Novel Hypoxia-Inducible Factor 1α (HIF-1α) Inhibitors for Angiogenesis-Related Ocular Diseases: Discovery of a Novel Scaffold via Ring-Truncation Strategy

Abstract

Ocular diseases featuring pathologic neovascularization are the leading cause of blindness, and anti-VEGF agents have been conventionally used to treat these diseases. Recently, regulating factors upstream of VEGF, such as HIF-1α, have emerged as a desirable therapeutic approach because the use of anti-VEGF agents is currently being reconsidered due to the VEGF action as a trophic factor. Here, we report a novel scaffold discovered through the complete structure−activity relationship of ring-truncated deguelin analogs in HIF-1α inhibition. Interestingly, analog 6i possessing a 2-fluorobenzene moiety instead of a dimethoxybenzene moiety exhibited excellent HIF-1α inhibitory activity, with an IC 50 value of 100 nM. In particular, the further ring-truncated analog 34f, which showed enhanced HIF-1α inhibitory activity compared to analog 2 previously reported by us, inhibited in vitro angiogenesis and effectively suppressed hypoxia-mediated retinal neovascularization. Importantly, the heteroatom-substituted benzene ring as a key structural feature of analog 34f was identified as a novel scaffold for HIF-1α inhibitors that can be used in lieu of a chromene ring.

Selective α-Methylation of Aryl Ketones Using Quaternary Ammonium Salts as Solid Methylating Agents

“… 33 SAR studies identified the latter as promising candidates for HIF-1α inhibitors. 34 One of those analogues, SH-1242, further inhibits Hsp90 activity and shows potent anticancer efficacy. 35 We could demonstrate the applicability of this method for benzylation of selected substrates using BnMe 3 NCl as a benzylating agent.…”

Nutraceuticals for the Treatment of Diabetic Retinopathy

“…It has also been shown to inhibit tube formation of human umbilical vein endothelial cells (HUVECs) and in vivo angiogenesis of chick chorioallantoic membrane [174], which is consistent with deguelin antiangiogenic activity. In addition, deguelin analogs have been recently produced which inhibit HIF-1α and reduce both in vitro angiogenesis and neovascularization in the OIR model [176].…”

Determining Essential Requirements for Fluorophore Selection in Various Fluorescence Applications Taking Advantage of Diverse Structure–Fluorescence Information of Chromone Derivatives

“…Next, various 7-amino chromones were obtained in two more steps. The 7-hydroxyl group was first functionalized with trifluoromethanesulfonic anhydride (Tf 2 O) under aqueous conditions to yield the triflate, − followed by the synthesis of the desired amine derivative. 7-Primary amine chromone analogues were obtained by removing benzophenone oxime in acidic conditions after palladium-catalyzed Buchwald–Hartwig coupling reactions of triflate with benzophenone imine.…”

“…7-Ethylamino chromone analogues were obtained by N-monoalkylation of a primary amine with alkyl halides. 7-Tertiary amine chromone analogues were synthesized by palladium-catalyzed Buchwald–Hartwig reactions of triflate with the corresponding amines in the presence of palladium acetate. , …”

“…The anhydrous conditions and oxygen removal are not seriously required. Moreover, the reaction went on quickly with decent yields for a wide range of substrates. − …”