A Review of the Pharmacological Activities and Recent Synthetic Advances of γ-Butyrolactones

γ-Butyrolactone, a five-membered lactone moiety, is one of the privileged structures of diverse natural products and biologically active small molecules. Because of their broad spectrum of biological and pharmacological activities, synthetic methods for γ-butyrolactones have received significant attention from synthetic and medicinal chemists for decades. Recently, new developments and improvements in traditional methods have been reported by considering synthetic efficiency, feasibility, and green chemistry. In this review, the pharmacological activities of natural and synthetic γ-butyrolactones are described, including their structures and bioassay methods. Mainly, we summarize recent advances, occurring during the past decade, in the construction of γ-butyrolactone classified based on the bond formation in γ-butyrolactone between (i) C5-O1 bond, (ii) C4-C5 and C2-O1 bonds, (iii) C3-C4 and C2-O1 bonds, (iv) C3-C4 and C5-O1 bonds, (v) C2-C3 and C2-O1 bonds, (vi) C3-C4 bond, and (vii) C2-O1 bond. In addition, the application to the total synthesis of natural products bearing γ-butyrolactone scaffolds is described

Concise Synthesis of Catechin Metabolites 5-(3′,4′-Dihydroxyphenyl)-γ-valerolactones (DHPV) in Optically Pure Form and Their Stereochemical Effects on Skin Wrinkle-Reducing Activities

A concise and scalable synthetic route for optically pure (4S) and (4R)-5-(3′,4′-dihydroxyphenyl)-γ-valerolactones (DHPVs), catechin metabolites, has been developed via the efficient construction of a γ-valerolactone moiety from hexenol. Noticeably, the different skin wrinkle-reducing activities of each metabolite were revealed via our unique syntheses of DHPVs in an enantiomerically pure form

Design of Anticancer 2,4-Diaminopyrimidines as Novel Anoctamin 1 (ANO1) Ion Channel Blockers

Pyrimidine is a privileged scaffold in many synthetic compounds exhibiting diverse pharmacological activities, and is used for therapeutic applications in a broad spectrum of human diseases. In this study, we prepared a small set of pyrimidine libraries based on the structure of two hit compounds that were identified through the screening of an in-house library in order to identify an inhibitor of anoctamin 1 (ANO1). ANO1 is amplified in various types of human malignant tumors, such as head and neck, parathyroid, and gastrointestinal stromal tumors, as well as in breast, lung, and prostate cancers. After initial screening and further structure optimization, we identified Aa3 as a dose-dependent ANO1 blocker. This compound exhibited more potent anti-cancer activity in the NCI-H460 cell line, expressing high levels of ANO1 compared with that in A549 cells that express low levels of ANO1. Our results open a new direction for the development of small-molecule ANO1 blockers composed of a pyrimidine scaffold and a nitrogen-containing heterocyclic moiety, with drug-like properties

Nicrophorusamides A and B, Antibacterial Chlorinated Cyclic Peptides from a Gut Bacterium of the Carrion Beetle <i>Nicrophorus concolor</i>

Nicrophorusamides A and B (<b>1</b> and <b>2</b>) were discovered from a rare actinomycete, <i>Microbacterium</i> sp., which was isolated from the gut of the carrion beetle <i>Nicrophorus concolor</i>. The structures of the nicrophorusamides were established as new chlorinated cyclic hexapeptides bearing uncommon amino acid units mainly based on 1D and 2D NMR spectroscopic analysis. The absolute configurations of the amino acid residues 5-chloro-l-tryptophan, d-<i>threo</i>-β-hydroxyasparagine/d-asparagine, l-ornithine, l-<i>allo</i>-isoleucine, d-leucine, and d-valine were determined using Marfey’s method and chemical derivatization with 2,3,4,6-tetra-<i>O</i>-acetyl-β-d-glucopyranosyl isothiocyanate followed by LC/MS analysis. Nicrophorusamide A (<b>1</b>) showed antibacterial activity against several Gram-positive bacteria

WS9326H, an Antiangiogenic Pyrazolone-Bearing Peptide from an Intertidal Mudflat Actinomycete

WS9326H (<b>1</b>), a new cyclic peptide, was isolated from a mudflat-derived <i>Streptomyces</i> strain. Based on analysis by 1D/2D NMR, UV spectroscopy, and mass spectrometry, compound <b>1</b> was determined to have the gross structure of a cyclic heptapeptide bearing an unprecedented pyrazolone ring connected to a d-arabinitol via an amide bond. The absolute configuration of <b>1</b> was established by multistep chemical derivatizations, comprehensive NMR, and LC/MS analyses of the derivatives and quantum mechanics-based computational methods. WS9326H (<b>1</b>) displayed significant antiangiogenesis activity

Novel hypoxia-inducible factor 1 alpha (HIF-1 alpha) inhibitors for angiogenesis-related ocular diseases: Discovery of a novel scaffold via ring-truncation strategy

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-1 alpha, 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-1 alpha inhibition. Interestingly, analog 6i possessing a 2-fluorobenzene moiety instead of a dimethoxybenzene moiety exhibited excellent HIF-1 alpha inhibitory activity, with an IC50 value of 100 nM. In particular, the further ring-truncated analog 34f, which showed enhanced HIF-la 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-1 alpha inhibitors that can be used in lieu of a chromene ring.N