Diazafulvenium Methides Research Articles

Novel Foscan®-derived ring-fused chlorins for photodynamic therapy of cancer

Photodynamic therapy (PDT) is an established anticancer treatment that combines the use of a photosensitiser (PS) and a light source of a specific wavelength for the generation of reactive oxygen species (ROS) that are toxic to the tumour cells. Foscan® (mTHPC) is a clinically-approved chlorin used for the PDT treatment of advanced head and neck, prostate and pancreatic cancers but is characterized by being photochemically unstable and associated with prolonged skin photosensitivity. Herein, we report the synthesis of new 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused chlorins, having the meso-tetra(3-hydroxyphenyl)macrocycle core of mTHPC, by exploring the [8π + 2π] cycloaddition of a meso-tetra(3-hydroxyphenyl)porphyrin derivative with diazafulvenium methides. These chlorins have photochemical properties similar to Foscan® but are much more photostable. Among the novel compounds, two chlorins with a hydroxymethyl group and its azide derivative present in the 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused system, are promising photodynamic agents with activity in the 100 nM range against triple-negative breast cancer cells and, in the case of azidomethyl chlorin, a safer phototherapeutic index compared to Foscan®.

Tetrahydropyrazolo[1,5-a]pyridine-fused steroids and their in vitro biological evaluation in prostate cancer

The androgen receptor (AR) is a steroid hormone receptor and its high expression and disruption of its regulation are strongly implicated in prostate cancer (PCa) development. One of the current therapies includes application of steroidal antiandrogens leading to blockade of the AR action by the abrogation of AR-mediated signaling. We introduced here novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused steroidal compounds, described their synthesis based on [8π+2π] cycloaddition reactions of diazafulvenium methides with different steroidal scaffolds and showed their biological evaluation in different prostate cancer cell lines in vitro.Our results showed the ability of novel compounds to suppress the expression of known androgen receptor targets, Nkx3.1 and PSA in two prostate cell lines, 22Rv1 and VCaP. Candidate compound diminished the transcription of AR-regulated genes in the reporter cell line in a concentration-dependent manner. Antiproliferative activity of the most promising steroid was studied by clonogenic assay and induction of apoptosis in treated cells was documented by immunoblot detection of cleaved PARP.

Synthesis and anti-cancer activity of chiral tetrahydropyrazolo[1,5-a]pyridine-fused steroids

Regio- and stereoselective synthesis of novel chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine–fused steroids via [8π+2π] cycloaddition of diazafulvenium methides with steroidal scaffolds is reported. The biological evaluation of the new family of hexacyclic steroids as anti-cancer agents was also carried out. Hexacyclic steroids bearing a benzyl group at C-22, derived from 16-dehydropregnenolone and 16-dehydroprogesterone, show considerable cytotoxicity against EL4 (murine T-lymphoma) in contrast with the corresponding C-22-unsubstituted derivatives showing low cytotoxicity. Thus, results indicate that the presence of the benzyl group is important to ensure cytotoxicity.

Chemistry of aza- and diazafulvenium methides in heterocyclic synthesis

Abstract Aza- and diazafulvenium methide systems are versatile building blocks for the synthesis of pyrroles and pyrazoles. These extended dipoles participate in sigmatropic [1,8]H shifts and 1,7-electrocyclizations giving vinyl pyrroles and pyrazoles. Under flash vacuum pyrolysis conditions these heterocycles undergo interesting rearrangements. Aza- and diazafulvenium methides can be intercepted by dipolarophiles. Derivatives with carboxylate groups at C-4 and/or C-5 act exclusively as 1,7-dipoles affording products resulting from the addition across the 1,7-positions. These 1,7-cycloadducts include chlorin and bacteriochlorin type macrocycles as well as steroidal analogues, compounds with relevance in medicinal chemistry. In contrast with this chemical behavior, 5-trifluoromethylazafulvenium methides can participate in both 1,7- and 1,3-dipolar cycloadditions. The generation and reactivity of benzodiazafulvenium methides is also discussed.

Synthesis of chiral hexacyclic steroids via [8π + 2π] cycloaddition of diazafulvenium methides.

First examples of [8π + 2π] cycloaddition of 16-dehydropregnenolone (16-DPA) acetate with diazafulvenium methides leading to chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused steroids are reported. These hexacyclic steroids were obtained exclusively or selectively with the approach of the 1,7-dipole by the less hindered α-face of 16-DPA. Quantum chemical calculations at the DFT level were carried out, using the cycloaddition of 1-methyl- and 1-benzyl-diazafulvenium methides with N-phenylmaleimide as model reactions, in order to rationalize the stereochemistry outcome. The results indicate that endo cycloadditions of the more stable dipole conformation, having the 1-substituent pointing outward, are significantly more favorable than the alternative exo cycloaddition.

Microwave-induced Pericyclic Reactions of Aza- and Diazafulvenium Methides

The pericyclic reactions of 4,5-dimethoxycarbonyl-substituted aza- and diazafulvenium methides generated under microwave-induced thermolysis conditions have been described. The 7,7-dimethyl-substituted derivatives undergo allowed suprafacial sigmatropic [1,8]-hydrogen shifts leading to the efficient synthesis of C-vinylpyrroles and Cvinylpyrazoles. These intermediates could not be trapped in [8Π+2Π] cycloaddition in the presence of dipolarophiles. Azaand diazafulvenium methides unsubstituted at C-1 and C-7 behave as 8Π 1,7-dipoles in the presence of dipolarophiles under microwave irradiation, leading to a range of pyrrolo and pyrazolo annulated heterocycles resulting from addition across positions 1 and 7. Aza- and diazafulvenium methide derivatives bearing only one methyl group at C-7 are intercepted in sigmatropic hydrogen shifts to give functionalized pyrroles and pyrazoles, respectively. In the presence of electron- deficient dipolarophiles, these 7-methyl-substituted derivatives act as 1,7-dipoles in [8Π+2Π] cycloadditions, however, competitive formation of the corresponding vinyl pyrroles and vinylpyrazoles is also observed.

