Straightforward Access to a New Class of Dual DYRK1A/CLK1 Inhibitors Possessing a Simple Dihydroquinoline Core

The DYRK (Dual-specificity tyrosine phosphorylation-regulated kinase) family of protein kinases is involved in the pathogenesis of several neurodegenerative diseases. Among them, the DYRK1A protein kinase is thought to be implicated in Alzheimer’s disease (AD) and Down syndrome, and as such, has emerged as an appealing therapeutic target. DYRKs are a subset of the CMGC (CDK, MAPKK, GSK3 and CLK) group of kinases. Within this group of kinases, the CDC2-like kinases (CLKs), such as CLK1, are closely related to DYRKs and have also sparked great interest as potential therapeutic targets for AD. Based on inhibitors previously described in the literature (namely TG003 and INDY), we report in this work a new class of dihydroquinolines exhibiting inhibitory activities in the nanomolar range on hDYRK1A and hCLK1. Moreover, there is overwhelming evidence that oxidative stress plays an important role in AD. Pleasingly, the most potent dual kinase inhibitor 1p exhibited antioxidant and radical scavenging properties. Finally, drug-likeness and molecular docking studies of this new class of DYRK1A/CLK1 inhibitors are also discussed in this article.     

A Simple Synthesis of Stable 1,4-Diionic Pyridinium Betaines

Summary.  Protonation of the reactive intermediate produced in the reaction between pyridine and dialkyl acetylenedicarboxylates by strong CH-acids such as N,N′-dimethylbarbituric acid, Meldrum’s acid, or indane-1,3-dione leads to a vinylpyridinium cation which undergoes an addition reaction with the enolate anion of the CH-acid to produce stable 1,4-diionic pyridinium betaines in good yields. Corresponding author. E-mail: isayavar@yahoo.com Received February 5, 2002. Accepted (revised) March 12, 2002     

A Simple Approach to the Synthesis of Fluoren-9-Ones

Cyclohexene-l-Carboxylic acid (I) undergoes reaction with various aromatic substrates (2a-i) in presence of Polyphosphoric acid (PPA) at 100[ddot]c to give cis-1,2,3,4,4a,9a - hexahydrofluoren-9-ones (3a-i) in good yield. Dehydrogenation of (3a-i) with selenium powder afforded corresponding fluoren-9-ones (4a-i) in high yield.     

A New Class of Polyconjugated Systems: Synthesis and Properties of Polymetacyclophanes

A unique polyconjugated systems having longitudinal π-electron overlaps was synthesized by using a metacyclophane monomer, 8, 16-dihydroxy-[2,2]-metacyclophane. The monomer was synthesized according to Tashiro's method and was converted to two types of polycyclophanes. One was obtained as a quinoid-type polymer from FeCI₃ -catalyzed oxidative coupling of the 2,5-disubstituted phenols. The polymer obtained was composed of [2,2,] -metacyclophane units polymerized via a diphenoquinone linkage. Amorphous, bright reddish-orange powders were obtained quantitatively under mild reaction condition. Another one was a phenol-type polymer that contained [2,2] -metacyclophane units linked with a 4,4′-dihydroxybiphenyl skeleton. This polymer was obtained by way of a unique polycondensation reaction characteristic of cyclophane compounds. The polymer obtained had a fine whisker form with a golden luster and partial crystallinity. The structures of these polymers were confirmed by various spectroscopic methods and elemental analysis. The electrical conductivity of both polymers was of almost the same order of magnitude (10^?8 S/cm). When doped with sulfuric acid (H₂SO₄) vapor, the phenol-type polymer exhibited a conductivity of 0.25 S/cm, which was much higher than that of the quinoidtype polymer (10^?4 S/cm).     

A Simple Procedure for Preparing Annulated p-Benzoquinones. Improved Synthesis of 1,4-Dihydro-1,4-methanonaphthalene-5,8-dione

A simple and efficient two-step, one-pot synthesis of substituted 1,4-dihydro-1,4-methanonaphthalene-5,8-diones is reported. This synthesis, which utilizes readily available starting materials and inexpensive reagents, can be used to prepare 1a-1c in 70–90% overall yield. This procedure was extended successfully to prepare a more highly complex annulated p-benzoquinone i.e., 8.     

A Simple Synthesis of New Phosphaalkenes

Abstract

Upon treatment of phosphanylsubstituted phosphorus ylides like la-c with two equivalents BF₃ *OEt₂ the compounds 2a-d are obtained almost quantitatively. In them a phosphonium-and a phosphenium ion compete for the electron density at the bridgeing carbon atom. A X-ray analysis of 2a and the reactivity of transient 3a,b so far studied reveal the olefinic character corresponding to phosphonium substituted phosphaalkenes.     

