Isolation, Semisynthesis, Covalent Docking and Transforming Growth Factor Beta-Activated Kinase 1 (TAK1)-Inhibitory Activities of (5Z)-7-Oxozeaenol Analogues

(5Z)-7-Oxozeanol and related analogues were isolated and screened to explore their activity as TAK1 inhibitors. Seven analogues were synthesized and more than a score of natural products isolated that examined the role that different areas of the molecule contribute to TAK1 inhibition. A novel nonaromatic difluoro-derivative was synthesized that had similar potency compared to the lead. This is the first example of a nonaromatic compound in this class to have TAK1 inhibition. Covalent docking for the isolated and synthesized analogues was carried out and found a strong correlation between the observed activities and the calculated binding

Thienopyrimidine Derivatives as GPR55 Receptor Antagonists: Insight into Structure-Activity Relationship

GPR55 is an orphan G-protein coupled receptor involved in various pathophysiological conditions. However, there are only a few noncannabinoid GPR55 ligands reported so far. The lack of potent and selective GPR55 ligands precludes a deep exploration of this receptor. The studies presented here focused on a thienopyrimidine scaffold based on the GPR55 antagonist ML192, previously discovered by high-throughput screening. The GPR55 activities of the new synthesized compounds were assessed using β-arrestin recruitment assays in Chinese hamster ovary cells overexpressing human GPR55. Some derivatives were identified as GPR55 antagonists with functional efficacy and selectivity versus CB1 and CB2 cannabinoid receptors.M.E.A., P.H.R., and N.J. are supported by National Institutes of Health grant R01 DA0455698. M.E.A. and P.Z. thank the financial support NIH P30 DA013429. P.M. and N.J. are supported by the Ministry of Science, Innovation, and Universities, Spain (MCIU)/FEDER grant RTI2018-095544-B-I00 and the Spanish National Research Council (CSIC) grant PIE-201580E033. P.M. acknowledges the Comunidad de Madrid (CM) programme “Atraccion de Talento” number 2018-T2/BMD-10819 and “Juan de la Cierva Incorporación Programme-MICIU” (IJC 2019-042182-I

Decarboxylative and dehydrative coupling of dienoic acids and pentadienyl alcohols to form 1,3,6,8-tetraenes

Dienoic acids and pentadienyl alcohols are coupled in a decarboxylative and dehydrative manner at ambient temperature using Pd(0) catalysis to generate 1,3,6,8-tetraenes. Contrary to related decarboxylative coupling reactions, an anion-stabilizing group is not required adjacent to the carboxyl group. Of mechanistic importance, it appears that both the diene of the acid and the diene of the alcohol are required for this reaction. To further understand this reaction, substitutions at every unique position of both cou- pling partners was examined and two potential mechanisms are presented

Mechanistic Study of the Biomimetic Synthesis of Flavonolignan Diastereoisomers in Milk Thistle

The mechanism for the biomimetic synthesis of flavonolignan diastereoisomers in milk thistle is proposed to proceed by single-electron oxidation of coniferyl alcohol, subsequent reaction with one of the oxygen atoms of taxifolin’s catechol moiety, and finally, further oxidation to form four of the major components of silymarin: silybin A, silybin B, isosilybin A, and isosilybin B. This mechanism is significantly different from a previously proposed process that involves the coupling of two independently formed radicals

Selective Formation of 1,5-Substituted Sulfonyl Triazoles Using Acetylides and Sulfonyl Azides

Abstract: The reaction of acetylides with sulfonyl azides was found to selectively form 1,5-substituted sulfonyl triazoles. This reaction thus provides access to the regioisomeric product as compared to the popular copper-catalyzed azide-alkyne cycloaddition. The reaction is efficient and selective with a variety of alkyne sources and sulfonyl azides and can incorporate an additional electrophile to yield 1,4,5-trisubstituted sulfonyl triazoles. chemistry | biochemistry | sulfonyl triazoles | acetylides | solfonyl aziders Keywords: Article: The copper-catalyzed reaction of terminal alkynes with azides to yield 1,2,3-triazoles has deservedly received much attention in recent years.(1) This reaction regioselectively forms 1,4-substituted triazoles using alkyl, aryl, or sulfonyl azides.(2) Although it was reported that 1,4-substituted sulfonyl triazoles could be converted to 2,4-substituted triazoles using amine bases,(3) there are no efficient methods to selectively convert terminal alkynes and sulfonyl azides to 1,5-substituted triazoles.(4-6) In 2004, there was an excellent report for the reaction of alkynyl Grignard reagents with carbon-substituted azides to yield 1,5-disubstituted triazoles and 1,4,5-trisubstituted triazoles

Sequential Pd(0)-, Rh(I)-, and Ru(II)-Catalyzed Reactions in a Nine-Step Synthesis of Clinprost

A step-economical synthesis of clinprost is reported that concludes with 3 different transition metal-catalyzed reactions: Pd-catalyzed decarboxylation with allylic rearrangement, Rh-catalyzed diene-ene [2+2+1] reaction, and Ru-catalyzed cross-metathesis reaction. The complexity bestowed to the molecule from these reactions converts a readily accessible ester to clinprost without using protecting groups in only 9 total steps

Semisynthesis, cytotoxicity, antiviral activity, and drug interaction liability of 7-O-methylated analogues of flavonolignans from milk thistle

Silymarin, an extract of the seeds of milk thistle (Silybum marianum), is used as an herbal remedy, particularly for hepatoprotection. The main chemical constituents in silymarin are seven flavonolignans. Recent studies explored the non-selective methylation of one flavonolignan, silybin B, and then tested those analogues for cytotoxicity and inhibition of both cytochrome P450 (CYP) 2C9 activity in human liver microsomes and hepatitis C virus infection in a human hepatoma (Huh7.5.1) cell line. In general, enhanced bioactivity was observed with the analogues. To further probe the biological consequences of methylation of the seven major flavonolignans, a series of 7-O-methylflavonolignans were generated. Optimization of the reaction conditions permitted selective methylation at the phenol in the 7-position in the presence of each metabolite’s 4–5 other phenolic and/or alcoholic positions without the use of protecting groups. These 7-O-methylated analogues, in parallel with the corresponding parent compounds, were evaluated for cytotoxicity against Huh7.5.1 cells; in all cases the monomethylated analogues were more cytotoxic than the parent compounds. Moreover, parent compounds that were relatively non-toxic and inactive or weak inhibitors of hepatitis C virus infection had enhanced cytotoxicity and anti-HCV activity upon 7-O-methylation. Also, the compounds were tested for inhibition of major drug metabolizing enzymes (CYP2C9, CYP3A4/5, UDP-glucuronsyltransferases) in pooled human liver or intestinal microsomes. Methylation of flavonolignans differentially modified inhibitory potency, with compounds demonstrating both increased and decreased potency depending upon the compound tested and the enzyme system investigated. In total, these data indicated that monomethylation modulates the cytotoxic, antiviral, and drug interaction potential of silymarin flavonolignans