Abstract
New Re(I) carbonyl complexes are proposed as candidates for photodynamic therapy after investigating the effects of the pyridocarbazole-type ligand conjugation, addition of substituents to this ligand, and replacement of one CO by phosphines in [Re(pyridocarbazole)(CO)3(pyridine)] complexes by means of the density functional theory (DFT) and time-dependent DFT. We have found, first, that increasing the conjugation in the bidentate ligand reduces the highest occupied molecular orbital (HOMO)–lowest unoccupied molecular orbital (LUMO) energy gap of the complex, so its absorption wavelength red-shifts. When the enlargement of this ligand is carried out by merging the electron-withdrawing 1H-pyrrole-2,5-dione heterocycle, it enhances even more the stabilization of the LUMO due to its electron-acceptor character. Second, the analysis of the shape and composition of the orbitals involved in the band of interest indicates which substituents of the bidentate ligand and which positions are optimal for reducing the HOMO–LUMO energy gap. The introduction of electron-withdrawing substituents into the pyridine ring of the pyridocarbazole ligand mainly stabilizes the LUMO, whereas the HOMO energy increases primarily when electron-donating substituents are introduced into its indole moiety. Each type of substituents results in a bathochromic shift of the lowest-lying absorption band, which is even larger if they are combined in the same complex. Finally, the removal of the π-backbonding interaction between Re and the CO trans to the monodentate pyridine when it is replaced by phosphines PMe3, 1,4-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (DAPTA), and 1,4,7-triaza-9-phosphatricyclo[5.3.2.1]tridecane (CAP) causes another extra bathochromic shift due to the destabilization of the HOMO, which is low with DAPTA, moderate with PMe3, but especially large with CAP. Through the combination of the PMe3 or CAP ligands with adequate electron-withdrawing and/or electron-donating substituents at the pyridocarbazole ligand, we have found several complexes with significant absorption at the therapeutic window. In addition, according to our results on the singlet–triplet energy gap, all of them should be able to produce cytotoxic singlet oxygen.
Highlights
Since Raab’s pioneering work on the effects of visible light and acridine dye on paramecia,[1] photodynamic therapy (PDT) has become a significant complementary or alternative wellestablished approach for cancer treatment.[2−15] PDT offers a temporal and spatial control of the treatment with minimal side effects, which starts with the administration of a photosensitizer (PS, a photoactivatable molecule), followed by its excitation by light irradiation at a specific wavelength.The light absorption promotes the PS from its singlet ground state (S0) to a singlet excited state (S1), which is an unstable and short-lived one
Starting from complex [Re(epycb)(CO)3(py)] (epycb = pyrido[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione, py = pyridine), several issues have been analyzed through the density functional theory (DFT) and time-dependent DFT (TDDFT) methodologies to rationalize their effect on the spectroscopic and photocytotoxic properties of this complex
We have found that, similar to the closely related Re(I) complexes previously reported, the greater the number of conjugated rings in the bidentate ligand is, the greater the bathochromic shift is. This is caused by a reduction in the energy gap corresponding to the highest occupied molecular orbital (HOMO) → lowest unoccupied molecular orbital (LUMO) transition, which has a mixed 1MLCT−1ILCT (dπRe(CO)2 + πbidentate → πb*identate) character
Summary
Since Raab’s pioneering work on the effects of visible light and acridine dye on paramecia,[1] photodynamic therapy (PDT) has become a significant complementary or alternative wellestablished approach for cancer treatment.[2−15] PDT offers a temporal and spatial control of the treatment with minimal side effects, which starts with the administration of a photosensitizer (PS, a photoactivatable molecule), followed by its excitation by light irradiation at a specific wavelength. Pyridocarbazole complexes for PDT with improved chemical stability and red-shifted visible-light-induced anticancer activity, derivatives of complex III were investigated (complexes IV−IX in Scheme 1).[27] The replacement of the weak π-accepting pyridine ligand in III with the strong σdonating imidazole one (complex IV in Scheme 1) does not practically change the value of λmax (Δλmax = 1 nm) in DMSO. Whereas those containing electron-withdrawing groups at the pyridine moiety do When both types of substituents are simultaneously present at the pyridocarbazole ligand (R1 = F and R2 = OMe, complex IX in Scheme 1), λmax increases from 513 nm (complex IV) to 542 nm (complex IX) in DMSO, retaining the photoinduced cytotoxic effect at λ ≥. Aiming at providing valuable information for the design of novel improved Re-based PSs for PDT, several aspects will be analyzed: the degree of conjugation, the effect of substituents at the pyridocarbazole ligand, and the replacement of a carbonyl ligand by phosphine ones
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