Novel 4-aminoquinoline analogs targeting the HIF-1α signaling pathway

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Novel Lead Generation through Hypothetical Pharmacophore Three-Dimensional Database Searching: Discovery of Isoflavonoids as Nonsteroidal Inhibitors of Rat 5α-Reductase

A hypothetical pharmacophore of 5α-reductase inhibitors was generated and served as a template in virtual screening. When the pharmacophore was used, eight isoflavone derivatives were characterized as novel potential nonsteroidal inhibitors of rat 5α-reductase. This investigation has demonstrated a practical approach toward the development of lead compounds through a hypothetic pharmacophore via three-dimensional database searching

Studies on Quinazolines. 11.^† Intramolecular Imidate-Amide Rearrangement of 2-Substituted 4-(ω-Chloroalkoxy)quinazoline Derivatives. 1,3 -O → N Shift of Chloroalkyl Groups via Cyclic 1,3-Azaoxonium Intermediates

The ω-chloroalkylation of 2-substituted quinazolin-4(3H)-one derivatives 1 and 2 with Br-(CH2)n-Cl (n = 2−4) and the intramolecular imidate-amide rearrangement of the alkylated products are described. At room temperature, the 2-phenyl substituent promoted O-alkylation, whereas the less steric 2-benzyl group led to a higher ratio of N-alkylation. The investigation of the O-alkylated products, 4-ω-chloroalkoxyquinazolines, revealed that the migration of ω-chloroethyl and ω-chloropropyl groups from oxygen to nitrogen should be intramolecular via five- and six-membered cyclic 1,3-azaoxonium intermediates, respectively. Competition between rearrangement and nucleophilic substitution results in the formation of 7a,b and 8a,b from the nucleophilic substitution of 4a,b and 6a,b, respectively

Anti-inflammatory Flavonoids from the Rhizomes of <i>Helminthostachys zeylanica</i>

Eight new prenylated flavonoids, ugonins M−T (1-8), together with five known compounds, ugonins J−L (9−11), 5,4′-dihydroxy-4′′,4′′-dimethyl-5′′-methyl-5′′H-dihydrofurano[2′′,3′′:6,7]flavanone, and quercetin, were isolated and purified from the rhizomes of Helminthostachys zeylanica. The structures of the new isolates were elucidated by spectroscopic and chemical methods. Compounds 1, 3, 5, 7, 8, and 11 showed inhibition of superoxide anion generation and elastase release by human neutrophils in response to formyl-l-methionyl-l-leucyl-l-phenylalanine/cytochalasin B (FMLP/CB)

Anti-inflammatory Flavonoids from the Rhizomes of <i>Helminthostachys zeylanica</i>

Eight new prenylated flavonoids, ugonins M−T (1-8), together with five known compounds, ugonins J−L (9−11), 5,4′-dihydroxy-4′′,4′′-dimethyl-5′′-methyl-5′′H-dihydrofurano[2′′,3′′:6,7]flavanone, and quercetin, were isolated and purified from the rhizomes of Helminthostachys zeylanica. The structures of the new isolates were elucidated by spectroscopic and chemical methods. Compounds 1, 3, 5, 7, 8, and 11 showed inhibition of superoxide anion generation and elastase release by human neutrophils in response to formyl-l-methionyl-l-leucyl-l-phenylalanine/cytochalasin B (FMLP/CB)

Targeting YAP Degradation by a Novel 1,2,4-Oxadiazole Derivative via Restoration of the Function of the Hippo Pathway

Recent evidence has linked the dysregulation of the Hippo pathway to tumorigenesis and cancer progression due to its pivotal role in regulating the stability of the oncoprotein YAP. Based on an unexpected finding from the SAR study of a recently reported oxadiazole-based EGFR/c-Met dual inhibitor (compound 1), we identified a closely related derivative, compound 2, which exhibited cogent antitumor activities while devoid of compound 1’s ability to promote EGFR/c-Met degradation. Compound 2 acted, in part, by facilitating YAP degradation through activation of its upstream kinase LATS1. However, it did not alter the phosphorylation status of MST1/2, a LATS1 kinase, suggesting an alternative mechanism for LATS1 activation. Orally administered compound 2 was effective in suppressing MDA-MB-231 xenograft tumor growth while exhibiting a satisfactory safety profile. From a therapeutic perspective, compound 2 might help foster new therapeutic strategies for cancer treatment by restoring the Hippo pathway regulatory function to facilitate YAP degradation

