Amphiphilic porphyrin photosensitisers (PSs) having combinations of directly substituted pyridyl group(s) at the meso-position of a porphyrin macrocycle, and/or indirectly linked pyridyl groups as benzamide derivatives are reported. The compounds 5,10,15,20-tetrakis-(4-pyridylbenzamide)porphyrin (A.2), 5,10,15,20-tetra[N-(pyridine-4-yl)benzamidium] porphyrin (A.3), 5-mono-(4-pyridyl)-10,15,20-tris-(4-pyridylbenzamide)porphyrin (B.2) and 5-mono-(4-methylpyridinium)-10,15,20-tris-(4-pyridiniumbenzamide)porphyrin (B.3) were synthesised. The compounds were successfully characterised through UV–Vis, Emission, 1H NMR, and ESI-HRMS techniques. To evaluate the effect of this combination of directly conjugated and non-conjugated pyridyl/cationic pyridinium groups on the porphyrin macrocycle, the efficacy of the synthesised compounds was compared to a known standard 5,10,15,20-tetrakis(1-methylpyridinium-4-yl)porphyrin (TMPyP). These compounds show better efficacy (IC50’s ranging between 0.66 ± 0.04 μM to 3.71 ± 1.01 μM) against A549 (human epithelial adenocarcinoma lung cancer) cell line under in vitro photodynamic conditions in comparison to MDA-MB-231 (breast cancer) (IC50’s ranging between 3.7 ± 0.087 μM to 12.1 ± 0.12 μM) and Pa-1 (ovarian cancer) (IC50’s ranging between 17.9 ± 0.01 μM to 42.45 ± 0.02 μM) cell lines. It was found that B.3, having a pyridinium group attached to the meso-position of the macrocycle along with three distal cationic pyridinium groups, independent of the porphyrinic electron delocalisation cycle, showed better photocytotoxic efficacy (IC50 = 0.66 ± 0.04 μM, A549 lung cancer cell line) and higher potential to promote apoptosis and hence better efficacy as PS towards cancer photodynamic therapy (PDT). The PDT activity of B.3 was further verified and established by various biological assays, viz. Annexin V assay, cell cycle assay, and reactive oxygen species (ROS) activity assay.

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https://doi.org/10.1016/j.jphotobiol.2017.11.014

Two Zn(II) nitro porphyrin derivatives bearing combinations of meso-4-nitrophenyl and meso-4-methylpyridinium moieties and their free-base precursors were synthesized through one-pot microwave process, purified and characterized. The biological activity of these nitroporphyrins was assessed under both photodynamic and non-photodynamic conditions to correlate their structure-activity relationship (SAR). Unlike, the free-base precursors, Zn(II) complexes of these nitroporphyrins displayed nearly complete inhibition in the entry of lentiviruses such as HIV-1 and SIVmac under non-photodynamic conditions. In addition, the Zn(II) complexes also exhibited a higher in vitro photodynamic activity towards human lung cancer cell-line A549 than their free-base precursors. Our results strongly suggest that incorporation of Zn(II) has improved the antiviral and anticancer properties of the nitroporphyrins. To the best of our knowledge, this is the first report demonstrating the dual activity of nitroporphyrin-zinc complexes as antiviral and anti-cancer, which will aid in their development as therapeutics in clinics.

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https://doi.org/10.1016/j.ejmech.2019.04.051

A new category of cationic meso-thiophenium porphyrins are introduced as possible alternatives to the popular meso-pyridinium porphyrins. Combinations of cationic porphyrins bearing meso-2-methylthiophenium and meso-4-hydroxyphenyl moieties T2(OH)2M (A2B2 type) and T(OH)3M (AB3 type) along with their zinc(II) complexes T2(OH)2MZn and T(OH)3MZn, are reported. The increase in the number of thienyl groups attached to the meso-positions of the porphyrin derivatives (A2B2 frame) has been shown to impart longer fluorescence lifetimes and stronger photocytotoxicity toward A549 lung cancer cells, as evident with T2(OH)2M and its corresponding diamagnetic metal complex T2(OH)2MZn. The photoactivated T2(OH)2MZn imparts an early stage reactive oxygen species (ROS) upregulation and antioxidant depletion in A549 cells and contributes to the strongest oxidative stress-induced cell death mechanism in the series. The DFT calculations of the singlet–triplet energy gap (ΔE) of all the four hydrophilic thiophenium porphyrin derivatives establish the potential applicability of these cationic photosensitizers as PDT agents.