Thiazolo[3,4-b]indazole-2,2-dioxides as Masked Extended Dipoles: Pericyclic Reactions of Benzodiazafulvenium Methides

Herein we report the first examples of 1,3-dipolar cycloadditions of thiazolidine-derived sydnones with benzyne leading to 1,3-dihydrothiazolo[3,4-b]indazoles. These heterocycles were converted into the corresponding sulfones which were used as precursors of novel benzo-2,3-diazafulvenium methides. These reactive intermediates reacted with N-substituted maleimides affording new 1H-indazoles characterized by an intense yellow color, a property that gives them a potential application as dyes. The synthesis of these heterocycles was rationalized considering the initial 1,3-cycloaddition of benzodiazafulvenium methides to maleimides. This chemical behavior is in contrast with the previously observed reactivity for 4,5-(methoxycarbonyl)diazafulvenium methides, which participate exclusively in [8π + 2π] cycloadditions to give 1,7-cycloadducts. Quantum chemical calculations, carried out at the DFT level of theory, were in agreement with the rationalization of the observed reactivity. Under flash vacuum pyrolysis or under microwave irradiation, 1-methyl- and 7,7-dimethylbenzo-2,3-diazafulvenium methides undergo sigmatropic [1,8]H shifts allowing the efficient synthesis of N-vinyl- and C-vinyl-2H-indazoles.

8π+2π] Cycloaddition of meso‐Tetra‐ and 5,15‐Diarylporphyrins: Synthesis and Photophysical Characterization of Stable Chlorins and Bacteriochlorins

AbstractThe synthesis of new types of stable 4,5,6,7‐tetrahydropyrazolo[1,5‐a]pyridine‐fused chlorins and bacteriorins through [8π+2π] cycloaddition of diazafulvenium methides with porphyrins and chlorins is reported. Detailed absorption and fluorescence spectral and quantum yield measurements have been made on all new compounds. These show potential for various biomedical applications.

Novel Approach to Chlorins and Bacteriochlorins: [8π+2π] Cycloaddition of Diazafulvenium Methides with Porphyrins

AbstractNew and unprecedented [8π+2π] cycloaddition of diazafulvenium methides with porphyrins and chlorins is reported. The synthetic methodology allowed the access to a new type of 4,5,6,7‐tetrahydropyrazolo[1,5‐a]pyridine‐fused chlorins and bacteriorins in a selective fashion.

Microwave-assisted generation and reactivity of aza- and diazafulvenium methides: heterocycles via pericyclic reactions

Azafulvenium methides and diazafulvenium methides have been generated under microwave irradiation from 2,2-dioxo-1 H,3 H-pyrrolo[1,2- c]thiazoles and 2,2-dioxo-1 H,3 H-pyrazolo[1,5- c]thiazoles, respectively. Pericyclic reactions of these 1,7-dipole intermediates, namely, sigmatropic [1,8]H shifts, 1,7-electrocyclization or [8π+2π] cycloaddition led to the synthesis of a range of pyrrole and pyrazole derivatives. The first evidence for the azafulvenium methides by intermolecular trapping via [8π+2π] cycloaddition is reported.

Chemistry of Diazafulvenium Methides in the Synthesis of Functionalized Pyrazoles.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Diazafulvenium Methides in Synthesis of Functionalized Pyrazoles

Diazafulvenium Methides in Synthesis of Functionalized Pyrazoles

Chemistry of Diazafulvenium Methides in the Synthesis of Functionalized Pyrazoles

The chemistry of diazafulvenium methides generated by the thermal extrusion of sulfur dioxide from 2,2-dioxo-1H,3H-pyrazolo[1,5-c] [1,3]thiazoles is described. The diazafulvenium methides unsubstituted at C-7 participate in [8 pi + 2 pi] cycloadditions giving pyrazolo-annulated heterocycles resulting from the addition across the 1,7-position. 1-Methyl-diazafulvenium methides and 7,7-dimethyl-diazafulvenium methides undergo intramolecular sigmatropic [1,8]H shifts giving vinyl-1H-pyrazoles.

Exploiting Azafulvenium Methides Chemistry

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Exploiting azafulvenium methides chemistry

The synthesis of heterocycles via reactive intermediates, (e.g. azadienes, munchnones, aza- and diazafulvenium methides) generated from 1,3-thiazolidines is described. The use of thiazolidines' diastereoselective reactions for the synthesis of chiral heterocyclic compounds is also reported.

New chemistry of diazafulvenium methides: one way to pyrazoles

Diazafulvenium methides generated from the solution pyrolysis of pyrazolo[1,5- c][1,3]thiazole-2,2-dioxides participate in [8π+2π] cycloadditions giving pyrazolo[1,5- a]pyridine derivatives. 1-Methyl-diazafulvenium, generated under flash vacuum pyrolysis reaction conditions, undergoes an intramolecular sigmatropic [1,8]H shift giving 1-vinyl-1 H-pyrazoles.