No abstract

No abstract

Ring substituted derivatives of 2-(4-aminophenyl)benzothiazole, 1a, 1b–1g, are under development as anti-tumor agents. One derivative, 1f, has reached Phase 1 clinical trials as the pro-drug, 2f, Phortress (NSC 710305). These amines are activated by CYP450 1A1, apparently into hydroxylamines, 8a–8g, that are likely metabolized into esters that ionize into nitrenium ions responsible for cellular damage. Previously we showed that 9a, the acetic acid ester of 8a, generates the long-lived (530 ns) nitrenium ion 11a by hydrolysis or photolysis in water. In this study, azide trapping shows that 9b–9g generate 11b–11g via rate-limiting N-O heterolysis. Ion lifetimes, estimated from azide/solvent selectivities, range from 250–1150 ns with identical lifetimes for 11a and 11f. Differences in biological activity of the amines are likely not due to differences in the chemistry of the cations, but to differences in metabolic activation/deactivation of individual amines. Unlike the nitrenium ions, lifetimes of the esters are strongly dependent on the 3′-Me substituent. Esters containing 3′-Me (9b, 9f, 9g) have lifetimes of 5–10 s compared to 400–800 s for esters without 3′-Me (9a, 9c, 9d, 9e). This restricts 3′-Me esters to cells/tissues in which activation occurs, concentrating their effects in tumor cells if metabolism is restricted to those cells.

ObjectiveEchocardiography-guided Percutaneous IntraMyocardial Septal Radiofrequency Ablation (PIMSRA, Liwen procedure) is a novel treatment option for hypertrophic obstructive cardiomyopathy (HOCM). The impact of PIMSRA on myocardial mechanics is unknown.MethodsBetween October 2016 and June 2019, PIMSRA and 3-dimentional speckle tracking echocardiography were performed in 82 patients. Echocardiographic imaging, qualitative and quantitative clinical assessment were completed at baseline, immediately postprocedure and 1-year follow-up.ResultsThere was a significant reduction in the peak left ventricular outflow tract (LVOT) gradients immediately following PIMSRA and at 1-year follow-up (resting gradients: from 83.50 (61.25) to 23.00 (41.75) mm Hg, p<0.001 and 13.50 (21.75) mm Hg, p<0.001, respectively; stress-induced gradients: from 118.25 (96.02) to 47.00 (74.50) mm Hg (1 year), p<0.001). There was an improvement in exercise time on stress echocardiography (p<0.001) and distance by 6 min walk test (p=0.034). Immediately after PIMSRA, there was a significant reduction in radial and circumferential strain in the ablated segments (p<0.001), with no change of longitudinal strain. At 1-year follow-up, the radial and circumferential strain recovered in the ablated segments. Meanwhile, left ventricular regional and global longitudinal strain had improved significantly (p<0.05).ConclusionsPIMSRA is an effective treatment for symptomatic HOCM that resulted in a sustained improvement in exercise capacity, a persistent decrease in LVOT gradient, and a measurable increase in myocardial contractile function.Trial registration numberNCT04777188.

No abstract