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https://doi.org/10.1021/acsmedchemlett.0c00266

This work establishes that in comparison with the popular synthetic synthon tetra-p-hydroxyphenyl porphyrin (THPP), used for developing various cancer photodynamic therapy (PDT) agents, the cis-A2B2 type porphyrin derivative, synthesized by replacing two p-hydroxyphenyl groups at the meso-positions with two p-nitrophenyl moieties, 5,10-bis-(4-hydroxyphenyl)-15,20-bis-(4-nitrophenyl)porphyrin PN2(OH)2 and its zinc(II) complex PN2(OH)2Zn have more promising photosensitizing and photobiological activities. The presence of the electron-withdrawing p-nitrophenyl moiety seems to strengthen and influence the photodynamic therapy (PDT) action against the A549 cell line by upregulating reactive oxygen species (ROS) and downregulating superoxide dismutase (SOD) in the same cancer cell line. Further, murine macrophage myeloperoxidase (MPO) inhibition and nitric oxide (NO) downregulation by PN2(OH)2 and PN2(OH)2Zn are indicative of a concomitant immunoprotective nature towards noncancerous cells.

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https://doi.org/10.1039/D0NJ05106C

This article compares a reported hydrophobic and photobiologically inert porphyrin synthon, (NPh)TPyP, bearing a single meso-4-nitrophenyl group and three meso-pyridyl groups (A3B type) with a new photobiologically active metal-free porphyrin, P3N, and its zinc-complex, P3NZn, which bear a meso-4-nitrophenyl group along with three distal pyridyl groups. Both P3N and P3NZn experience ruptured π-conjugation with the porphyrin macrocycle and attain hydrophilicity, as indicated via density functional theory (DFT) calculations, becoming photobiologically active under in vitro conditions. The non-invasive photodynamic activity (PDA) predominantly shown by the zinc-complex P3NZn (with higher hydrophilicity) towards KRAS-mutated human lung-cancer cells (A549) was studied. The results indicate the existence of intracellular singlet oxygen inflicted anticancer PDA, which is apparent through the upregulation of intracellular reactive oxygen species (ROS) and the downregulation of both intracellular superoxide dismutase (SOD) and intracellular reduced glutathione (GSH) levels. The trends obtained from both SOD and GSH assays were indicators of therapeutic defence against oxidative stress via neutralizing superoxide anions (SOA).

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https://doi.org/10.1039/D0PP00319K

A water-soluble nanohybrid, referred to here as E-NP, comprising superparamagnetic Fe3O4 NPs functionalised with tripyridyl porphyrin PS was introduced through a rigid 4-carboxyphenyl linker. As a PDT agent, the efficacy of E-NP toward the AGS cancer cell line showed enhanced photosensitising ability as determined through in vitro photobiological assays. The cellular uptake of E-NPs by AGS cells led to apoptosis by upregulating ROS through cell-cycle arrest and loss of mitochondrial membrane potential. The subcellular localisation of the PSs in mitochondria stimulated apoptosis through upregulation of p21, a proliferation inhibitor capable of preventing tumour development. Under both PDT and non-PDT conditions, this nanohybrid can act as an anti-inflammatory agent by decreasing the production of NO and superoxide ions in murine macrophages, thus minimising collateral damage to healthy cells.

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https://doi.org/10.1002/cmdc.202100550

The anti-HIV-1 and antimicrobial activities of novel cationic meso-thiophenium porphyrins and their zinc-complex are reported under in vitro non-photodynamic (PDT) conditions. While all the cationic porphyrins led to the inhibition of de novo virus infection, the Zn(II)-complexes of T2(OH)2M (A2B2-type) and T(OH)3M (AB3-type) displayed potent inhibition of HIV-1 entry with T2(OH)2MZn displaying maximal anti-HIV activity. The Zinc complex of both the thiophenium porphyrins T2(OH)2M and T(OH)3M also depicted antibacterial activities against Escherichia coli (ATCC 25922) and more prominently against Staphylococcus aureus (ATCC 25923). Again, the antibacterial activity was more potent for T2(OH)2MZn. Our study highlighted that the presence of two thiophenium groups at the meso-positions of the A2B2-type porphyrins along with zinc strongly enhanced anti-HIV and antimicrobial properties of these novel thiophenium porphyrins under non-PDT conditions.

