Browsing by Author "Kwon, Sangil"

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    Enantioselective Synthesis of Homoisoflavanones by Asymmetric Transfer Hydrogenation and Their Biological Evaluation for Antiangiogenic Activity
    (ACS Publications, 2019-08-05) Heo, Myunghoe; Lee, Bit; Sishtla, Kamakshi; Fei, Xiang; Lee, Sanha; Park, Soojun; Yuan, Yue; Lee, Seul; Kwon, Sangil; Lee, Jungeun; Kim, Sanghee; Corson, Timothy W.; Seo, Seung-Yong; Ophthalmology, School of Medicine
    Neovascular eye diseases are a major cause of blindness. Excessive angiogenesis is a feature of several conditions, including wet age-related macular degeneration, proliferative diabetic retinopathy, and retinopathy of prematurity. Development of novel anti-angiogenic small molecules for the treatment of neovascular eye disease is essential to provide new therapeutic leads for these diseases. We have previously reported the therapeutic potential of anti-angiogenic homoisoflavanone derivatives with efficacy in retinal and choroidal neovascularization models, although these are racemic compounds due to the C3-stereogenic center in the molecules. This work presents asymmetric synthesis and structural determination of anti-angiogenic homoisoflavanones and pharmacological characterization of the stereoisomers. We describe an enantioselective synthesis of homoisoflavanones by virtue of ruthenium-catalyzed asymmetric transfer hydrogenation accompanying dynamic kinetic resolution, providing a basis for the further development of these compounds into novel experimental therapeutics for neovascular eye 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.
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    Small-molecule inhibitors of ferrochelatase are antiangiogenic agents
    (Elsevier, 2022-01-31) Sishtla, Kamakshi; Lambert-Cheatham, Nathan; Lee, Bit; Han, Duk Hee; Park, Jaehui; Sardar Pasha, Sheik Pran Babu; Lee, Sanha; Kwon, Sangil; Muniyandi, Anbukkarasi; Park, Bomina; Odell, Noa; Waller, Sydney; Park, Il Yeong; Lee, Soo Jae; Seo, Seung-Yong; Corson, Timothy W.; Ophthalmology, School of Medicine
    Activity of the heme synthesis enzyme ferrochelatase (FECH) is implicated in multiple diseases. In particular, it is a mediator of neovascularization in the eye and thus an appealing therapeutic target for preventing blindness. However, no drug-like direct FECH inhibitors are known. Here, we set out to identify small-molecule inhibitors of FECH as potential therapeutic leads using a high-throughput screening approach to identify potent inhibitors of FECH activity. A structure-activity relationship study of a class of triazolopyrimidinone hits yielded drug-like FECH inhibitors. These compounds inhibit FECH in cells, bind the active site in cocrystal structures, and are antiangiogenic in multiple in vitro assays. One of these promising compounds was antiangiogenic in vivo in a mouse model of choroidal neovascularization. This foundational work may be the basis for new therapeutic agents to combat not only ocular neovascularization but also other diseases characterized by FECH activity.
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    Total Synthesis of Naturally Occurring 5,7,8-Trioxygenated Homoisoflavonoids
    (American Chemical Society, 2020-05-06) Kwon, Sangil; Lee, Sanha; Heo, Myunghoe; Lee, Bit; Fei, Xiang; Corson, Timothy W.; Seo, Seung-Yong; Ophthalmology, School of Medicine
    Homoisoflavonoids are in the subclass of the larger family of flavonoids but have one more alkyl carbon than flavonoids. Among them, 5,7,8-trioxygenated homoisoflavonoids have not been extensively studied for synthesis and biological evaluation. Our current objective is to synthesize 2 5,7,8-trioxygenated chroman-4-ones and 12 5,7,8-trioxygenated homoisoflavonoids that have been isolated from the plants Bellevalia eigii, Drimiopsis maculata, Ledebouria graminifolia, Eucomis autumnalis, Eucomis punctata, Eucomis pallidiflora, Chionodoxa luciliae, Muscari comosum, and Dracaena cochinchinensis. For this purpose, 1,3,4,5-tetramethoxybenzene and 4'-benzyloxy-2',3'-dimethoxy-6'-hydroxyacetophenone were used as starting materials. Asymmetric transfer hydrogenation using Noyori's Ru catalyst provided 5,7,8-trioxygenated-3-benzylchroman-4-ones with R-configuration in high yield and enantiomeric excess. By selective deprotection of homoisoflavonoids using BCl3, the total synthesis of natural products including 10 first syntheses and three asymmetric syntheses has been completed, and three isomers of the reported dracaeconolide B could be provided. Our research on 5,7,8-trioxygenated homoisoflavonoids would be useful for the synthesis of related natural products and pharmacological applications.