Angela Scala

Supramolecular Assemblies Based on Complexes of Nonionic Amphiphilic Cyclodextrins and a meso-Tetra(4-sulfonatophenyl)porphine Tributyltin(IV) Derivative: Potential Nanotherapeutics against Melanoma

Amphiphilic cyclodextrin (ACyD) provides water-soluble and adaptable nanovectors by modulating the balance between the hydrophobic and hydrophilic chains at both CyD sides. This work aimed to design nanoassemblies based on nonionic and hydrophilic ACyD (SC6OH) for the delivery of a poor-water-soluble organotin(IV)-porphyrin derivative [(Bu3Sn)4TPPS] to melanoma cancer cells. To characterize the porphyrin derivatives under simulated physiological conditions, a speciation was performed using complementary techniques. In aqueous solution (≤ 20 μM), (Bu3Sn)4TPPS primarily exists as a monomer (2 in Figure 1), as suggested by the low static anisotropy (ρ ≈ 0.02) with a negligible formation of porphyrin supramolecular aggregates. MALDI-TOF spectra indicate the presence of moieties (i.e., [(Bu3Sn)3TPPS](-)) that are derivatives of the monomeric species. Spectrofluorimetry coupled with potentiometric measurements primarily assesses the presence of the hydrolytic [(Bu3Sn)4TPPS (OH)4](4-) species under physiological conditions. Nanoassemblies of (Bu3Sn)4TPPS/SC6OH were prepared by dispersion of organic films in PBS at pH 7.4 and were investigated using a combination of spectroscopic and morphological techniques. The UV-vis and emission fluorescence spectra of the (Bu3Sn)4TPPS/SC6OH reveal shifts in the peculiar bands of the organotin(IV)-porphyrin derivative due to its interaction with the ACyD supramolecular assemblies in aqueous solution. The mean size was within the range of 100-120 nm. The ξ-potential was negative (-16 mV) for the (Bu3Sn)4TPPS/SC6OH nanoassemblies, with an entrapment efficiency of approximately 67%. The intracellular delivery, cytotoxicity, nuclear morphology and cell growth kinetics were evaluated via fluorescence microscopy on A375 human melanoma cells. The delivery of (Bu3Sn)4TPPS by ACyD with respect to free (Bu3Sn)4TPPS increases the internalization efficiency and cytotoxicity to induce apoptotic cell death and, at lower concentrations, changes the cellular morphology and prevents cell proliferation.

Nanoassembly of an amphiphilic cyclodextrin and Zn(II)-phthalocyanine with the potential for photodynamic therapy of cancer

Due to their poor solubility and propensity to aggregate in aqueous media, therapeutic application of several photosensiting agents, such as phthalocyanines, in photodynamic therapy (PDT) of solid tumors is severely hampered. With the aim to propose a novel nanotechnological approach, in this paper biodegradable nanoassemblies based on heptakis (2-oligo(ethyleneoxide)-6-hexadecylthio-)-β-CD (SC16OH) and zinc-phthalocyanine (ZnPc) were developed and tested. Nanoassemblies, prepared by the emulsion–solvent evaporation technique, displayed a hydrodynamic diameter around 200 nm, a negative zeta potential and a satisfactory entrapment efficiency of ZnPc. Steady-state and time resolved fluorescence emission spectroscopy studies showed the entrapment of ZnPc as a monomer in the carrier, with a low tendency to self-aggregate and consequently a fairly good propensity to generate singlet oxygen after photoactivation. The interaction of ZnPc with SC16OH was elucidated by 1H-NMR, which suggested the formation of complexes between drug and both hydrophobic and hydrophilic moieties of the amphiphile. Finally, in vitro potential of the nanoassembly was evaluated in HeLa cells by following cellular uptake and photobiological activity. Overall, results suggest the suitability of the nanoassembly based on SC16OH for delivering ZnPc to cancer cells, thus inducing photodynamic anticancer effects.

Diastereoselective multicomponent synthesis and anti-HSV-1 evaluation of dihydrofuran-fused derivatives

Enolizable 6-membered cyclic 1,3-dicarbonyls undergo an efficient and diastereoselective domino condensation/addition/heterocyclization reaction with arylaldehydes and phenacyl chloride, producing highly substituted dihydrofuran-fused derivatives. Ring size of the cyclic 1,3-dicarbonyls and the presence of at least one keto group are crucial to the reaction’s success. The new compounds were evaluated in vitro for antiviral activity against herpes simplex virus type-1 (HSV-1). Interestingly, some of them appeared able to interfere with HSV-1 replication, without detection of cytotoxic effects.

Synthesis and anti HSV-1 evaluation of novel indole-3,4-diones

A novel class of water soluble indole-3,4-diones has been synthesized and evaluated in vitro for antiviral activity against HSV-1. The results showed lack of cytotoxicity and significant antiviral activity. The cellular internalization efficiency and the antiherpetic effect were successfully increased by incorporation into nanoaggregates of an amphiphilic β-cyclodextrin.

β-Cyclodextrin-grafted on multiwalled carbon nanotubes as versatile nanoplatform for entrapment of guanine-based drugs

The design of β-cyclodextrin/multiwalled carbon nanotubes hybrid (β-CD-MWCNT) as nanoplatform for the entrapment and delivery of guanine based drugs is described here. The functionalized carbon nanomaterials have been characterized by XPS spectroscopy, electron microscopy (FEG-SEM and TEM), AFM, TGA, and FT-IR to achieve insights on structure, morphology and chemical composition. The drug binding abilities of nanocarrier towards the guanine (G) and Acyclovir (Acy) were proved by UV-vis and DSC experiments. Host-guest equilibrium association constants and drug loading have been evaluated for G/β-CD-MWCNT and Acy/β-CD-MWCNT complexes. The release studies showed a sustained delivery of Acy without initial burst effect confirming a strong interaction of drug with the nanoplatform sites. The preliminary antiviral data indicated that the Acyclovir loaded into the β-CD-MWCNT platform interferes with HSV-1 replication and the antireplicative effect was higher than the free drug.

