Synthesis and Evaluation of α-Methylidene-γ-butyrolactone bearing flavone and xanthone moieties

In a search for inhibitors of platelet aggregation, a number of α-methylidene-γ-butyrolactones 5 and 6 bearing flavone or xanthone moieties, respectively, were synthesized and evaluated for their antiplatelet activity against thrombin(Thr)-, arachidonic-acid(AA)-, collagen(Col)?, and platelet-activating-factor(PAF)-induced aggregation in washed rabbit platelets. These compounds were synthesized from 7-hydroxyflavone ( 1 ) or 3-hydroxyxanthone ( 2 ) via O-alkylation (→ 3 and 4 , resp.) and Reformatsky-type condensation (Scheme). Most of the flavone-containing α-methylidene-γ-butyrolactones 5a – d showed potent antiplatelet effects on AA- and Col-induced aggregation, while xanthone derivatives 6c – e were found to have the same pharmacological profile than aspirin in which only AA-induced aggregation was inhibited (Table 1). However, 6c – e were approximately three to ten times more potent than aspirin (Table 2). For the vasorelaxing effects, 5a was the only compound which exhibited significant inhibitory activity on the high-K⁺ medium, Ca²⁺-induced vasoconstriction (Table3). Both 5a and 6a , with an aliphatic Me substituent at C(γ) of the lactone, were active against norepinephrine-induced phasic and tonic constrictions while their γ-aryl-substituted counterparts 5b – f and 6b – f were inactive.     

Antiplatelet α-Methylidene-γ-butyrolactones: Synthesis and evaluation of quinoline,flavone, and xanthone derivatives

As a continuation of our previous studies on the synthesis and antiplatelet activity of coumarin derivatives of α-methylidene-γ-butyrolactones, certain quinoline, flavone, and xanthone derivatives were synthesized and evaluated for antiplatelet activity against thrombin (Thr)-, arachidonic acid (AA)-, collagen (Col)-, and platelet-activating factor (PAF)-induced aggregation in washed rabbit platelets. These compounds were synthesized from quinolin-8-ol, flavon-7-ol, and xanthon-3-ol, respectively, via alkylation and Reformatsky-type condensation (Schemes 1–3). By the comparison with comparison with coumarin α-methylidene-γ-butyrolactone 3a , flavone and xanthone derivatives, 3b and 3c , respectively, are more selective in which only AA- and collagen-induced aggregation are strongly inhibited. Most of the quinoline derivatives ( 9a–e ) exhibited broad-spectrum antiplatelet activities.     

Synthesis and Antitumor Activity Evaluation of γ-Monofluorinated and γ,γ-Difluorinated Goniothalamin Analogues

A series of novel γ,γ‐difluorinated Goniothalamin analogues 4a – 4i and 6a – 6i were synthesized. The key steps included the construction of C‐5 stereocenter adjacent to gem‐difluoromethylene group by way of lipase AK catalyzed kinetic resolution, the introduction of aryl group via Stille coupling, and lactonization by 1,5‐oxidative cyclization. These γ,γ‐difluorinated Goniothalamin analogues 4a – 4i and their enantiomers 6a – 6i , together with several corresponding γ‐monofluorinated Goniothalamin analogues were biologically evaluated against four different cancer cell lines. Compound 7h showed a nearly equivalent potency as the parent (R)‐Goniothalamin in the micromolar range. The different fluorine effects between fluoromethylene and gem‐difluoromethylene on antitumor activity were discussed through the analysis of bioassay data.     

Synthesis and Evaluation of 2-{[(2-Oxo-1H-quinolin-8-yl)oxy]methyl}-Substituted α-Methylidene-γ-butyrolactones

O-Alkylation of 8-hydroxy-1H-quinolin-2-one ( 1 ) afforded 8-(2-oxopropoxy)-1H-quinolin-2-one ( 2 ) which was immediately cyclized to form the tricyclic 2,3-dihydro-3-hydroxy-3-methyl-5H-pyrido[1,2,3-de][1,4]benzoxazine,-5-one ( 3). The Reformatsky-type condensation of 3 furnished antiplatelet 8-[(2,3,4,5-tetrahydro-2-methyl-4-methylidene-5-oxofuran-2-yl)melhoxy]-1H-quinolin-2-one ( 4 ). Its counterparts 7a – f , Ph-substituted at C(2) of the furan ring, were obtained from 1 via alkylation and the Reformatsky-type condensation. Although compound 4 was less active against platelet aggregation than 7a – f , it was the only compound which exhibited significant inhibitory activity on high-K⁺ medium, Ca²⁺-induced vasoconstriction and was more active than most of its Ph-substituted counterparts against norepinephrine-induced vasoconstrictions.     

