Enhanced anti-microbial effect through cationization of a mono-triazatricyclodecane substituted asymmetric phthalocyanine
Graphical abstract
A new asymmetric zinc phthalocyanine conjugated with triazatricyclodecane (3) was synthesized. Upon methylation to compound 4, the agent exhibited potent anti-bacterial activity with an IC50 value at nano-molar range and >4 logs reduction of bacteria load.
Introduction
Phthalocyanines have many important industrial applications, including dyes and pigments in fabric, demonstrating that they are safe and environment-friendly materials. They also possess remarkable stability and unique photochemical and photophysical properties, broadening their uses in many high technology fields, including semiconductor materials [1,2], solar cells [3,4], optical data storage [5], chemical sensors [6,7], oxidation-reduction catalysts [[8], [9], [10], [11]] and photocatalysts [12], as well as photodynamic therapy (PDT) for antimicrobial [[13], [14], [15]] or antitumor applications [[16], [17], [18]]. The emergence of multi-resistant bacteria due to the over-use of antibiotics has become a global challenge [19,20]. Phthalocyanines have emerged as a new class of photosensitizer possessing potent antimicrobial effect, even toward drug-resistant bacterial strains separated from hospitals [[21], [22], [23], [24]].
In this study, we designed a new asymmetric Zn(II) phthalocyanine (ZnPc): triazatricyclo-substituted Zn(II) phthalocyanine (compound 3) by conjugating with a Nitrogen-rich compound (1,3,5-triazatricyclo [3.3.1.1(3, 7)] decane-7-amine, Scheme 1). The substituent is quite bulky in size and can reduce the aggregation of phthalocyanine. Aggregation of Pc typically leads to the quench of photodynamic effect. Moreover, the triazatricyclodecane is water soluble, and will be protonated at aqueous solution, potentially rendering the conjugate aqueous solubility and positive charges in a weakly acidic environment. The positive charge is a common property of antimicrobial agents, which allows the adsorption and binding to bacterial surface that carry large amount of negative charges [25,26]. We also wanted to avoid the positional isomer on ZnPc during conjugation because single compound is a key for approval by regulatory agent, should the compound proceeds to clinical trial stage.
It turned out that compound 3 was not water soluble, and did not show desirable antimicrobial effect toward bacterial strains. We suspect that the compound 3 was not protonated at aqueous solution. Quaternization of aliphatic or aromatic nitrogen atom at the end of the synthetic pathway of phthalocyanine is a common way to prepare cationic phthalocyanine [27]. Most of the published cationic phthalocyanines with quaternary amine groups exhibit excellent photodynamic antimicrobial effect [[28], [29], [30], [31], [32]]. Moreover, it was discovered recently by Hamblin group that aPDT can be greatly enhanced by the addition of simple inorganic salts especially iodine ion at micromolar concentration [33]. Thus, we carried out methylation on the tertiary amine group of compound 3 in a hope to form an cationic phthalocyanine compound 4. Photophysical and photochemical properties including UV–Vis spectra, photodynamic antibacterial and hemolysis activities of these compounds were characterized and evaluated. Encouragingly, the compound 4 exhibited very potent antimicrobial effect.
