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Yohimbine as a Starting Point to Access Diverse Natural Product-Like Agents with Re-programmed Activities against Cancer-Relevant GPCR Targets.

ABSTRACT: G protein-coupled receptors (GPCRs) constitute the largest protein superfamily in the human genome. GPCRs play key roles in mediating a wide variety of physiological events including proliferation and cancer metastasis. Given the major roles that GPCRs play in mediating cancer growth, they present promising targets for small molecule therapeutics. One of the principal goals of our lab is to identify complex natural products (NPs) suitable for ring distortion, or the dramatic altering of the inherently complex architectures of NPs, to rapidly generate an array of compounds with diverse molecular skeletal systems. The overarching goal of our ring distortion approach is to re-program the biological activity of select natural products and identify new compounds of importance to the treatment of disease, such as cancer. Described herein are the results from biological screens of diverse small molecules derived from the indole alkaloid yohimbine against a panel of GPCRs involved in various diseases. Several analogues displayed highly differential antagonistic activities across the GPCRs tested. We highlight the re-programmed profile of one analogue, Y7g, which exhibited selective antagonistic activities against AVPR2 (IC₅₀ = 459 nM) and OXTR (IC₅₀ = 1.16 µM). The activity profile of Y7g could correlate its HIF-dependent anti-cancer activity to its GPCR antagonism since these receptors are known to be upregulated in hypoxic cellular environments. Our findings demonstrate that the ring distortion of yohimbine can lead to the identification of new compounds capable of interacting with distinct cancer-relevant targets.

SUBMITTER: Paciaroni NG

PROVIDER: S-EPMC7392148 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background and objectivesFistulas, the preferred form of hemodialysis access, are difficult to establish and maintain. We examined the effect of a multidisciplinary vascular access team, including nurses, surgeons, and radiologists, on the probability of using a fistula catheter-free, and rates of access-related procedures in incident patients receiving hemodialysis.Design, setting, participants, & measurementsWe examined vascular access outcomes in the first year of hemodialysis treatment before (2004-2005, preteam period) and after the implementation of an access team (2006-2008, early-team period; 2009-2011, late-team period) in the Calgary Health Region, Canada. We used logistic regression to study the probability of fistula creation and the probability of catheter-free fistula use, and negative binomial regression to study access-related procedure rates.ResultsWe included 609 adults (mean age, 65 [±15] years; 61% men; 54% with diabetes). By the end of the first year of hemodialysis, 102 participants received a fistula in the preteam period (70%), 196 (78%) in the early-team period (odds ratios versus preteam, 1.47; 95% confidence interval, 0.92 to 2.35), and 139 (66%) in the late-team period (0.85; 0.54 to 1.35). Access team implementation did not affect the probability of catheter-free use of the fistula (odds ratio, 0.87; 95% confidence interval, 0.52 to 1.43, for the early; and 0.89; 0.52 to 1.53, for the late team versus preteam period). Participants underwent an average of 4-5 total access-related procedures during the first year of hemodialysis, with higher rates in women and in people with comorbidities. Catheter-related procedure rates were similar before and after team implementation; relative to the preteam period, fistula-related procedure rates were 40% (20%-60%) and 30% (10%-50%) higher in the early-team and late-team periods, respectively.ConclusionIntroduction of a multidisciplinary access team did not increase the probability of catheter-free fistula use, but resulted in higher rates of fistula-related procedures.

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Yohimbine as a Starting Point to Access Diverse Natural Product-Like Agents with Re-programmed Activities against Cancer-Relevant GPCR Targets.

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