DBU: An Efficient Base Catalyst for Synthesis of the New Oxazolo[5,4-d]pyrimidine Derivatives

<div><p></p><p>New types of oxazolo[5,4-d]pyrimidines were synthesized via 1,8-diazabicyclo[5,4,0]undec-7-ene-catalyzed heteroannulation of 2-substituted 5-amino-4-cyano-1,3-oxazoles with various isothiocyanates.</p> </div

Synthesis of Pyrimido[4,5-<i>e</i>]tetrazolo[5,1-<i>b</i>][1,3,4]thiadiazepine as a Novel Fused Heterocyclic System

<p>Several derivatives of the novel fused seven-membered heterocyclic system of pyrimido[4,5-<i>e</i>]tetrazolo[5,1-<i>b</i>][1,3,4]thiadiazepine <b>(5a–f)</b> have been synthesized through the heterocyclization reaction of 2,4-dichloro-5-(chloromethyl)-6-methylpyrimidine <b>(1)</b> with sodium 1-amino-1H-tetrazole-5-thiolate <b>(2)</b> under basic conditions. Various derivatives were obtained via treatment with secondary amines.</p

Pure Water-Induced Dehalogenation of 2,4-Di-<i>tert</i>-amino-6-substituted-5-halogenopyrimidines

Dehalogenation of 5-halogenopyrimidine derivatives in boiling pure water was accomplished in high yields. The substrate and pure water are the only two reaction components in this process. Dehalogenation takes place in the absence of any catalysts, additives, basic, or acidic conditions, introducing water as a potential dehalogenation reagent

<i>O</i>-prenylated 3-carboxycoumarins as a novel class of 15-LOX-1 inhibitors

<div><p>Allyloxy, Isopentenyloxy, geranyloxy and farnesyloxy derivatives of 3-carboxycoumarin, at position 5, 6, 7, and 8, were synthesized and their inhibitory potency against human 15-lipoxygenase-1 (human 15-LOX-1) were determined. Among the synthetic coumarins, <i>O</i>-allyl and <i>O</i>-isopentenyl derivatives demonstrated no considerable lipoxygenase inhibition while <i>O</i>-geranyl and <i>O</i>-farnesyl derivatives demonstrated potent inhibitory activity. 5-farnesyloxy-3-carboxycoumarin demonstrated the most potent inhibitory activity by IC₅₀ = 0.74 μM while 6-farnesyloxy-3-carboxycoumarin was the weakest inhibitor among farnesyl analogs (IC₅₀ = 10.4 μM). Bonding affinity of the designed molecular structures toward 15-LOX-1 3D structure complexed with RS75091, as potent 15-LOX-1 inhibitor, was studied by utilizing docking analysis. There was a direct relationship between lipoxygenase inhibitory potency and prenyl length chain. The ability of the prenyl portion to fill the lipophilic pocket which is formed by Ile663, Ala404, Arg403, Ile400, Ile173 and Phe167 side chains can explain the observed relationship. Similarity rate between the docked models and complexed form of RS75091, from point of view of configuration and conformation, could explain inhibitory potency variation between each prenyloxy substitution of 3-carboxycoumarins.</p></div

General procedure for the synthesis of <i>O</i>-prenylated-3-carboxycoumarins.

<p>General procedure for the synthesis of <i>O</i>-prenylated-3-carboxycoumarins.</p

Michaelis-Menten (left) and Lineweaver-Burk (right) plots of human 15-LOX-1 inhibition by 4d.

<p>The Y-intercept average (1/V_max) of the Lineweaver-Burk plot is 376 ± 45 min.Abs^-1 and K_M = 8.73 ± 0.43 μM. The error bars are stated as ± SD (n = 4).</p

Data of the docking analyses results: Ki of the most populated cluster (Ki_MPC), average of all the lowest Ki from each cluster (Ki_LEC), average Ki of all the conformers (Ki_AC) and average Ki of a cluster in which lactone portion of coumarin directed towards Fe-OH core (Ki_LFC).

<p>N = number of conformers. The data are shown as ± SEM.</p

Superimposition of consensus structures of compounds 4c (pink stick) and 4d (green stick) from LFC on RS75091 (yellow stick) in rabbit 15-LOX-1 active site (left). Superimposition of consensus structure of 4d (green stick) from LFC on consensus structure of 4d' (brown stick) from similar cluster (right).

<p>In both figures, Ile663 is not shown.</p

Inhibitory assessment data of the synthetic compounds in comparison with 4-methyl-2-(4-methylpiperazinyl)pyrimido[4, 5-b]benzothiazine (4-MMPB) against human 15-LOX-1.

<p>The data are shown as ± SD (n = 3).</p

Synthesis of pyrimido[4′,5′:5,6][1,4]dithiepino[2,3-b]quinoxalines: Derivatives of a novel seven membered ring system

<p></p> <p>A convenient and efficient procedure for the synthesis of tetracyclic dithiepin derivatives is described through the condensation reaction of 2,4-dichloro-5-(chloromethyl)-6- methylpyrimidine and quinoxaline-2,3-dithiol followed by treatment with secondary amines.</p