Analogs of the antimitotic herbicide oryzalin (3,5-dinitro-N4,N4-di-n-propylsulfanilamide) were recently prepared that were more potent in vitro than the parent compound against the kinetoplastid parasite Leishmania donovani (Bioorg Med Chem Lett 12:2395-2398. In the present work, we show that the most active molecule in the group,

Summary Romidepsin has shown promise in the treatment of T‐cell lymphomas, and so we evaluated molecular endpoints gathered from 61 patients enrolled on a phase II trial of romidepsin in cutaneous and peripheral T‐cell lymphoma at the National Institutes of Health. The endpoints included histone H3 acetylation and ABCB1 gene expression in peripheral blood mononuclear cells (PBMCs); ABCB1 gene expression in tumour biopsy samples; and blood fetal haemoglobin levels (HbF), all of which were increased following romidepsin treatment. The fold increase in histone acetylation in PBMCs at 24 h was weakly to moderately well correlated with the pharmacokinetic parameters Cmax and area under the curve (AUC)last (ρ = 0·37, P = 0·03 and ρ = 0·36, P = 0·03 respectively) and inversely associated with clearance (ρ = −0·44; P = 0·03). Histone acetylation in PBMCs at 24 h was associated with response (P = 0·026) as was the increase in fetal haemoglobin (P = 0·014); this latter association may be due to the longer on‐study duration for patients with disease response. Together, these results suggest that pharmacokinetics may be an important determinant of response to histone deacetylase inhibitors (HDIs) – the association with histone acetylation in PBMCs at 24 h is consistent with a hypothesis that potent HDIs are needed for a critical threshold of drug exposure and durable activity.

ABCG2 is a transporter with potential importance in cancer drug resistance, drug oral absorption, and stem cell biology. In an effort to identify novel inhibitors of ABCG2, we examined the ability of commercially available bisindolylmaleimides (BIM) and indolocarbazole protein kinase inhibitors (PKI) to inhibit ABCG2, given the previous demonstration that the indolocarbazole PKI UCN-01 interacted with the transporter. At a concentration of 10 Mmol/L, all of the compounds tested increased intracellular fluorescence of the ABCG2-specific substrate pheophorbide a in ABCG2-transfected HEK-293 cells by 1.3-to 6-fold as measured by flow cytometry; the ABCG2-specific inhibitor fumitremorgin C increased intracellular fluorescence by 6.6-fold. In 4-day cytotoxicity assays, wild-type ABCG2-transfected cells were not more than 2-fold resistant to any of the compounds, suggesting that the PKIs are not significantly transported by ABCG2. BIMs I, II, III, IV, and V, K252c, and arcyriaflavin A were also able to inhibit [ 125 I]iodoarylazidoprazosin labeling of ABCG2 by 65% to 80% at 20 Mmol/L, compared with a 50% to 70% reduction by 20 Mmol/L fumitremorgin C. K252c and arcyriaflavin A were the most potent compounds, with IC 50 values for inhibition of [ 125 I]iodoarylazidoprazosin labeling of 0.37 and 0.23 Mmol/L, respectively. K252c and arcyriaflavin A did not have any effect on the ATPase activity of ABCG2. Four minimally toxic compounds-BIM IV, BIM V, arcyriaflavin A, and K252c-reduced the relative resistance of ABCG2-transfected cells to SN-38 in cytotoxicity assays. We find that indolocarbazole and BIM PKIs directly interact with the ABCG2 protein and may thus increase oral bioavailability of ABCG2 substrates.

Purpose-ABCG2 overexpression has been linked to resistance to topoisomerase inhibitors, leading us to examine the potential interaction between ABCG2 and becatecarin.Methods-Interaction with ABCG2 was determined by ATPase assay, competition of [ 125 I] iodoarylazidoprazosin (IAAP) photolabeling and flow cytometry. Cellular resistance was measured in four-day cytotoxicity assays. ABCG2 expression was measured by fluorescent-substrate transport assays and immunoblot.Results-Becatecarin competed [ 125 I]-IAAP labeling of ABCG2, stimulated ATPase activity and, at concentrations greater than 10 μM, inhibited ABCG2-mediated transport. Becatecarin-selected A549 Bec150 lung carcinoma cells were 3.1-fold, 15-fold, 8-fold, and 6.8-fold resistant to becatecarin, mitoxantrone, SN-38 and topotecan, respectively. A549 Bec150 cells transported the ABCG2 substrates pheophorbide a, mitoxantrone and BODIPY-prazosin and displayed increased staining with the anti-ABCG2 antibody 5D3 compared to parental cells. Increased ABCG2 expression was confirmed by immunoblot.Conclusions-Our results suggest that becatecarin is transported by ABCG2 and can induce ABCG2 expression in cancer cells.