Porphyrins with combinations of 4-carboxyphenyl and 4-hydroxyphenyl substituents in meso-positions as anti-HIV-1 agents.

A series of 4-carboxyphenyl/4-hydroxyphenyl meso-substituted porphyrins were synthesized, purified, and characterized. The compounds exhibited anti-HIV-1 activities, in vitro, under both non-photodynamic (non-PDT) and photodynamic (PDT) conditions. Specifically, the porphyrins inhibited HIV-1 virus entry, with c-PB2(OH)2 and PB(OH)3 showing significant anti-HIV-1 activity. All of the porphyrins inhibited HIV-1 subtype B and C virus entry under PDT conditions. Our study demonstrated that the compounds bearing combinations of 4-carboxyphenyl/4-hydroxyphenyl moieties were not toxic even at higher concentrations, as compared to the reference porphyrins 5,10,15,20-tetra-(4-carboxyphenyl)porphyrin (TCPP) and 5,10,15,20-tetra-(4-hydroxyphenyl)porphyrin (THPP), under PDT conditions. This study underscores the promising potential of these compounds as HIV entry inhibitors in both non-PDT and PDT scenarios.

Two cationic meso-thiophenium porphyrins and their zinc-complexes as anti-HIV-1 and antibacterial agents under non-photodynamic therapy (PDT) conditions.

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.

An Anti-inflammatory Fe3 O4 -Porphyrin Nanohybrid Capable of Apoptosis through Upregulation of p21 Kinase Inhibitor Having Immunoprotective Properties under Anticancer PDT Conditions.

We report the influence of Fe3 O4 nanoparticles (NPs) on porphyrins in the development of photosensitizers (PSs) for efficient photodynamic therapy (PDT) and possible post-PDT responses for inflicting cancer cell death. Except for Au, most metal-based nanomaterials are unsuitable for clinical applications. The US Food and Drug Administration and other agencies have approved Feraheme and a few other iron oxide NPs for clinical use, paving the way for novel biocompatible immunoprotective superparamagnetic iron oxide nanohybrids to be developed as nanotherapeutics. A water-soluble nanohybrid, referred to here as E-NP, comprising superparamagnetic Fe3 O4 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.

Photodynamic activity attained through the ruptured π-conjugation of pyridyl groups with a porphyrin macrocycle: synthesis and the photophysical and photobiological evaluation of 5-mono-(4-nitrophenyl)-10,15,20-tris-[4-(phenoxymethyl)pyridine]-porphyrin and its Zn(ii) complex.

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).

meso-Thiophenium Porphyrins and Their Zn(II) Complexes: A New Category of Cationic Photosensitizers.

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.

Dual activity of amphiphilic Zn(II) nitroporphyrin derivatives as HIV-1 entry inhibitors and in cancer photodynamic therapy.

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.

Benzamide porphyrins with directly conjugated and distal pyridyl or pyridinium groups substituted to the porphyrin macrocycles: Study of the photosensitising abilities as inducers of apoptosis in cancer cells under photodynamic conditions.

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±0.04µM to 3.71±1.01µM) 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±0.087µM to 12.1±0.12µM) and Pa-1 (ovarian cancer) (IC50's ranging between 17.9±0.01µM to 42.45±0.02µM) 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±0.04µM, 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.