Stereoselective Synthesis of Spiro Bis-<i>C,C</i>-α-arylglycosides by Tandem Heck Type <i>C</i>‑Glycosylation and Friedel–Crafts Cyclization

Spiro bis-C,C-α-arylglycosides were synthesized in three steps in 78–85% overall yields starting from exo-glycals. The initial Heck type C-aryl addition of exo-glycals with arylboronic acids afforded α-aryl-β-substituted C-glycosides with exclusive α-stereoselectivity. Among the products, β-ethanal α-aryl C-glycosides further reacted with alkylthiol in the presence of InCl3, followed by in situ Friedel–Crafts cyclization to yield the desirable final products. We proposed a mechanism to explain how the α-aryl group serves as a main determinant of the cyclization

Development of Novel Irreversible Pyruvate Kinase M2 Inhibitors

As cancer cells undergo metabolic reprogramming in the course of tumorigenesis, targeting energy metabolism represents a promising strategy in cancer therapy. Among various metabolic enzymes examined, pyruvate kinase M2 type (PKM2) has received much attention in light of its multifaceted function in promoting tumor growth and progression. In this study, we reported the development of a novel irreversible inhibitor of PKM2, compound 1, that exhibits a differential tumor-suppressive effect among an array of cancer cell lines. We further used a clickable activity-based protein profiling (ABPP) probe and SILAC coupled with LC-MS/MS to identify the Cys-317 and Cys-326 residues of PKM2 as the covalent binding sites. Equally important, compound 1 at 10 mg/kg was effective in suppressing xenograft tumor growth in nude mice without causing acute toxicity by targeting both metabolic and oncogenic functions. Together, these data suggest its translational potential to foster new strategies for cancer therapy

Development of Novel Irreversible Pyruvate Kinase M2 Inhibitors

As cancer cells undergo metabolic reprogramming in the course of tumorigenesis, targeting energy metabolism represents a promising strategy in cancer therapy. Among various metabolic enzymes examined, pyruvate kinase M2 type (PKM2) has received much attention in light of its multifaceted function in promoting tumor growth and progression. In this study, we reported the development of a novel irreversible inhibitor of PKM2, compound 1, that exhibits a differential tumor-suppressive effect among an array of cancer cell lines. We further used a clickable activity-based protein profiling (ABPP) probe and SILAC coupled with LC-MS/MS to identify the Cys-317 and Cys-326 residues of PKM2 as the covalent binding sites. Equally important, compound 1 at 10 mg/kg was effective in suppressing xenograft tumor growth in nude mice without causing acute toxicity by targeting both metabolic and oncogenic functions. Together, these data suggest its translational potential to foster new strategies for cancer therapy

Design, Synthesis, and Antipicornavirus Activity of 1-[5-(4-Arylphenoxy)alkyl]-3-pyridin-4-ylimidazolidin-2-one Derivatives

A series of pyridylimidazolidinone derivatives was synthesized and tested in vitro against enterovirus 71 (EV71). On the basis of compound 33 (DBPR103), introduction of a methyl group at the 2- or 3-position of the linker between the imidazolidinone and the biphenyl resulted in markedly improved antiviral activity toward EV71 with IC50 values of 5.0 nM (24b) and 9.3 nM (14a), respectively. Increasing the branched chain to propyl resulted in a progressive decrease in activity, while inserting different heteroatoms entirely rendered the compound only weakly active. The introduction of a bulky group (cyclohexyl, phenyl, or benzyl) led to loss of activity against EV71. The 4-chlorophenyl moiety in 14a was replaced with bioisosteric groups such as oxadiazole (28a−d) or tetrazole (32a,b), dramatically improving anti-EV71 activity and selectivity indices. Compounds 14a, 24b, 28b, 28d, and 32a exhibited a strong activity against lethal EV71, and no apparent cellular toxicity was observed. Three of the more potent imidazolidinone compounds, 14a, 28b, and 32b, were subjected to a large group of picornaviruses to determine their spectrum of antiviral activity