Abdellatif Chouai

Exploitation of Long-Lived 3IL Excited States for Metal–Organic Photodynamic Therapy: Verification in a Metastatic Melanoma Model

Members of a family of Ru(II)-appended pyrenylethynylene dyads were synthesized, characterized according to their photophysical and photobiological properties, and evaluated for their collective potential as photosensitizers for metal-organic photodynamic therapy. The dyads in this series possess lowest-lying (3)IL-based excited states with lifetimes that can be tuned from 22 to 270 μs in fluid solution and from 44 to 3440 μs in glass at 77 K. To our knowledge, these excited-state lifetimes are the longest reported for Ru(II)-based dyads containing only one organic chromophore and lacking terminal diimine groups. These excited states proved to be extremely sensitive to trace amounts of oxygen, owing to their long lifetimes and very low radiative rates. Herein, we demonstrate that (3)IL states of this nature are potent photodynamic agents, exhibiting the largest photocytotoxicity indices reported to date with nanomolar light cytotoxicities at very short drug-to-light intervals. Importantly, these new agents are robust enough to maintain submicromolar PDT in pigmented metastatic melanoma cells, where the presence of melanin in combination with low oxygen tension is known to compromise PDT. This activity underscores the potential of metal-organic PDT as an alternate treatment strategy for challenging environments such as malignant melanoma.

Ultrafast ligand exchange: detection of a pentacoordinate Ru(II) intermediate and product formation.

The ultrafast kinetics of ligand exchange of cis-[Ru(bpy)(2)(CH(3)CN)(2)](2+) were measured in H(2)O and CH(3)CN. The formation of the (3)MLCT excited-state and a five-coordinate intermediate are observed in both solvents within 2 ps after excitation (310 nm, fwhm approximately 300 fs). The (3)MLCT excited-state undergoes vibrational cooling (5-6 ps), then decays to regenerate the ground-state with a lifetime of approximately 50 ps. In CH(3)CN, ligand recombination takes place in 28 ps, while the formation of cis-[Ru(bpy)(2)(CH(3)CN)(H(2)O)](2+) in H(2)O takes place with tau = 77 ps.

Kilogram-Scale Synthesis of a Second-Generation Dendrimer Based on 1,3,5-Triazine Using Green and Industrially Compatible Methods with a Single Chromatographic Step

A kilogram scale, divergent and iterative synthesis of a second generation, triazine dendrimer with 12 protected amines on the periphery using common laboratory equipment is reported. The route benefits from common reaction conditions, inexpensive reagents, and aqueous solvents. From the monomers, the desired product dendrimer--the last uncommitted intermediate that leads to a range of committed, generation three targets--can be obtained in 70% overall yield. Of critical importance in the execution of this divergent synthesis is the differential reactivity of chlorine atoms of trichlorotriazine. The stepwise, nucleophilic aromatic substitution of these atoms with amine nucleophiles is both the basis for the dendrimer growth as well as incorporation of solubilizing piperidine groups. Intermediates are obtained and purified through precipitation and/or extraction protocols with the exception of the final product. Isolation of the target dendrimer requires a single silica gel plug filtration. The purity of this material is assessed at >93%, a level consistent with and/or exceeding other commercially available targets.

Photobiological Activity of Ru(II) Dyads Based on (Pyren-1-yl)ethynyl Derivatives of 1,10-Phenanthroline

Several mononuclear Ru(II) dyads possessing 1,10-phenanthroline-appended pyrenylethynylene ligands were synthesized, characterized, and evaluated for their potential in photobiological applications such as photodynamic therapy (PDT). These complexes interact with DNA via intercalation and photocleave DNA in vitro at submicromolar concentrations when irradiated with visible light (lambda(irr) > or = 400 nm). Such properties are remarkably sensitive to the position of the ethynylpyrenyl substituent on the 1,10-phenanthroline ring, with 3-substitution showing the strongest binding under all conditions and causing the most deleterious DNA damage. Both dyads photocleave DNA under hypoxic conditions, and this photoactivity translates well to cytotoxicity and photocytotoxicity models using human leukemia cells, where the 5- and 3-substituted dyads show photocytotoxicity at 5-10 microM and 10-20 microM, respectively, with minimal, or essentially no, dark toxicity at these concentrations. This lack of dark cytotoxicity at concentrations where significant photoactivity is observed emphasizes that agents with strong intercalating units, previously thought to be too toxic for phototherapeutic applications, should not be excluded from the arsenal of potential photochemotherapeutic agents under investigation.

Synthesis and Characterization of Anionic Triazine Dendrimers with a Labile Disulfide Core

Anionic dendrimers based on melamine with disulfide bonds at the core were prepared to investigate the solubility of these architectures, the ability of these molecules to solubilize pyrene as a model drug, and the ability of these architectures to undergo thiol-disulfide exchange. The ability to solubilize pyrene is directly correlated with molecular weight of the dendrimer-aggregation of dendrons does not occur. Thiol-disulfide exchange occurs rapidly using dithiothreitol as the reductant to yield dendrimers with thiol cores that can undergo oxidation in air to yield the original dendrimer.

Structural and magnetic properties of iron(II) complexes with 1,4,5,8,9,12-hexaazatriphenylene (HAT).

Reactions of Fe(II) salts with the ligand 1,4,5,8,9,12-hexaazatriphenylene (HAT) led to the isolation and characterization of four new compounds: [Fe3(HAT)(H2O)12](SO4)3.3.3H2O (1), [Fe2(HAT)(SO4)(H2O)5](SO4).2H2O.CH3OH (2), [Fe2(HAT)(SO4)(H2O)5](SO4).3H2O (3), and [Fe3Cl5(HAT)(CH3OH)4(H2O)]Cl (4). Compound 1 crystallizes as a trinuclear cluster in which HAT acts as a tris-chelating ligand. Compounds 2 and 3 are two polymorphs of an infinite one-dimensional structure in which the Fe atoms are coordinated to HAT and then connected into the chain through bridging sulfate anions. Compound 4 exhibits a similar chain structure, but with bridging chloride ligands. The magnetic behavior of the new compounds is indicative of weak antiferromagnetic coupling between the Fe(II) centers through the HAT ligand.