There are hundreds of ligands which can interact with G-quadruplex DNA, yet very few which target i-motif. To appreciate an understanding between the dynamics between these structures and how they can be affected by intervention with small molecule ligands, more i-motif binding compounds are required. Herein we describe how the drug mitoxantrone can bind, induce folding of and stabilise i-motif forming DNA sequences, even at physiological pH. Additionally, mitoxantrone was found to bind i-motif forming sequences preferentially over double helical DNA. We also describe the stabilisation properties of analogues of mitoxantrone. This offers a new family of ligands with potential for use in experiments into the structure and function of i-motif forming DNA sequences.

Aldehyde dehydrogenase 1A3 (ALDH1A3) has recently gained attention from researchers in the cancer field. Several studies have reported ALDH1A3 overexpression in different cancer types, which has been found to correlate with poor treatment recovery. Therefore, finding selective inhibitors against ALDH1A3 could result in new treatment options for cancer treatment. In this study, ALDH1A3-selective candidates were designed based on the physiological substrate resemblance, synthesized and investigated for ALDH1A1, ALDH1A3 and ALDH3A1 selectivity and cytotoxicity using ALDH-positive A549 and ALDH-negative H1299 cells. Two compounds (ABMM-15 and ABMM-16), with a benzyloxybenzaldehyde scaffold, were found to be the most potent and selective inhibitors for ALDH1A3, with IC50 values of 0.23 and 1.29 µM, respectively. The results also show no significant cytotoxicity for ABMM-15 and ABMM-16 on either cell line. However, a few other candidates (ABMM-6, ABMM-24, ABMM-32) showed considerable cytotoxicity on H1299 cells, when compared to A549 cells, with IC50 values of 14.0, 13.7 and 13.0µM, respectively. The computational study supported the experimental results and suggested a good binding for ABMM-15 and ABMM-16 to the ALDH1A3 isoform. From the obtained results, it can be concluded that benzyloxybenzaldehyde might be considered a promising scaffold for further drug discovery aimed at exploiting ALDH1A3 for therapeutic intervention.

Previous factor-analytic studies of self-rating scales have yielded a factor on which negatively worded items loaded separately. The present study investigated the existence for such a factor in a questionnaire for course and teacher evaluation which included one negative item. The questionnaire was administered in 1,095 university classes. Two factors emerged, an exclusively positive-item factor and another factor on which the single negative item and one positive item loaded. It was suggested that both items of Factor 2 were ambiguous and may identify tendencies such as acquiescence, random responding, and response sets.

Aldehyde dehydrogenases (ALDHs) are overexpressed in various tumor types including prostate cancer and considered a potential target for therapeutic intervention. 4-(Diethylamino)benzaldehyde (DEAB) has been extensively reported as a pan-inhibitor of ALDH isoforms, and here, we report on the synthesis, ALDH isoform selectivity, and cellular potencies in prostate cancer cells of 40 DEAB analogues; three analogues ( 14 , 15 , and 16 ) showed potent inhibitory activity against ALDH1A3, and two analogues ( 18 and 19 ) showed potent inhibitory activity against ALDH3A1. Significantly, 16 analogues displayed increased cytotoxicity (IC 50 = 10–200 μM) compared with DEAB (>200 μM) against three different prostate cancer cell lines. Analogues 14 and 18 were more potent than DEAB against patient-derived primary prostate tumor epithelial cells, as single agents or in combination treatment with docetaxel. In conclusion, our study supports the use of DEAB as an ALDH inhibitor but also reveals closely related analogues with increased selectivity and potency.

The functional role of aldehyde dehydrogenases (ALDHs) in prostate cancer remains an area of some controversy. Many studies have used high ALDH functional activity to isolate putative cancer stem cells with tumour-initiating and propagating properties, while evidence is also emerging about the involvement of specific isoforms in migration, invasiveness and metastasis. Identification of specific ALDH isoforms, which contribute to both drug resistance and aggressiveness of the disease remains a challenge within the complex heterogeneity of prostate cancer. The purpose of this perspective is to dissect functional roles for ALDH in the tumour microenvironment and to evaluate the potential of the ALDH gene family as biomarkers and/or targets for therapeutic intervention. ABSTRACTArticle history: