D-Ring-Modified Analogues of Luotonin A with Reduced Planarity: Design, Synthesis, and Evaluation of Their Topoisomerase Inhibition-Associated Cytotoxicity

A- and D-ring-modified luotonin-inspired heterocycles have been synthesized and were evaluated for their activity against the viability of four cancer cell lines in vitro, namely, MCF7, HCT116, JURKAT, and NCI-H460. The analysis of results indicated that two of the synthesized derivatives displayed good inhibition against the growth of the human colon cancer HCT116 cell line, with potencies lower than but in the same order of magnitude as camptothecin (CPT). These two luotonin analogues also showed an activity similar to that of the highly potent alkaloid CPT as inhibitors of topoisomerase I and also inhibited topoisomerase II. These results show that complete planarity is not a strict requirement for topoisomerase inhibition by luotonin-related compounds, paving the way to the design of analogues with improved solubility.

Bias toward long gene misregulation in synaptic disorders can be an artefact of amplification-based methods

SUMMARYSeveral recent studies have suggested that genes that are longer than 100 kilobases are more likely to be misregulated in neurological diseases associated with synaptic dysfunction, such as autism and Rett syndrome. These length-dependent transcriptional changes are modest in Mecp2-mutant samples, but, given the low sensitivity of high-throughput transcriptome profiling technology, the statistical significance of these results needs to be re-evaluated. Here, we show that the apparent length-dependent trends previously observed in MeCP2 microarray and RNA-Sequencing datasets, particularly in genes with low fold-changes, disappeared after accounting for baseline variability estimated from randomized control samples. As we found no similar bias with NanoString technology, this long-gene bias seems to be particular to PCR amplification-based platforms. In contrast, authentic long gene effects, such as those caused by topoisomerase inhibition, can be detected even after adjustment for baseline variability. Accurate detection of length-dependent trends requires establishing a baseline from randomized control samples.HIGHLIGHTSLength-dependent gene misregulation is not intrinsic to Mecp2 disruption.Topoisomerase inhibition produces an authentic long gene bias.PCR amplification-based high-throughput datasets are biased toward long genes.