Cyclic Β-diketones Research Articles

Use of a Cyclic α-Alkylidene-β-Diketone as a Cleavable Linker Strategy for Antibody-Drug Conjugates.

In the fast-evolving landscape of targeted cancer therapies, the revolutionary class of biotherapeutics known as antibody-drug conjugates (ADCs) are taking center stage. Most clinically approved ADCs utilize cleavable linkers to temporarily attach potent cytotoxic payloads to antibodies, allowing selective payload release under tumor-specific conditions. In this study, we explored the utilization of 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde), a cyclic β-diketone featuring an active alkylidene group, to develop a novel chemically labile linker. This linker was designed to exploit the difference in reduction potential between the intracellular compartment and plasma. Upon reduction of an azido trigger strategically installed neighboring the cyclic β-diketone, the resulting nucleophilic primary amine reacts with the alkylidene group facilitated by a favorable ring closure reaction in accordance with Baldwin's rules. Consequently, this reaction enables the simultaneous release of the attached cytotoxic payload. The therapeutic utility of this novel linker strategy was demonstrated by separate conjugation of the linker to two epidermal growth factor receptor (EGFR)-targeting ligands to afford a peptide-drug conjugate and an ADC. This work comprises a significant contribution to the bioconjugation field by introducing the alkylidene cyclic β-diketone as a tunable scaffold used for the temporary conjugation of therapeutic agents to peptides and proteins.

Crystal structure, tautomerism and photostability of 2-(2-pyridyl)-phenalene-1,3-dione

Tautomerism of cyclic β-diketones has been of scientific interest for decades due to the practical applications it can render, from sensors to photostable materials. In this work the tautomerism of 2-(2-pyridyl)-phenalene-1,3-dione (PPD) was studied in solid state, in solution, and in gas phase through a combination of experimental and theoretical methods. Single-crystal X-ray diffraction analysis of PPD revealed its existence in diketo form in the solid state with protonated pyridyl nitrogen that is stabilized by the intramolecular hydrogen bond of N-H···O type. A very large Stokes shift was observed in the emission spectra in DMSO (ca. 177 nm) and in ethanol (ca. 160 nm), indicating on possible excited-state intramolecular proton transfer (ESIPT) process. DFT calculations in ground state (gas phase and water medium) and in the excited singlet state (B3LYP-6311++G(d,p)) agree very well with the experimental data and suggest reverse order of the possible OH and NH tautomers in the ground and the excited singlet state, namely the diketo NH tautomer is the most stable one in the ground state whereas in the excited singlet state the enol OH form is more stable. The photostability of PPD was estimated by irradiation experiments that were performed in comparison with 2-acetylindan-1,3-dione (2AID), which is a compound with proven high photostability in ethanol and fast ESIPT. The data showed that unlike 2AID, the 2-(2-pyridyl)-phenalene-1,3-dione exhibits lower photostability in ethanol. These results could suggest that either the ESIPT process is not the only transformation that takes place in the excited state of PPD, or it is not as fast as the one of 2AID.

Activator-free reactions of carboxylic ortho esters with cyclic β-diketones

Activator-free reactions of carboxylic ortho esters with cyclic β-diketones

CuI-catalyzed thioarylation of active methylene compounds with in situ generated benzenethiols: Preparation of α-thioaryl-β-dicarbonyls and 4-thioaryl-5-pyrazolones

In this paper, a one-step copper-catalyzed procedure for oxidative coupling of active methylene compounds including cyclic β-diketones, cyclic β-ketoesters and 5-pyrazolone with benzenethiols is described. Benzenethiols are in situ generated in the reaction mixture from aryl halides and thiourea as sulfur transfer reagent. α-Thioaryl compounds are obtained in excellent yields and in short reaction time via the process which is free from the foul smell of thiols.

