10.1021/ja00524a043
The research focuses on the controlled chemical synthesis of enzymatically produced eicosanoids, specifically 11-, 12-, and 15-HETE, which are derived from arachidonic acid and are precursors to hydroperoxides (HPETEs). The purpose of the study was to develop effective and selective chemical syntheses of these biologically important compounds, filling critical gaps in previous chemical knowledge and providing multigram laboratory preparation methods. The researchers achieved this by employing new synthetic methodologies, such as the use of the magnesium derivative of isopropylcyclohexylamine (MICA) for the epoxide-allylic alcohol conversion, which proved to be superior to other reagents. Key chemicals used in the process included arachidonic acid, isopropylcyclohexylamine, methylmagnesium bromide, tetrahydrofuran (THF), sodium dihydrogen phosphate, ether, silica gel, and various other reagents for specific conversion steps. The conclusions of the research demonstrated the successful synthesis of the targeted eicosanoids and the development of new synthetic methods, which are significant for both the chemical synthesis of biologically active compounds and the understanding of enzymatic processes.
10.1007/s00044-010-9411-5
The research focuses on the design, synthesis, and evaluation of novel substituted-piperazine analogues for their antiplatelet aggregation activity, which is crucial for managing cardiovascular and thromboembolic diseases. The study involves the synthesis of new carbamoylpyridine and carbamoylpiperidine analogues containing a nipecotic acid scaffold, with a series of chemical reactions utilizing reactants such as nicotinoyl chloride, various aryl and aroyl-piperazines, alkyl or aroylhalides, and potassium carbonate. The synthesized compounds were evaluated for their inhibitory activity against platelet aggregation using different agonists like ADP, adrenaline, collagen, arachidonic acid, and ristocetin. The experiments included quaternization, catalytic hydrogenation, and molecular modeling investigations to understand the structure-activity relationship and the impact of lipophilicity on activity. The most active compounds identified were N1-[1-(4-bromobenzyl)-3-piperidino-carbonyl]-N4-(2-chlorophenyl)-piperazine hydrobromide (20) and 1,4-bis-[3-[N4-(2-chlorophenyl)-N1-(piperazino-carbonyl)]-piperidin-1-yl-methyl]-benzene dibromide (30), both exhibiting significant antiplatelet aggregating effects at a concentration of 0.06 μM. The analyses included NMR spectroscopy, mass spectrometry, and molecular docking studies to elucidate the compounds' structures and their interactions with the thrombin receptor.
10.1021/acsinfecdis.9b00034
This study investigated the anti-schistosomal properties of sclareol, a plant-derived diterpenoid, and its Heck-coupled derivatives against Schistosoma mansoni, a parasitic trematode that causes schistosomiasis. Sclareol, known for its antimicrobial and anticancer properties, is active against the larval, juvenile, and adult stages of S. mansoni. The researchers synthesized a series of sclareol derivatives guided by Matsy decision trees to improve their anthelmintic activity. The most potent derivative, compound 12, showed enhanced potency and selectivity against schistosomes. The study aimed to understand the mechanism of action of sclareol, which is different from that of the standard anti-schistosomal drug praziquantel (PZQ). Metabolomic analysis revealed that compound 12 affects membrane lipid homeostasis by interfering with arachidonic acid metabolism, primarily altering sugar metabolism. These findings provide insights into the development of more effective anti-schistosomal sclareol derivatives.
10.1021/jm00163a058
The research focused on the synthesis, biological evaluation, and structure-activity relationships of a series of 2-substituted-1-naphthols, which are potent inhibitors of 5-lipoxygenase (5-LO) and cyclooxygenase (CO) enzymes. These compounds were investigated for their potential as topical anti-inflammatory agents, particularly for treating inflammatory skin diseases like psoriasis and contact dermatitis. The study concluded that 2-substituted-1-naphthols, especially 2-(arylmethyl)-1-naphthols, showed significant anti-inflammatory potency in a mouse model, with DuP 654 (2-benzyl-1-naphthol) demonstrating an attractive profile for topical anti-inflammatory activity and being considered for clinical trials as a topically applied antipsoriatic agent. The research involved a variety of chemicals, including 1-naphthols, arylmethyl derivatives, and several synthetic peptides, which were tested for their inhibitory effects on 5-LO and CO, as well as their ability to reduce ear edema in mice induced by arachidonic acid. The study provided insights into the structure-activity relationships of these compounds, highlighting the importance of specific substituents on the naphthalene ring for enzyme inhibition and anti-inflammatory activity.
10.1246/cl.1988.1785
This research focuses on the first enantiospecific total synthesis of dimorphecolic acid, a compound with significant biological interest due to its role as a self-defensive substance against rice blast disease and its cation-specific ionophoric activity. The study also describes the synthesis of 5(S)-HETE and 12(S)-HETE, which are important monohydroxylated metabolites of arachidonic acid involved in inflammation and other health issues. The purpose of the research is to provide efficient and stereocontrolled routes for synthesizing these compounds, which are difficult to obtain from natural sources, thereby facilitating further biological investigations. The key chemicals used in the synthesis include methyl oleate, t-butyl hydroperoxide (TBHP), D(-) DIPT, Ti(O-i-Pr)4, I2, 1-heptyne, Pd(PPh3)4, CuI, and various reagents for specific reactions such as hydroborations and oxidative work-ups. The study concludes that the synthesized dimorphecolic acid from the rice plant exists as a mostly racemic mixture with the (S)-enantiomer being predominant, and the methods developed are applicable for synthesizing other HETEs, including 12(S)-HETE and 5(S)-HETE, with high optical purity and yield.