Access to 14C-Ring labelled phenothiazines. Synthesis of 2-chlorophenolhiazine-5a,9-14C

Through the use of a recently reported ring expansion reaction, a new route to phenolhiazines has been developed suitable for the preparation of ring labelled derivatives. As an example, the preparation of 2-chloropheno thiazine-5a,9-¹⁴C ( 1 ) is reported. Condensation of cyclohexanone-2-¹⁴C with 2-amino-4-chlorothiophenol gave the spiro-2,3-dihydro-l, 3-benzothiazole 4 which was protected by acetylation ( 5 ). Treatment of 5 with sulfuryl chloride gave the tetrahydro-phenothiazine olefin mixture 6 and 7 which was directly converted to labelled 1 via treatment with DDQ in refluxing benzene followed by hydrolysis of the acetyl group.     

A New Route to Pyrrolidines: One-Step Cyclization of 1,4-Azido Alcohol Synthesis of 1,4-Dideoxy-1,4-Imino-L-Lyxitol

Several optically active 3,4-dihydroxy-2-hydroxymethyl pyrrolidines are potent α-glycosidase inhibitors; for example, 1,4-dideoxy-1,4-imino-D-lyxitol (1) is a powerful inhibitor of α-galactosidase.¹ Furthermore, pyrrolidine 1 can be easily converted into the indolizidine alkaloid swainsonine to which it is structurally related.² (-) Swainsonine exhibits α-D-mannosidase inhibitory activity and immunoregulatory activity. Certain swainsonine stereoisomers have glycosidase inhibitory activity as well, and therefore have attracted considerable interest.³ 1,4-Dideoxy-1,4-imino-L-lyxitol (2) (enantiomer of 1) could be of biological interest. This communication describes the first synthesis of 2, starting from D-ribonolactone.     

A Total Synthesis of a New Class of Biazine Thioglycosides

Abstract

A new method for the synthesis of bipyridinyl S‐glycosides 11 and 12 has provided the title compounds in a higher yield. Application of a one‐pot glycosylation methodology resulted in an efficient, high‐yield synthesis of biazine S‐glycosides 17–20 An X‐ray diffraction analysis of 11 disclosed the conformation of this glycoside as the S‐glycoside and not the corresponding N‐form.     

A Simple Approach to the Synthesis of 1,4-Bis(arylsulfonyl)tetrahydropyrazine-2,5-diones

Summary.  The addition of triphenylphosphine to dimethyl acetylenedicarboxylate in the presence of arylsulfonylglycyl chlorides leads to 1,4-bis-arylsulfonyl-tetrahydropyrazine-2,5-diones and dimethyl (E)-2-chloro-2-butenedioate. Corresponding author. E-mail: isayavar@yahoo.com Received June 3, 2002; accepted June 10, 2002     

New synthesis of 1,4-diketones via rhodium-catalysed 1,4 carbonylative addition of arylboronic acids to alpha,beta-unsaturated ketones

The reaction of various arylboronic acids with alpha,beta-unsaturated ketones under CO pressure and in the presence of rhodium catalyst yields 1,4-diketones.     

Hypervalent Iodine in Synthesis: 9. A New,Effective Synthesis of Acetylenic Sulfones

Alkynylphenyliodonium salts can easily react with sodium sulfinates under PTC conditions at room temperature to afford a convenient, effective method for the preparation of acetylenic sulfones.     

氯化铜参与的制备对称二硫化合物的新方法

报道了在正丁基锂和氯化铜条件下氧化硫醇生成对称的二硫化合物的新方法.所实施的十个例子都具有很高的产率.     

A New Stereospecific Synthesis of 1,2,4-Trideoxy-1,4-Imino-D-Erythro-Pentitol

ABSTRACT

1,2,4-Trideoxy-1,4-imino-D-erythro-pentitol [(2R,3S)-3-hydroxy-2-hydroxyme-thylpyrrolidine] (4) was synthesised from 2,5-di-O-tosyl-D-ribono-1,4-lactone in 42% overall yield. The key steps were deoxygenation at C-2 and a stereospecific inversion of the configuration at C-4. Compound 4 inhibited α-D-glucosidase (K_i = 25 μM) and β-D-glucosidase (K_i = 80 μM).     

Heterocyclic compound studies. II. Synthesis of 1,4-benzodioxin, 1,4-benzoxathiin, 1,4-benzoxazine and 1,4-benzothiazine derivatives

Benzocondensed six-membered heterocyclic rings containing two heteroatoms have been synthesized by a generally applicable method starting from disubstituted benzene compounds and methyl 4-chlorobutynoate ( 1 ) or methyl 4-bromobutenoate ( 2 ). The reactions with 1 yield a mixture of endo and exo (E or Z) isomers. The ¹³C nmr spectroscopy was used to assign the structure of the synthesized compounds.