Synthesis of quinazolinones and benzazoles utilizing recyclable sulfated metal-organic framework-808 catalyst in glycerol as green solvent

Zirconium-based metal-organic framework MOF-808 was synthesized, and sulfated with aqueous sulfuric acid. Sulfated MOF-808 was utilized as a recyclable heterogeneous catalyst for the synthesis of quinazolinones from β-ketoesters and benzamides, and for the synthesis of benzimidazoles from β-ketoesters and o-phenylenediamines in glycerol as a green solvent. The sulfated MOF-808 catalyst was more active than many heterogeneous and homogeneous catalysts. The combination of the sulfated MOF-808 and glycerol was also effective for the reaction of o-aminothiophenols with β-diketones or cyclic β-diketones to produce benzothiazoles. To our best knowledge, MOF-based catalysts were not previously utilized as heterogeneous catalyst in glycerol as green solvent.

Small-molecule optical probes for cell imaging of protein sulfenylation and their application to monitor cisplatin induced protein oxidation

Reactive oxygen species (ROS) are considered versatile second messengers mediating fundamental biological functions. A molecular pathway by which ROS determine functional diversity is the selective oxidation of cysteine residues to form sulfenic acid (SOH) products, known as sulfenylation or S-hydroxylation. This crucial post-translational modification is responsible for the alteration of protein stability, function and signalling. Despite considerable advances on the identification of sulfenic residues on individual proteins, improved methods are needed for direct visualization and accurate quantification of the extent of total protein sulfenylation. Herein we present the synthesis of two new cell-permeable fluorescent probes containing dimedone (a cyclic β-diketone with high specificity for sulfenic acids), and apply them to study oxidation processes in individual cells via microscopy. The low cytotoxicity, cell permeability and optical features of the probes allowed us to visualize and quantify the oxidation of cysteine residues in live cells during H2O2-mediated oxidative burst (i.e. exogenously administered H2O2). We present preliminary cellular imaging studies with these probes to analyse the oxidation process in cells treated with the anticancer drug cisplatin.

Isopropylmagnesium chloride-promoted unilateral addition of Grignard reagents to β-diketones: one-pot syntheses of β-tertiary hydroxyl ketones or 3-substituted cyclic-2-enones.

The regioselective unilateral additions of Grignard reagents to acyclic or cyclic β-diketones were effectively promoted by sub-stoichiometric amounts of i-PrMgCl to afford β-tertiary hydroxyl ketones or 3-substituted cyclic-2-enones, respectively. Also, the addition of Grignard reagents to acyclic β-diketones followed by a reaction with cyclic β-diketones in a one-pot process was put forward. The reaction mechanism was discussed in detail to explain the high regioselectivity via chemical experiments, hydrogen-deuterium exchange and mass spectrometry.

Sawdust-SO3H: A Highly Efficient, Cheap and Recyclable Solid Acid Catalyst for the Synthesis of Quinoline Derivatives under Neat Conditions

Sawdust as a biomass waste material was treated with chlorosulfonic acid and sulfonated sawdust (SD-SO3H) was prepared which characterized with a variation of methods containing TGA, SEM and elemental analysis. This solid acid showed excellent catalytic activity for the synthesis of various quinolines derivatives through the Friedlander condensation of 2-aminoaryl ketones with cyclic and acyclic β-diketone, β- keto esters and cyclic ketone compounds under solvent-free conditions with high yields (70-95%). This new method offers some benefits such as simple procedure, short reaction times, high yields and use of a green, cheap and reusable catalyst.

A Tandem and Domino Protocol for Synthesis of Chromeno-, Pyrano- and Quinolinofused Spiro[pyrazolo[3,4-b]pyridine-indolines

An efficient tandem and domino protocol for the synthesis of chromeno-, pyrano-, and quinolino- fused spiro[pyrazolo[3,4- b]pyridine-indolines] has been developed. The present method involves one-pot pseudo five-component reaction of hydrazine hydrate and ethyl acetoacetate with isatin, malonitrile/ cyclic β-diketones and ammonium acetate/ primary aromatic amines in ethanol without using catalyst.