Design and Synthesis of α,β‐Epoxyketones as New Anticancer Agents

As epoxy functional group has high anticancer activity, α,β‐epoxyketones were designed and synthesized as new anticancer agents, and their structures were confirmed by UV, ¹H NMR, IR, MS technigeces and elemental analysis. Their in vitro anticancer activities were evaluated by MTT method and the results showed that the compound 4c exhibited good activity with IC₅₀ of 17.8, 22.0 and 24.1 µg/mL against A‐549, Hela and HepG2 cells, respectively. The dose of LD50 of the mice by intragastric administration was 1864.4 mg/kg. Therefore, the α,β‐epoxyketones could potentially provide as new anticancer agents.     

Concise Synthesis and Pharmacological Applications of New α‐Lapachone Analogues

Synthesis of novel 1,4‐naphthoquinones structurally related to α‐lapachone skeleton and its annulated compounds were synthesized from lawsone (2‐hydroxynaphthalene‐1,4‐dione). Pharmacological studies provided indication of biological activities, including effects against hepatocellular carcinoma (HePG‐7) and mammary gland breast cancer (MCF‐7). The molecular structures of the target molecules were examined.     

Stereodivergent Synthesis of 17‐α and 17‐β‐Aryl Steroids: Application and Biological Evaluation of D‐Ring Cortistatin Analogues

One stereocenter makes all the difference : The synthesis and biological evaluation of 17‐epi‐cortistatin A is reported from a common intermediate used to procure natural cortistatin A. The synthesis features a unique stereocontrolled Raney‐Ni reduction process that can be employed to reliably produce both α‐ and β‐configured D‐ring aryl steroids. Biological evaluations of these “cortalogs” are reported for the first time.

     

Copper(I)‐Mediated Denitrogenative Macrocyclization for the Synthesis of Cyclic α3β‐Tetrapeptide Analogues

A copper(I)‐mediated denitrogenative reaction has been successfully developed for the preparation of cyclic tetrapeptides. The key reactive intermediate, ketenimine, triggers intramolecular cyclization through attack of the terminal amine group to generate an internal β‐amino acid with an amidine linkage. The chemistry developed herein provides a new synthetic route for the preparation of cyclic α₃β‐tetrapeptide analogues that contain important biological properties and results in rich structural information being obtained for conformational studies. With the success of this copper(I)‐catalyzed macrocyclization, two histone deacetylase inhibitor analogues consisting of the cyclic α₃β‐tetrapeptide framework have been successfully synthesized.     

Synthesis,Characterization, Molecular Docking,and Anticancer Evaluation of 4‐Thiazolidinone Analogues

Scaffolds containing one or more heteroatoms are ubiquitous in nature and are responsible for almost every biological processes in flora and fauna. The fact that heterocyclic cores have high propensity for biological targets, several nitrogen, oxygen, and sulfur‐containing heterocyclic compounds have been reported in the last few decades. One such intriguing class is 4‐thiazolidinone that exhibit diverse range of pharmacological activities. In the present study, we report synthesis, characterization, molecular docking, and anticancer evaluation of 10 new 4‐thiazolidinone analogues ( 5 – 14 ). One of the compounds ( 11 ) was structurally characterized using single crystal X structure. Anticancer evaluation against hepatocellular carcinoma cell line (HepG2) revealed that compound ( 7 ) was the most potent (IC₅₀ = 75 μM) while other showed moderate to low activity (85–530 μM). To underpin the druggability and possible modes of action, drug‐likeness was determined and docking studies were carried out against β‐carbonic anhydrase receptor (PDB ID: 3IA). Attempts have also been made to establish a structure–activity relationship of the reported compounds.     

Synthesis and Conformational Analysis of (α‐D‐Galactosyl)phenylmethane and α‐,β‐Difluoromethane Analogues: Interactions with the Plant Lectin Viscumin

To bend about : The conformations of three phenyl‐C‐galactosides in solution were evaluated by using theoretical calculations and NMR spectroscopic studies. The α‐CF₂ derivative (see scheme) showed significant flexibility of the pyranose ring and around the pseudoanomeric center, whereas the other two analogues more closely resemble the natural galactosides. Regardless, all three compounds bind to a plant lectin.

     

Synthesis of novel α,α′,β-trisubstituted β-lactones

A concise and efficient synthesis of α,α′,β-trisubstituted β-lactones is presented. These novel lactones are easily obtained in five steps and will be dedicated to anionic ring opening polymerization.     

α-Alkyl-α-aminosilanes: Synthesis via Alkylation and Hydrosilylation

The readily available aminomethylsilanes can be utilized to prepare the less available α-alkyl-α-aminosilanes. Versatile t-butoxy-carbonal (Boc) derivatives can be metalated between nitrogen and silicon, and then alkylated by an electrophile at this position. Two alternative procedures were also developed, including an aza-reverse-Brook rearrangement of metalated N-silylcarbamates and hydrosilylation of N-alkenylcarbamates. © 1997 by John Wiley & Sons, Ltd.