Direct synthesis of C3-mono-functionalized oxindoles from N-unprotected 2-oxindole and their antileishmanial activity.

A novel approach for the synthesis of unprecedented C3-mono-functionalized indolin-2-ones is reported, starting from 2-oxindole and chalcones. The reactions proceed regioselectively under mild conditions, without di- and tri-alkylated side products. The new compounds have been evaluated in vitro for their antiproliferative effects against the protozoan Leishmania infantum. Interestingly, they appear able to kill L. infantum promastigotes and amastigotes, without significant cytotoxic effects.

Synthesis of Stannyl Porphyrins and Porphyrin Dimers via Stille Coupling and Their 119Sn NMR and Fluorescence Properties

Free base stannyl porphyrins and free base porphyrin dimers have been successfully synthesized via copper-free Stille coupling in 21-67% yields. This approach provides an access to stannyl porphyrin synthons that were previously unavailable. Moreover, variation of the reaction conditions selectively provides access to either stannyl porphyrins or porphyrin dimers. Full (119/117)Sn NMR analysis was used for characterization of the stannyl porphyrins and detailed (119)Sn-(1)H-(13)C NMR analyses were carried out on a series of the starting tin reagents and the stannyl porphyrins. These investigations indicate that significant structural information can be gathered by use of commonly known NMR techniques. Photophysical properties of the novel porphyrins prepared including absorption, emission, and fluorescence lifetimes were investigated. The stannyl porphyrins emitted in the visible region, and in all cases large Stokes shifts were observed. The emission intensities of the stannyl porphyrins were 100-fold higher than those of the starting bromoporphyrins. Measured fluorescence lifetime (S(0)-->S(1)) of the stannyl and dimeric porphyrins were in the 7.7-12 ns region.

Self-Catalyzed Mannich-Type Reaction of Enolizable Cyclic 1,3-Dicarbonyls to Acyclic Nitrones: An Entry to Functionalized β-Enamino Diones

A new method for the preparation of highly functionalized β-enamino diones has been developed. The protocol involves an initial self-catalyzed Mannich-type reaction of enolizable cyclic 1,3-dicarbonyls to nitrones, followed by a spontaneous intramolecular reorganization of the resulting nonisolated hydroxylamine to enamino derivatives. These compounds retain the features of unnatural α-amino acids. The ease of preparation makes them attractive intermediates for the synthesis of peptidomimetics, polyheterocycles, and other multifunctional compounds. All experimental results have been efficiently rationalized by in silico studies at the M06-2X level of theory, and a valid mechanistic pathway has been proposed.

Nanoassemblies based on non-ionic amphiphilic cyclodextrin hosting Zn(II)-phthalocyanine and docetaxel: Design, physicochemical properties and intracellular effects.

The combination of conventional anticancer therapy with other treatment modalities such as photodynamic therapy (PDT) is paving the way to novel more effective treatment of solid tumors via light exposure. With this idea in mind, in this paper, nanoparticles (NPs) based on Heptakis (2-oligo(ethyleneoxide)-6-hexadecylthio-)-β-CD (SC16OH) for dual delivery of Zinc-Phthalocyanine (ZnPc) and Docetaxel (DTX) were developed pointing to their potential application as nanomedicine for the combined photodynamic and chemo-therapy of solid tumors. NPs prepared by the emulsion-solvent evaporation technique displayed a hydrodynamic diameter of ≅ 200nm, a negative zeta potential (≅ -27mV) and a satisfactory entrapment efficiency of both drugs at a specific mass ratio. On these bases, NPs containing DTX and ZnPc with theoretical loading of 5% and 0.2% respectively (ZnPc/DTX5-NPs) were selected for further investigations. The allocation of ZnPc and DTX into the colloid was investigated by complementary spectroscopic techniques. In particular, fluorescence emission studies showed the entrapment of ZnPc as a monomer in the carrier, with a low tendency to self-aggregate and consequently a fairly high propensity to photogenerate singlet oxygen. The interaction of SC16OH with DTX, co-entrapped with ZnPc, was elucidated by (1)H NMR and 2D ROESY, which suggested the presence of the chemotherapeutic in the hydrophobic portion of SC16OH. ZnPc/DTX5-NPs were fairly stable in different biological relevant media within 24h. Finally, in vitro potential of the nanoassembly was evaluated in HeLa cancer cells by cell viability exploring both effects of DTX and ZnPc. Overall, results suggest the suitability of NPs based on SC16OH for delivering a combination of DTX with ZnPc to cancer cells, thus inducing photodynamic and antimitotic effects.

Targeting of the Leishmania mexicana cysteine protease CPB2.8ΔCTE by decorated fused benzo[b]thiophene scaffold

A potent and highly selective anhydride-based inhibitor of Leishmania mexicana cysteine protease CPB2.8ΔCTE (IC50 = 3.7 μM) was identified. The details of the interaction of the ligand with the enzyme active site were investigated by NMR biomimetic experiments and docking studies. Results of inhibition assays, NMR and theoretical studies indicate that the ligand acts initially as a non-covalent inhibitor and later as an irreversible covalent inhibitor by chemoselective attack of CYS 25 thiolate to an anhydride carbonyl.