Geminally activated β-nitrostyrenes in reactions with cyclic β-diketones

The interaction of gem-benzoylnitroethenes and gem-alkoxycarbonylnitroethenes with cyclic β-diketones (dihydroresorcinol and dimedone) occurs as a one-pot process via sequential AdN and SN steps followed by denitration to give functionally substituted hexahydrobenzofurans. The intermediate products of the nucleophilic addition have been isolated in the reactions of gem-acetylnitroethenes with dihydroresorcinol. The structures of the synthesized compounds have been confirmed by IR, 1H, and 13C-{1H} spectroscopy including the heteronuclear correlation experiments (1H-13C HMQC and 1H-13C HMBC).

Efficient Ultrasound Synthesis, Characterizations and Antimicrobial Screening of Novel Cyclic β-Diketones

Hydroxyphenyl)-3-propane,1,3-diones 4(LA-LF) have been synthesized by a simple and convenient method employing Baker-Venkatraman transformation on corresponding 2- acetylphenyl benzoate by conventional as well as ultrasound irradiation method. The structure of synthesized compounds has been assigned on the basis of elemental and spectral analysis (IR, 1 H NMR, 13 C NMR, UV/Vis, Mass). The synthesized compounds were evaluated for antibacterial and antifungal activities. Utilization of ultrasound irradiation, simple reaction conditions, isolation and purification makes this manipulation very interesting from an economic and environmental perspective.

A Rapid Combinatorial Library Synthesis of Benzazolo[2,1-b]quinazolinones and Triazolo[2,1-b]quinazolinones

Benzazolo [2,1-b]quinazolinones and triazolo[2,1-b]quinazolinones were synthesized in high yields by the condensation reaction of an aldehyde and a cyclic β-diketone with 2 - aminobenzimidazole, 2 - aminobenzothiazole or 1, 2, 4 - triazole derivatives in 1 - butyl - 3 -methylimidazolium bromide as an ionic liquid under classic heating conditions within 5-60 minutes.

Microwave-Assisted Synthesis of Spirofused Heterocycles Using Decatungstodivanadogermanic Heteropoly Acid as a Novel and Reusable Heterogeneous Catalyst under Solvent-Free Conditions

Decatungstodivanadogermanic acid (H6GeW10V2O40·22H2O) was synthesized and used as a novel, green heterogeneous catalyst for the synthesis of spirofused heterocycles from one-pot three-component cyclocondensation reaction of a cyclic ketone, aldehyde, and urea in high yields under solvent-free condition in microwave irradiation at 80°C. This catalyst is efficient not only for cyclic ketones, but also for cyclic β-diketones, β-diester, and β-diamide derivatives such as cyclohexanone, dimedone, and Meldrum's acid, or barbituric acid derivatives.

ChemInform Abstract: Microwave‐Assisted Synthesis of Fused Pyrazolo[3,4‐b]pyrazines by the Reaction of ortho‐Aminonitrosopyrazoles and Cyclic β‐Diketones.

Abstract Novel fused pyrazolo[3,4- b ]pyrazines 3 were prepared by assisted microwave cyclocondensation reaction of ortho -aminonitrosopyrazoles 1 and cyclic β-diketones 2 in dimethylformamide. This protocol provides a simple procedure for the synthesis of the title compounds with the advantages of easy work-up, mild reaction conditions and good yields.

Silica supported Fe(HSO4)3 as an efficient, heterogeneous and recyclable catalyst for synthesis of β-enaminones and β-enamino esters

A series of β-substituted enaminones were prepared through the one-pot reaction of β-dicarbonyl compounds with various amines in the presence of silica ferric hydrogensulfate under solvent free conditions at room temperature. The reactions proceed smoothly in excellent yield, high chemoselectivity and with an easy work-up. Catalytic amount of Fe(HSO4)3·SiO2 catalyzed one-pot reaction of linear and cyclic β-diketones and β-keto esters with aromatic and aliphatic amines. The B3LYP/6-31G** full optimizations were carried out for enol-enamine tautomers of enaminones.

Amberlyst-15® in PEG: A novel catalytic system for the facile and efficient one-pot synthesis of benzothiazolo-[2,3-b]-quinazolinone derivatives

A simple and convenient approach for the synthesis of tetraheterocyclic benzothiazolo-[2,3-b]-quinazolin-1-ones has been developed utilizing the MCR methodology, which involves the condensation of 2-aminobenzothiazole, cyclic β-diketones and various aldehydes using Amberlyst-15® in PEG 400 as an environmentally benign and reusable catalyst system. Environmental benignity, recyclability, cost-effectiveness, easy workup and excellent yields are the major attributes of this one-pot procedure.

