Structure-Activity and Mechanism Studies on Silicon Phthalocyanines with Plasmodium falciparum in the Dark and Under Red Light

Syntheses for the new photosensitizers HOSiPc-OSi(CH₃)₂(CH₂)₃N(CH₂)₁ or ₃(CH₃)₂, Pc 34 and Pc 25, have been developed and the order of activity of these photosensitizers and the previously reported photosensi-tizer Pc 4, HOSiPcOSi(CH₃)₂(CH₂)₃N(CH₃)₂, in the dark and with broad-band red light toward Plasmodium falciparum in red blood cell (RBC) suspensions has been studied. The order of activity has been found to be Pc 4 Pc 34 Pc 25. Thus, the activity of the photosensitizers under both sets of conditions is inversely proportional to the length of their terminal amino alkyl chains. The 50% inhibition dye concentration (IC₅₀) in the dark for the parasites in RBC suspension with Pc 4 is 24 nM and the dye concentration and light fluence that yield:3 log₁₀ of parasite inactivation with Pc 4 are 2 mM and 3 J/cm², respectively. The synthesis of DNA and proteins by the parasites in culture was strongly inhibited by Pc 4 in the dark while parasite lactate dehydrogenase (pLDH) activity was unaffected. With Pc 4 and light, DNA and protein synthesis of the parasites in culture was strongly inhibited, pLDH activity of the parasites was moderately inhibited and ribosome density of the parasite cells was reduced. Gel electrophoresis studies showed that synthesis of all parasite proteins was inhibited to a similar extent. These results suggest that Pc 4 both in the dark and with light inactivates the cells by disturbing their machinery for the synthesis of not just one but a whole series of proteins. It is concluded that Pc 4 and light may be able to serve as a practical sterilization combination not only for HIV and other viruses but also for malaria parasites in RBC concentrates, and that Pc 4 by itself may have potential as a chemotherapeutic agent toward malaria.     

QUENCHING OF SINGLET MOLECULAR OXYGEN BY PHTHALOCYANINES AND NAPHTHALOCYANINES

Using the direct measurement of the photosensitized luminescence of singlet molecular oxygen (1O2) the rate constants (kq) have been determined for 1O2 quenching by the monomeric molecules of the following phthalocyanines and naphthalocyanines in chloroform: tetra-(4-tert-butyl) phthalocyanine (I); octa-(3,6-butoxy) phthalocyanine (II), tetra-(6-tert-butyl)-2,3 naphthalocyanine (III), aluminium tetra-(1-tert-phenyl)-2,3 naphthalocyanine (IV), tri-(n-hexyl-siloxy) derivatives of silicon- (V), tin- (VI), aluminium- (VII) and gallium- (VIII) 2,3 naphthalocyanine. The following kq values were obtained (kq x 10(-8) M-1 s-1): 2.9 (I), 59 (II), 100 (III), 20 (IV), 3.9 (V), 53 (VI), 33 (VII), 110 (VIII). As most of the quenchers have the low-lying triplet levels, a contribution of the quenching mechanism based on the energy transfer from 1O2 to these levels has been analysed. A formula is proposed describing the relation between kq values caused by this mechanism, and photophysical constants of the quencher triplet state. This formula was applied to phthalocyanines, naphthalocyanines, beta-carotene and bacterochlorophyll a. The data suggest that the energy transfer can fully explain the activity of V and strongly contributes into the activities of II, III and VI-VIII. A charge transfer interaction might be an additional mechanism involved in 1O2 quenching by compounds studied. As some phthalocyanines and naphthalocyanines are strong physical quenchers of singlet oxygen they can be used as efficient inhibitors for photodestructive processes in photochemical systems.     

Synthesis and characterization of near-infrared absorption tin octabutoxy naphthalocyanines

Synthesis and characterization of a series of tin octabutoxy naphthalocyanines are presented, which show near infrared absorptions (900–930 nm) with high extinction coefficients (ca. 1 × 10⁵ M⁻¹ cm⁻¹). The position of the Q-band is more red-shifted with the heavier halogen, which corresponds to the HOMO–LUMO gaps calculated with density functional theory (0.932, 0.911, 0.905, 0.893 eV). The interaction with SnNc(OBu)₈Br₂ and C₆₀ moves the Q-band further to the infrared region (928 nm). In ¹¹⁹Sn NMR, the upfield shift (−120 ppm) of SnNc(OBu)₈I₂ represents a relatively electron-rich environment at the tin nucleus, and the ¹¹⁹Sn-resonance (237 ppm) of SnNc(OBu)₈F₂ is different from the other halides, where ¹¹⁹Sn–¹⁹F coupling, a triplet splitting (1:2:1), was observed with 1820 Hz coupling constant. In the optimized structures obtained with BLYP, the distortion angles vary from F to I (N–Sn–N angles 178.8°, 173.1°). The tin naphthalocyanine with the heavy halide ligand becomes more concave, and the Sn–X bond is located at a longer distance out of ring. The difference of the two axial bonds varies significantly from 0.003 to 0.104 Å with the change of the axial ligands from F to I. The distorted shape is larger in the order I > Br > Cl > F with increase of the atomic size (1.33, 1.15, 0.99, 0.71 Å, respectively) and decrease of electronegativity (2.21, 2.74, 2.83, 4.10, respectively). SnNc(OMe)₈X₂ has an electric dipole moment perpendicular to the naphthalocyanine plane, and the magnitudes are, 0.81, 0.50, 0.35 and 0.01 for F, Cl, Br and I, respectively. The transition dipole moment lies in the naphthalocyanine plane along the x- or y-axis perpendicular to the permanent dipole moment in the z-axis, which indicates a π → π^∗ ligand–ligand transition. The energies of the molecular orbitals which are mainly contributed to by the naphthalocyanine ring, including the HOMO and LUMO, are slightly changed as the axial ligands change from F to I.     