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https://doi.org/10.1016/j.bmcl.2022.128699

In the realm of nanomaterials, most metal-based substances lack regulatory approval for clinical pharmacology applications, except for the FDA-approved Feraheme (ferumoxytol). The approval of certain iron nanoparticles (NPs) for nanotherapeutics has spurred interest in developing an immunoprotective biomaterial (BM) using superparamagnetic iron oxide NPs. This article explores the influence of superparamagnetic NPs on porphyrins, with a focus on enhancing their biological activities under biocompatible conditions. Specifically, a hydrophilic BM comprising superparamagnetic Fe3O4 NPs functionalized with a tri-pyridyl porphyrin photosensitizer (PS) linked through a flexible 4-phenylaminoacetic acid linker is investigated. The study found high uptake of the BM in human gastric cancer cells, and the BM demonstrated the potential to induce apoptosis, upregulate p21 expression, and arrest the cell cycle. Under photodynamic therapy conditions, the BM exhibited greater apoptosis rates compared to its precursor, and the Fe3O4 NPs enhanced the porphyrin's anti-inflammatory properties by reducing nitric oxide, myeloperoxidase, and superoxide production in macrophages.

 

https://doi.org/10.1007/s12668-023-01104-2

This article reports the synthesis isolation and characterization of 5,10,15-tris-(4’-(4-formylphenoxy)propoxyphenyl)-20-(4-nitrophenyl)-porphyrin (PN(OH)3A) as a A3B type template for preparation of synthetic formulations of porphyrin based photosensitizers. The compound was synthesized through a multi-step pathway involving initial synthesis of a porphyrin ester precursor 5,10,15-tri-(4-propionyloxyphenyl)-20-(4-nitrophenyl) porphyrin (PN3) followed by its hydrolysis to obtain 5,10,15-tri-(4-hydroxyphenyl)-20-(4-nitrophenyl) porphyrin (PN(OH)3). Nucleophilic substitution reaction of (PN(OH)3) with 4-(3-bromopropoxy) benzaldehyde resulted in the formation of PN(OH)3A. The compounds were characterized through various spectroscopic techniques.

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https://doi.orhttps://doi.org/10.1080/00304948.2023.2207443g/10.1080/00304948.2023.2207443

Microwave synthesis is a valuable and eco-friendly method for efficiently producing organic molecules like quinazolines, offering shorter reaction times and increased efficiency by rapidly distributing thermal energy. The objective of this study was to create hydrazine hydrate or thiourea derivatives of quinazolines via microwave synthesis as small-molecule scaffolds for further customization, isolation, and characterization. The research successfully yielded two quinazolinone derivatives, 3-amino-2-phenylquinazolin-4(3H)-one (QH) and 4-oxo-2-phenylquinazoline-3(4H)-carbothioamide (QTh), through a multi-step synthesis strategy starting from anthranilic acid. These compounds were synthesized under microwave irradiation, resulting in high yields of 81% for QH and 85% for QTh. Their structures were confirmed through spectroscopic techniques and theoretical optimization using DFT, revealing HOMO-LUMO differences of 4.60 and 4.47 eV for QH and QTh, respectively. This method offers significant advantages over traditional quinazoline synthesis from benzoxazin-4-ones, providing quicker reactions (4 min) and increased stability, as indicated by the higher energy gap of QH compared to QTh.

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https://doi.org/10.2174/2213335610666230516165046

In the context of HIV-infected individuals who are susceptible to opportunistic infections like tuberculosis (TB), this study aimed to develop an industrial-scale microwave-assisted production method for compounds with both antiviral and antibacterial properties. The research successfully yielded hydrophilic 2,3-substituted quinazolinones, 4-oxo-2-phenylquinazoline-3(4H)-carboximidamide (Qg) and 4-oxo-2-phenylquinazoline-3(4H)-carboxamide (Qu), with promising yields. These compounds were synthesized by reacting 2-benzamidobenzoyl chloride with guanidine hydrochloride or urea in the presence of potassium carbonate in DMF. Geometrical optimization and vibrational frequency analysis using DFT calculations confirmed the compounds' properties. Additionally, the hydrophilicity of Qg and Qu was supported by the calculated free energies of solvation (ΔGsol). The study investigated the anti-HIV-1 activities of these quinazolinone derivatives, finding that they effectively inhibit HIV entry into receptor cells with low cytotoxicity (EC50 = 50.53 nM for Qu and EC50 = 97.92 nM for Qg). Notably, these compounds, previously known for their antitubercular activity, exhibit potential antiviral properties. The results suggest promising avenues for further synthetic exploration of these quinazolinone scaffolds in drug design, pharmaceutics, and clinical research.

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https://doi.org/10.1002/slct.202302115