Heterocyclization of 3-aminocamphor and 3-aminoisoborneol derivatives with cyclic β-diketones and formaldehyde. Synthesis of optically active 1,2,3,4-tetrahydroquinoline derivatives with terpene substituents

Spirocyclic 1,2,3,4-tetrahydroquinoline derivatives were prepared in quantitative yield by three-component condensation of dimedone or Meldrum’s acid with formaldehyde and (1S,3R,4S)-1,7,7-trimethyl-3(arylamino)bicyclo[2.2.1]heptan-2-one or (1S,2S,3R,4S)-1,7,7-trimethyl-3-(arylamino)bicyclo[2.2.1]heptan2-ol.

Solvent-dependent reactivities of acyclic nitrones with β-diketones: catalyst-free syntheses of endiones and enones

Reactions of the nitrones −O+N(Me)C(H)Ar 1 (Ar=phenyl 1a, 4-methylphenyl 1b, 2,4,6-trimethylphenyl 1c, and anthracen-9-yl 1d) with the cyclic β-diketones 1,3-indandione 2 or barbituric acid 3 in CH2Cl2, afford the corresponding endiones 2′a–2′d or 3′a–3′d. In contrast, dimedone 4 reacts with 1a or 1b to give the endione 4′a or 4′b and the bis-adduct 4″a or 4″b. Nevertheless, reaction of 4 with 1c or 1d in CH2Cl2 furnishes only the endione adducts 4′c or 4′d. However, the reaction of 4 with 1a or 1b in methanol gives only 4″a or 4″b, respectively. Among acyclic β-diketones only malonic acid 7 reacts with 1a–1c. Reaction of 7 with 1a in CH2Cl2 forms cinnamic acid 7″a, whereas in the case of 1b, the endione 7′b and (E)-3-p-tolylacrylic acid 7″b are obtained. The nitrone 1c reacts with 7 in CH2Cl2 to afford the endione 7′c or with acetone yielding (E)-4-mesitylbut-3-en-2-one 8. X-ray analyses are reported for 4′c, 5, and 7″b. In addition, the calculated acidity of the hydrogen at the α-C atom is shown to correlate with the reactivity of the β-diketones with nitrones.

Use of SO3H-functionalized halogenfree ionic liquid ([MIM(CH2)4SO3H] [HSO4]) as efficient promoter for the synthesis of structurally diverse spiroheterocycles

Structurally diverse spiroheterocycles with fused systems incorporating medicinally privileged systems have been synthesized by an efficient and convenient synthetic method involving four component domino reaction of 2-aminobenzothiazoles with isatin and cyclic β-diketones using SO3H-functionlized halogenfree ionic liquid ([MIM(CH2)4SO3H][HSO4]) in aqueous medium.

Microwave-assisted CAN-catalyzed solvent-free synthesis of N-allyl quinolone-based pyrano[4,3-b]chromene and benzopyrano[3,2-c]chromene derivatives and their antimicrobial activity

A new series of pyrano[4,3-b]chromene and benzopyrano[3,2-c]chromene derivatives have been synthesized via microwave-assisted one-pot, three-component reaction of N-allyl quinolones, cyclic β-diketones, and 4-hydroxy-6-methyl-2H-pyran-2-one/4-hydroxy coumarin in the presence of catalytic amount of ceric ammonium nitrate under solvent-free condition. The protocol offers expeditious and solvent-free synthesis with excellent yield to furnish fused chromenes for their antimicrobial activity. The chemical structures of the synthesized compounds were elucidated by 1H NMR, 13C NMR, FT-IR, elemental analysis, and mass spectral data. All the compounds were screened against a representative panel of pathogenic strains by broth micro dilution minimum inhibitory concentration method. Among these derivatives, compounds 6i, 6k, 6l, and 6m were found to have admirable activity when compared to the standard drugs.