A series of lamellarin derivatives have been studied as topoisomerase I (Top1) inhibitors. Molecular models of the ternary complexes formed between the DNA-Top1 ensemble and lamellarin D (LMD) or camptothecin (CPT) fully intercalated into the duplex DNA have been built and studied by means of nanosecond molecular dynamics simulations in aqueous solution. Our results show that the 20-OH and 8-OH of LMD can participate in hydrogen-bonding interactions with the side chains of Glu356 and Asn722, respectively, the latter being consistent with the finding that CEM/C2 cells, which are resistant to CPT, are cross-resistant to LMD. Our models also account for the observation that LMD stabilizes Top1 cleavage at CG sites in addition to the TG sites observed for CPT and rationalize the structure-activity relationships within the series. The deleterious effect of replacing the 20-OH in LMD with a hydrogen was confirmed using a set of thermodynamic integration free energy simulations.

Sulfur heterocycles are found in low concentrations in most coalderived liquids and shale oils, and therefore, isolation of the heterocyclic sulfur fraction is necessary for individual compound Identification. In this report, a new methodology for the isolation and subsequent separation and identification of sulfur heterocycles is described and applied to selected coal liquids and shale oils. Identification was accomplished by sulfur-selective flame photometrk detection and comparison of mass spectral and chromatographic retention data of mixture components with standard reference compounds. Chromatographic retention data for 32 standard sulfur heterocycles were determined.