Peptide‐Targeted Gold Nanoparticles for Photodynamic Therapy of Brain Cancer

Targeted drug delivery using epidermal growth factor peptide‐targeted gold nanoparticles (EGF_pep‐Au NPs) is investigated as a novel approach for delivery of photodynamic therapy (PDT) agents, specifically Pc 4, to cancer. In vitro studies of PDT show that EGF_pep‐Au NP‐Pc 4 is twofold better at killing tumor cells than free Pc 4 after increasing localization in early endosomes. In vivo studies show that targeting with EGF_pep‐Au NP‐Pc 4 improves accumulation of fluorescence of Pc 4 in subcutaneous tumors by greater than threefold compared with untargeted Au NPs. Targeted drug delivery and treatment success can be imaged via the intrinsic fluorescence of the PDT drug Pc 4. Using Pc 4 fluorescence, it is demonstrated in vivo that EGF_pep‐Au NP‐Pc 4 impacts biodistribution of the NPs by decreasing the initial uptake by the reticuloendothelial system (RES) and by increasing the amount of Au NPs circulating in the blood 4 h after IV injection. Interestingly, in vivo PDT with EGF_pep‐Au NP‐Pc 4 results in interrupted tumor growth when compared with EGF_pep‐Au NP control mice when selectively activated with light. These data demonstrate that EGF_pep‐Au NP‐Pc 4 utilizes cancer‐specific biomarkers to improve drug delivery and therapeutic efficacy over untargeted drug delivery.     

PHOTOPROPERTIES OF ALKOXY-SUBSTITUTED PHTHALOCYANINES WITH DEEP-RED OPTICAL ABSORBANCE

Triplet-state properties of 1,4,8,11,15,18,22,25-octa-n-butoxyphthalocyanine and its zinc derivative were determined for the first time. The T1 state of the metal-free phthalocyanine was characterized by a short lifetime (tau T = 17 microseconds) and low quantum yield (phi T = 0.095), and quenching of the triplet by O2 occurred with a bimolecular rate constant (kT sigma = 1.3 x 10(8) M-1 s-1) that is indicative of an endogonic reaction. The zinc complex (ZnPc(OBu)8) was markedly better as a triplet photosensitizer with respect to both tau T (60 microseconds) and phi T (0.5). Quenching by O2 produced singlet oxygen with nearly 100% efficiency, and kT sigma (1.7 x 10(9) M-1s-1) was close to the spin-statistical diffusion-controlled limit. Phosphorescence measurements showed the energy of the T1 state of ZnPc(OBu)8 to be 100 kJ/mol, which is 6 kJ/mol above the 1 delta g state of O2. These photoproperties, together with Q-band absorption maxima in the mid-700 nm range indicate that metal-centered 1,4,8,11,15,18,22,25-octaalkoxyphthalocyanines have excellent potential as sensitizers in photodynamic therapy.     

Non-localized ligand-to-metal charge transfer excited states in (Cp)2Ti(IV)(NCS)2

The bent d(0) titanium metallocene (Cp)(2)Ti(NCS)(2) exhibits an intense phosphorescence from a ligand-to-metal charge transfer triplet excited state at 77 K in an organic glass substrate and a poly(methyl methacrylate) plastic substrate. Quantum chemical calculations and spectroscopic studies show that the orbital parentage of this triplet state arises from the promotion of an electron from an essentially nonbonding symmetry adapted pi molecular orbital located on the NCS(-) ligands to a d(z)2-(y)2 orbital located on the Ti metal. Standard infrared spectroscopy of (Cp)(2)Ti(NCS)(2) in its ground electronic state at 77 K reveals a pair of closely spaced absorptions at (2072 cm(-1), 2038 cm(-1))(glass) and (2055 cm(-1), 2015 cm(-1))(plastic) that are assigned, respectively, to the symmetric and antisymmetric CN stretching modes of the two coordinated NCS(-) ligands. Low-temperature (77 K) time-resolved infrared spectroscopy that accesses the phosphorescing triplet excited state on the ns time scale shows an IR bleach that is coincident with the two ground state CN stretching bands and an associated grow-in of a pair of new IR bands at slightly lower energies (2059 cm(-1), 2013 cm(-1))(glass) and (2049 cm(-1), 1996 cm(-1))(plastic) that are assigned, respectively, to the symmetric and antisymmetric CN stretches in the emitting triplet state. These transient IR bands decay with virtually identical lifetimes to those observed for the phosphorescence decays when measured under identical experimental conditions. Singular value decomposition analysis of the time-resolved infrared data shows that the observed transient IR features arise from the same electronic manifold as measured through luminescence studies. The close similarity between the ground state and excited-state CN stretching bands in (Cp)(2)Ti(NCS)(2) indicates that symmetry breaking does not occur in forming the charge-transfer triplet excited-state manifold; i.e., electron density is withdrawn from a delocalized pi MO spread across both NCS(-) ligands. Calculations at several levels of theory reveal a delocalized ligand-to-metal charge transfer excited triplet manifold. These calculations closely reproduce the relative intensity ratios and frequencies of the symmetric and antisymmetric transient infrared vibrations in the CN region. This study is the first time-resolved infrared investigation of a ligand-to-metal charge-transfer excited state and the first to be performed at cryogenic temperatures in thin-film organic glass and plastic substrates.