presence of a disulfide bond may not be an absolute requirement for antiviral activity in this series.…”

“…Addition of H2S to the double bond was achieved in the presence of ZnCI, to give exclusively the cis dithiol (20). Oxidation gave the ETP compound (21) in 81% overall yieldlgb (Scheme 5).…”

Influx of Calcium through a Redox-sensitive Plasma Membrane Channel in Thymocytes Causes Early Necrotic Cell Death Induced by the Epipolythiodioxopiperazine Toxins

“…Typical of many toxins, the mode of cell death switches from apoptotic to necrotic at relatively higher concentrations (9). Although the exact cellular targets of the ETP toxins have yet to be defined, they have been shown to inhibit a variety of enzymes including alcohol dehydrogenase (10), creatine kinase (11), the transcription factor NFB (12), farnesyl transferase (13), and RNA polymerase (14). In particular the ETP toxins target proteins with accessible thiol groups and gliotoxin has been shown to induce intramolecular disulfide formation in creatine kinase (11).…”