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To identify new chemical series with enhanced binding affinity to the BTB domain of B-cell lymphoma 6 protein, we targeted a subpocket adjacent to Val18. With no opportunities for strong polar interactions, we focused on attaining close shape complementarity by ring fusion onto our quinolinone lead series. Following exploration of different sized rings, we identified a conformationally restricted core which optimally filled the available space, leading to potent BCL6 inhibitors. Through X-ray structure-guided design, combined with efficient synthetic chemistry to make the resulting novel core structures, a300-fold improvement in activity was obtained by the addition of seven heavy atoms.

Deregulation of the transcriptional repressor BCL6 enables tumorigenesis of germinal center B-cells, and hence BCL6 has been proposed as a therapeutic target for the treatment of diffuse large B-cell lymphoma (DLBCL). Herein we report the discovery of a series of benzimidazolone inhibitors of the protein–protein interaction between BCL6 and its co-repressors. A subset of these inhibitors were found to cause rapid degradation of BCL6, and optimization of pharmacokinetic properties led to the discovery of 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (CCT369260), which reduces BCL6 levels in a lymphoma xenograft mouse model following oral dosing.

Background Cardiovascular autonomic dysfunction is an early marker for cardiovascular disease. Anthracycline chemotherapy and left-sided radiation for breast cancer are associated with negative autonomic function changes. This study's objectives were to characterize changes in, and the association of exercise training with, clinical indices of cardiovascular autonomic function across the trajectory of breast cancer therapy. Subjects, Materials, and Methods Seventy-three patients receiving adjuvant chemotherapy participated to varying degrees in supervised aerobic and resistance exercise during chemotherapy ± radiation and for 20 weeks after. Resting heart rate (HRrest) and blood pressure were measured weekly during chemotherapy. HRrest, exercise heart rate recovery (HRrecovery), and aerobic fitness were measured at enrollment, end of chemotherapy ± radiation, and 10 and 20 weeks after treatment. Results During chemotherapy, HRrest increased in a parabolic manner within a single treatment and with increasing treatment dose, whereas systolic and diastolic blood pressure decreased linearly across treatments. Tachycardia and hypotension were present in 32%–51% of participants. Factors associated with weekly changes during chemotherapy included receiving anthracyclines or trastuzumab, days since last treatment, hematocrit, and exercise attendance. Receipt of anthracyclines, trastuzumab, and left-sided radiation individually predicted impairments of HRrest and HRrecovery during chemotherapy ± radiation; however, aerobic fitness change and at least twice-weekly exercise attendance predicted improvement. By 10 weeks after treatment, HRrest and blood pressure were not different from prechemotherapy. Conclusion In this study, chemotherapy resulted in increased HRrest and tachycardia, as well as decreased blood pressure and hypotension. Anthracyclines, trastuzumab, and left-sided radiation were associated with HRrest elevations and impairments of HRrecovery, but exercise training at least twice a week appeared to mitigate these changes. Implications for Practice This study characterized changes in clinically accessible measures with well-established prognostic value for cardiovascular disease, and investigated associations with cardiotoxic treatments and the positive influence of exercise. The chemotherapy-related incremental increase in resting heart rate, with tachycardia occurring in one third of patients, and decrease in blood pressure, with hypotension occurring in one half of the patients, is relevant to oncology practitioners for clinical examination or patient report of related symptoms (i.e., dizziness). The weekly dose of two 60-minute sessions of moderate-intensity aerobic and resistance exercise that was identified as protective of cardiovascular autonomic impairments can easily be prescribed to patients by oncologists.

A regio- and stereoselective one-pot C-H insertion/olefination protocol has been developed for the late stage installation of α-methylene-γ-butyrolactones into conformationally restricted cyclohexanol-derivatives. The method has been successfully applied in the total synthesis of eudesmanolide natural product frameworks, including α-cyclocostunolide.

We read with interest the paper by Thibodeau et al. [(1)][1] describing the role of the clinical examination in patients with heart failure. Zema [(2)][2] should also be commended for his letter emphasizing the role of the Valsalva maneuver in the diagnosis of heart failure. We regularly perform

Baroreflex‐mediated changes in heart rate and vascular resistance in response to variations in blood pressure are critical to maintain homeostasis. We aimed to develop time domain analysis methods to complement existing cross‐spectral techniques in the investigation of the vascular resistance baroreflex response to orthostatic stress. A secondary goal was to apply these methods to distinguish between levels of orthostatic tolerance using baseline data. Eleven healthy, normotensive males participated in a graded lower body negative pressure protocol. Within individual neurogenic baroreflex cycles, the amount of muscle sympathetic nerve activity (MSNA), the diastolic pressure stimulus and response amplitudes, diastolic pressure to MSNA burst stimulus and response times, as well as the stimulus and response slopes between diastolic pressure and MSNA were computed. Coherence, gain, and frequency of highest coherence between systolic/diastolic arterial pressure (SAP/DAP) and RR‐interval time series were also computed. The number of MSNA bursts per low‐frequency cycle increased from 2.55 ± 0.68 at baseline to 5.44 ± 1.56 at −40 mmHg of LBNP. Stimulus time decreased (3.21 ± 1.48–1.46 ± 0.43 sec), as did response time (3.47 ± 0.86–2.37 ± 0.27 sec). At baseline, DAP‐RR coherence, DAP‐RR gain, and the time delay between decreases in DAP and MSNA bursts were higher in participants who experienced symptoms of presyncope. Results clarified the role of different branches of the baroreflex loop, and suggested functional adaptation of neuronal pathways to orthostatic stress.

Phosphorylated cyclopropanes, generated via the Rh(ii)-catalysed intramolecular cyclopropanation of α-(diethoxyphosphoryl)acetates, have been found to be useful precursors in the synthesis of α-alkylidene-γ-butyrolactones. These cyclopropyl intermediates undergo regioselective reductive ring-opening and subsequent Horner-Wadsworth-Emmons olefination to complete the synthesis. Total syntheses of (±)-savinin and (±)-gadain, as well as the first total synthesis of (±)-peperomin E, are all described using this method.

The arterial baroreflex is crucial for short‐term blood pressure control – abnormal baroreflex function predisposes to syncope and falling. Hypersensitive responses to carotid baroreflex stimulation using carotid sinus massage (CSM) are common in older adults and may be associated with syncope. The pathophysiology of this hypersensitivity is unknown, but chronic denervation of the sternocleidomastoid muscles is common in elderly patients with carotid sinus hypersensitivity (CSH), and is proposed to interfere with normal integration of afferent firing from the carotid baroreceptors with proprioceptive feedback from the sternocleidomastoids, producing large responses to CSM. We hypothesized that simulation of sternocleidomastoid “denervation” using pharmacological blockade would increase cardiovascular responses to CSM. Thirteen participants received supine and tilted CSM prior to intramuscular injections (6–8 mL distributed over four sites) of 2% lidocaine hydrochloride, and 0.9% saline (placebo) in contralateral sternocleidomastoid muscles. Muscle activation was recorded with electromyography (EMG) during maximal unilateral sternocleidomastoid contraction both pre‐ and postinjection. Supine and tilted CSM were repeated following injections and responses compared to preinjection. Following lidocaine injection, the muscle activation fell to 23 ± 0.04% of the preinjection value (P 0.05). Neural block of the sternocleidomastoid muscles does not increase cardiovascular responses to CSM. The pathophysiology of CSH remains unknown.