Browsing by Subject "SH-11037"

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    The molecular mechanism of action of the antiangiogenic natural product, cremastranone
    (2016-07) Basavarajappa, Halesha Dhurvigere; Corson, Timothy W.; Grant, Maria B.; Hurley, Thomas D.; Quilliam, Lawrence A.; Chan, Rebecca
    Prevention of pathological angiogenesis is a key strategy for treatment of common blinding ocular diseases such as retinopathy of prematurity, proliferative diabetic retinopathy, and wet age-related macular degeneration. The current treatment strategies are associated with partial vision loss and are ineffective in a significant patient population. Hence novel drugs as well as new ways to target ocular angiogenesis are needed for treating these diseases. I pursued a natural antiangiogenic compound, cremastranone, to develop novel drug leads and to find new targets. The objective of my doctoral thesis project was to elucidate cremastranone’s molecular mechanism of action and optimize its structureactivity relationship (SAR). In order to achieve this goal, with the help of chemistry collaborators cremastranone was synthesized for the first time. I showed that cremastranone has 50-fold more potency against endothelial cells as compared to nonendothelial cells, and also tested a novel active isomer, SH-11052. By SAR studies I identified a potent molecule, SH-11037, that has 10-fold more selectivity against retinal endothelial cells as compared to macrovascular endothelial cells. I then elucidated cremastranone’s molecular mechanism using a chemical proteomic approach. I identified ferrochelatase (FECH) as a specific interacting protein partner of cremastranone using photoaffinity chromatography. Hence, I hypothesized that cremastranone exerts its antiangiogenic activities through modulation of the functions of FECH. Cremastranone inhibited the enzymatic activity FECH in endothelial cells. Therefore, I investigated the role of FECH in ocular angiogenesis. Partial loss of FECH, using a siRNA-based knock down approach, decreased retinal angiogenesis both in vitro and in vivo in mouse models. Knock down of FECH decreased the expression levels of key proangiogenic proteins HIF-1α, eNOS, and VEGFR2. This work suggests that ferrochelatase plays an important, previously undocumented role in angiogenesis and that targeting of this enzyme by cremastranone might be exploited to inhibit pathological angiogenesis in ocular diseases.
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    Mouse Pharmacokinetics and In Vitro Metabolism of SH-11037 and SH-11008, Synthetic Homoisoflavonoids for Retinal Neovascularization
    (MDPI, 2022-10-24) Kim, Eun-yeong; Lee, Bit; Kwon, Sangil; Corson, Timothy W.; Seo, Seung-Yong; Lee, Kiho; Biochemistry and Molecular Biology, School of Medicine
    Cremastranone is a member of the homoisoflavanone family with anti-angiogenic activity in the eyes. SH-11037, a potent and selective synthetic homoisoflavonoid derived from cremastranone, was studied here for pharmacokinetics and metabolism characterization with a special focus on esterase-mediated hydrolysis. SH-11037 was shown to be converted rapidly and nearly completely to SH-11008 following an intravenous dose in mice. SH-11008 showed a high systemic clearance well exceeding the hepatic blood flow in mice. Neither SH-11037 nor SH-11008 were detected in plasma following oral administration of SH-11037 and SH-11008 in mice. Carboxylesterase was shown to be responsible for the rapid and quantitative hydrolysis of SH-11037 to SH-11008 in mouse plasma; the hydrolytic bioconversion was much slower in dog and human plasma, with butyrylcholinesterase and paraoxonase 1 likely being responsible. In vitro metabolism studies with liver S9 fractions suggested that SH-11008 was likely to have a high hepatic metabolic clearance with a predicted hepatic extraction ratio close to 1 in both mouse and human. In conclusion, SH-11037 and SH-11008 both appear to possess pharmacokinetic profiles suboptimal as a systemic agent. SH-11008 is suggested to possess a low potential for systemic toxicity suitable as a topical ocular therapeutic agent.