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Annexin uptake was normalized to the saline-injected control animals

Annexin uptake was normalized to the saline-injected control animals. an important contributor to doxorubicin cardiotoxicity and suggest that modulation of this pathway could be beneficial in the clinical setting. that has previously been used as an herbal remedy for kidney stones and high blood pressure. In cultured cells exposed to DOX, cotreatment with C1 decreased apoptosis in cardiomyocytes but did not affect apoptosis LECT1 in a number of tumor cell lines. Likewise, C1 preserved cardiac function during acute and chronic DOX administration in adult mice, though it did not affect the tumoricidal activity of DOX in mouse and zebrafish xenograft models. Here we describe structure-activity relationship (SAR) studies of C1, guided primarily by large-scale in vivo phenotypic assessment allowing for rapid determination of efficacy and toxicity in a whole-organism model. The identification of structural modifications that improve the in vivo potency of C1 may facilitate the development of this family of compounds as cardioprotective brokers for patients receiving anthracycline chemotherapy. Open in a MZ1 separate window Physique 1 Optimization of compound 1 (C1, visnagin) in an in vivo model of DOX-induced cardiac toxicity.EC50 values were calculated based on the percent of zebrafish rescued from the DOX cardiomyopathy phenotype (decreased cardiac contraction, pericardial edema, and decreased tail blood flow) as assessed under light microscopy at 40 hours after treatment. Initial SAR experiments included modification of the tricyclic structure of C1, addition of a methoxy group to the middle phenyl ring, and modification of substituents around the pyrone ring. Results Determination MZ1 of SAR in zebrafish. Using the zebrafish DOX cardiotoxicity model to explore SAR, we began by assessing the MZ1 contribution of the tricyclic aromatic structure of C1 to in vivo potency (Physique MZ1 1 and Supplemental Physique 1; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.96753DS1). We discovered that removal of either the pyrone or furan rings (C2 and C3) abolished activity. Although C2 and C3 also lack additional substituents around the pyrone and benzene rings, these substituents were not essential to activity in subsequent studies (e.g., C11), highlighting the importance of maintaining the tricyclic structure as a scaffold for further modifications. We then turned our attention to the ring substituents around the chromone portion of C1. Addition of a methoxy group to the 9 position (C4) modestly improved activity. Movement of the carbonyl group from the 7 position to the 5 position (C5) resulted in a further improvement in potency, as did substitution of a thiocarbonyl in the 5 position. As C5 was commercially available, we chose to use it as a scaffold for subsequent SAR studies. To further optimize C5, we started with modification of the furan moiety to determine the contribution of this ring to activity in zebrafish (Physique 2A). We first moved the furan ring to the [2,3-h] position and found that the resulting C7 had comparable potency to C5. Removal of the furan ring and substitution of an additional methoxy group in the 7 position (C8) resulted in decreased activity relative to C5. Interestingly, removal of both the furan ring and the 4-methoxy group around the chromone core of C5 (C9) resulted in a complete loss of activity. We then studied reduction of the double bond of the.