Section snippets
Synthesis of compound 3
The target compound (3) was synthesized using the scheme shown in Scheme 1. The intermediate compound (1) was prepared by statistic condensation method. Condensation of trimellitic anhydride or phthalic anhydride in the presence of urea and catalyst at high temperature can produce tetra-formamido-phthalocyanine or phthalocyanine, respectively. Using a mixture of trimellitic anhydride and phthalic anhydride at a ratio of 1:7 for condensation, we made a mixture of 2-formamidophthalocyanine zinc (1
Materials and instruments
All the reactions were carried out under the atmosphere of nitrogen. The beta-carboxy Zn(II) phthalocyanine compound 2 was synthesized in our lab according to our previously published method [42]. 1,3,5-Triazatricyclo [3. 3. 1. 1 (3, 7)] decan-7-amine, O-benzotriazole-N,N, N′,N′-tetramethyl-uronium-hexafluorophosphate (HBTU), N,N-diisopropylethylamine (DIPEA), dimethyl sulfoxide-d6 and dry DMF (dried with molecular sieves) were purchased from the J & K Scientific LTD. The common solvents such
Conclusions
In conclusion, a new asymmetric mono-substituted Zn(II) phthalocyanine compound 3 and its cationic derivative compound 4 were synthesized and characterized. The photodynamic antimicrobial data showed that compound 3 only inactivated Gram-positive bacterial strains. However, the cationic compound 4 induced >4 logs antimicrobial effect against both of Gram-positive and Gram-negative strains under short incubation time and low light dose. In addition, the compound 4 exhibited negligible toxicity
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Our research work is financially supported by grants from National Key R&D Program of China (2017YFE0103200), and National Natural Science Foundation of China (31370737, 31400637, 31570745, 31670739).
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
References (42)
- et al.
Nano Energy
(2016) - et al.
Coord. Chem. Rev.
(1998) - et al.
Coord. Chem. Rev.
(2010) - et al.
J. Inorg. Biochem.
(2018) Curr. Opin. Microbiol.
(2016)- et al.
Dyes Pigments
(2017) - et al.
Coord. Chem. Rev.
(2010) - et al.
J. Inorg. Biochem.
(2017) - et al.
Dyes Pigments
(2013) - et al.
Dyes Pigments
(2017)
Eur. J. Med. Chem.
Photodiagn. Photodyn. Ther.
Biomaterials
Inorg. Chem. Commun.
Org. Electron.
Nano-Micro Lett.
J. Mater. Chem. A
Appl. Organomet. Chem.
K.M. Kadish
Inorg. Chem.
ACS Catal.
Appl. Organomet. Chem.
Cited by (12)
Inactivation of Nosema spp. with zinc phthalocyanine
2024, Journal of Invertebrate PathologyFrom disinfectants to antibiotics: Enhanced biosafety of quaternary ammonium compounds by chemical modification
2023, Journal of Hazardous MaterialsA3B type unsymmetrical and amphiphilic phthalocyanines: Synthesis, characterization, thermal stability and aggregation studies
2020, Spectrochimica Acta - Part A: Molecular and Biomolecular SpectroscopyCitation Excerpt :The synthesis of the symmetric metal-free and metalled phthalocyanines is well known, on the other hand, unsymmetrical synthesis of the phthalocyanines attracted attention in the recent years. Some studies in this field were listed in [13–22]. The unsymmetrical phthalocyanines have unique electronic and optical properties, and different synthesis strategies.
Binding and photodynamic action of the cationic zinc phthalocyanines with different types of DNA toward understanding of their cancer therapy activity
2019, Journal of Inorganic BiochemistryCitation Excerpt :The key advantages of closed-shell transition metal phthalocyanines for PDT applications lie in their easily tunable optical properties and triplet state formation, which in turn are responsible for effective singlet oxygen production needed for photodynamic action. Recently, studies have been performed on the effectiveness of the polycationic zinc phthalocyanines (ZnPcs) for antimicrobial [32] and anticancer PDT applications [33]; however, unlike in well studied sulfonated AlPc derivatives, very little is known about the binding and photodynamic action of such Pcs with different DNA secondary structures [34–36]. Thus, in this paper we discuss the binding and photodynamic activities of two cationic ZnPcs (Pc1 and Pc2, Chart 1) for single-stranded (SS-DNA), double-stranded (DS-DNA), and G-quadruplex DNA (G4-DNA).
Nanostructured AABB Zn (II) Phthalocyanines as Photodynamic Agents for Bacterial Inactivation
2023, Advanced TherapeuticsDouble-Grafted PET Fiber Material to Remove Airborne Bacteria with High Efficiency
2022, ACS Applied Materials and Interfaces