Tetra-2,3-pyrazinoporphyrazines with Externally Appended Pyridine Rings. 9. Novel Heterobimetallic Macrocycles and Related Hydrosoluble Hexacations as Potentially Active Photo/Chemotherapeutic Anticancer Agents

Abstract

New homo- and heterobimetallic porphyrazine complexes of general formula [(M'Cl(2))LM] (L = tetrakis-2,3-[5,6-di-(2-pyridyl)pyrazino]porphyrazinato dianion), with M = Zn(II), Mg(II)(H(2)O), or Pd(II) in the central cavity and one M'Cl(2) unit (M' = Pd(II), Pt(II)) peripherally coordinated at the pyridine N atoms of one of the dipyridinopyrazine fragments, were prepared and characterized by elemental analyses and IR/UV-visible spectroscopy. Related water-soluble salt-like species, carrying the hexacations [(PtCl(2))(CH(3))(6)LM](6+) (neutralized by I(-) ions), were also prepared and similarly characterized. Retention of clathrated water molecules is a common feature of all the compounds. A detailed (1)H and (13)C NMR investigation in dimethylformamide (DMF-d(7)) and dimethyl sulfoxide (DMSO-d(6)) provided useful information on the type of arrangement in the neutral and hexacationic species of the metalated dipyridinopyrazine fragments, in which the metal centers (Pd(II)/Pt(II)) are bound to the pyridine N atoms ("py-py" coordination) with formation of N(2(pyr))PdCl(2) or N(2(pyr))PtCl(2) coordination sites, the latter one featuring a cis-platin-like functionality. Data obtained in DMF solution of the quantum yield (Φ(Δ)) for the generation of singlet oxygen, (1)O(2), the cytotoxic agent in photodynamic therapy (PDT), indicate that all the neutral and charged complexes, among them particularly those carrying centrally Zn(II) or Pd(II), exhibit excellent photosensitizing properties, this qualifying the externally platinated complexes as potential bimodal PDT/chemotherapeutic anticancer agents. Fluorescence data (Φ(F)) provided additional information on the photoactivity of all the species studied. The following companion paper describes the observed interaction of the Zn(II) hexacation [(PtCl(2))(CH(3))(6)LZn](6+) with a G-quadruplex (G4) structure of the telomeric DNA sequence 5'-d[AGGG(TTAGGG)(3)]-3' in water.

Tetrapyrazinoporphyrazines and their metal derivatives. Part I: Synthesis and basic structural information

“…It is worth noting that the N 2 MCl 2 plane is nearly perpendicular to the plane of the pyrazine core (the dihedral angles are 78.3 and 85.3°, and 80.3 and 87.0° for A and B units in Pd II and Pt II derivatives, respectively). For the macrocyclic bimetallic complexes [(M'Cl 2 )TPyz42PzM] (Scheme 31, E) in the absence of single crystal X-ray data the "py-py" coordination for the M'Cl 2 unit was confirmed by 1 H and 13 C NMR solution spectral data [56]. Besides, the species with central Zn II has been the object of detailed investigations as to its photoactivity and interaction with a G-quadruplex telomeric structure [57] and similarly for the related octacation [Me 8 TPyz42PzZn] 8+ [213], and also with B-DNA models [59].…”

“…mononuclear complexes [TPyz42PzM] (B) [204,207,209,210], the related quaternized octacations [Me 8 TPyz42PzM] 8+ (C) [206,207,209,210], the homo/hetero pentanuclear derivatives [(M'Cl 2 ) 4 TPyz42PzM] (D) [58,207,209,210], the neutral heterobinuclear [(M'Cl 2 )TPyz42PzM] (E) [56] and the externally monoplatinated quaternized hexacations, [(PtCl 2 )Me 6 TPyz42PzM] 6+ [56].…”

“…Variably from batch to batch for each single species the number of clathrated water molecules can reach 15-20 for macrocyclic unit. The UV-vis and fluorescence spectral response of the most of the macrocycles and their potentialities as photosensitizers for the generation of singlet oxygen ( 1 O 2 ), of interest in photodynamic therapy [53,56,58,59,209,210,213], and as bi-multimodal anticancer drugs [57,59] were also studied. The metal free macrocycle [TPyz42PzH 2 ] (A in Scheme 31) was obtained by direct cyclotetramerization of the dinitrile precursor Pyz42, in the presence of DBU [119].…”

“…Thus, homo/hetero bi-and pentanuclear derivatives were isolated and studied. [56]. Among the two possible modes of chelate complexation, Py-M-Py ("py-py" coordination) and Py-M-Pyz ("py-pyz" coordination) (see Chart 13), the former appears highly favourable since "py-pyz" coordination would require coplanarity of pyridine and pyrazine rings, this implying for the binuclear TPyzPz macrocycle high steric hindrance.…”

“…Peripheral substituents endow TPyzPzs not only with solubility in organic or aqueous solvents, but also fine-tune spectral and other physico-chemical properties and biological activity. In the recent decade, these new peripherally substituted macrocycles have been especially studied as promising species for application in photodynamic therapy (PDT) [49][50][51][52][53][54][55] and plurimodal cancer therapy [56][57][58][59] and as active catalysts in redox processes [60][61][62][63][64][65]. In the following sections, different types of pyrazine-annulated porphyrazines and their metal derivatives will be considered with an emphasis primarily on the synthetic and structural aspects.…”