Synthetic Metalloporphyrins Research Articles

Metalloporphyrins as chemical mimics of cytochrome P-450 systems

Certain synthetic metalloporphyrins have been shown to mimic the in vivo metabolism of some pharmaceuticals. Oxidation, hydroxylation and N-demethylation yielded synthetic metabolites. If found to be general, this lays the foundation of a predictive basis to optimize analog desing of inhibitors with reduced oxidative reactivity, to determine the proclivity of drugs to form biological active metabolites, and provides a convenient methodology for their preparation. Certain Synthetic metalloporphyrins have been shown to mimic the in vivo metabolism of some pharmaceuticals. Oxidation. hydroxylation and N-demethylation yielded synthetic metabolites. If found to be general, this lays the foundation of a predictive basis to optimize analog design of inhibitors with reduced oxidative reactivity, to determine the proclivity of drugs to form biologically active metabolites, and provides a convenient methodology for their preparation.

14 EFFECT OF Sn- PROTOPORPHYRIN IN RATS WITH HYPERILURUBINEMIA

Sn-protoporphyrin is a synthetic metalloporphyrin that potently inhibits heme oxygenase, the rate limiting enzyme for heme degradation to bile pigment. Bile duct ligation producing cholestatis results in a marked increase in hepatic microsomal heme oxygenase.

Incorporation of metalloporphyrin inhibitors of heme oxygenase into micelles and liposomes.

Spectral and photodynamic properties of a porphyrin are sensitive to the environment in which it is localized. By comparison of absorption maxima of porphyrins bound to micelles, proteins or artificial membranes with peak wavelengths in homogeneous solutions of known dielectric constant, the relative polarity of the microenvironment surrounding a porphyrin can be estimated. We have focused our examination on the ability of two synthetic metalloporphyrin inhibitors of heme oxygenase, Sn(IV)-mesoporphyrin (SnMP) and Zn(II)-mesoporphyrin (ZnMP), to partition into charged and uncharged detergent micelles and liposomes. SnMP and ZnMP are intercalated into micelles with cationic surface charges but only ZnMP into nonionic micelles, suggesting that the ionic character of the two anionic axial ligands of SnMP, as well as that of the ionized carboxylic acids of both porphyrins, is a predominant force in the interactions of these compounds. Absorbance shifts of SnMP and ZnMP bound to serum albumin suggest that both porphyrins are localized within an environment with polarity similar to that of ethanol. Spectral changes upon incubation of ZnMP into liposomes (with or without surface charges) indicate that the porphyrin is incorporated into the polar region of the bilayer, i.e. at the border between hydrophilic headgroups and hydrophobic lipids. Illumination of ZnMP within the liposomal membrane resulted in a rapid rate of oxygen uptake, consistent with lipid peroxidation occurring within the bilayer.

Heme Oxygenase, a Likely Regulator of cGMP Production in the Brain: Induction in Vivo of HO-1 Compensates for Depression in NO Synthase Activity

To examine the role of carbon monoxide (CO) as a putative neuronal messenger and regulator of cGMP level in vivo, we exploited an animal model to increase brain capability to generate CO. The sole source of CO in mammalian systems is the α-meso carbon bridge of the heme molecule cleaved by heme oxygenase isozymes, HO-1 and HO-2. In adult animals, the noninducible isozyme HO-2 is the predominant form in the brain. We chose to increase, rather than inhibit, brain heme oxygenase activity because synthetic metalloporphyrins, such as Zn-protoporphyrin, which are the only known effective inhibitors of the isozymes, are also potent inhibitors of soluble guanylate cyclase, the enzyme that generates cGMP. In newborn rats both heme oxygenase isozymes were found expressed at low levels, and in the cerebellum heme oxygenase activity could be induced by treatment of 2-day-old animals with a selective depletor of glutathione, buthionine-SR-sulfoximine. The increase in activity was accompanied by marked increases in HO-1 protein and the 1.8 kb HO-1 mRNA in the cerebellum. Despite a pronounced decrease in activity of the hemoprotein nitric oxide synthase, no change in cGMP level was observed. The decrease in the synthase could not be explained by an inhibited heme biosynthesis activity. This unchanged level of cGMP suggests that NO is not the only gaseous heme ligand that can activate guanylate cyclase resulting in the generation of cGMP, but rather that CO may also function in this capacity. Increased capability of select cerebellar cell populations to generate CO, as indicated by an increase in their HO-1 protein content, points to the active role of this isozyme in maintenance of cGMP level under stress conditions, when nitric oxide production is compromised. The cell populations expressing HO-1 protein included those in pia matter and glia, such as astrocytes.

Aerobic oxygenation/dehydrogenation of olefins and 14-dihydropyridines catalyzed by tris(tetrazolyl enolate)iron(III) complexes

The catalytic epoxidation of olefins 4 – 7 catalyzed by synthetic metalloporphyrin analogues [FeL 3] 3 associated with molecular oxygen in the presence of an electron source (isobutyraldehyde) is described. Furthermore, it is shown, that 4-substituted 1,4-dihydropyridines 12 can be dehydrogenated and dealkylated, respectively, by the same system. The analogy to cytochrome P-450 is obvious.

Photodynamic properties of Sn/protoporphyrin: clinical investigations and phototesting in human subjects.

Pure synthetic metalloporphyrins have been developed for experimental and clinical use as inhibitors of heme oxygenase, the rate limiting enzyme in the catabolism of heme to bilirubin. Tin (Sn)-protoporphyrin is one such compound, which potently suppresses bilirubin production and thus jaundice in animals and man. We have previously reported that this metalloporphyrin in conjunction with UVA might be useful as a treatment for psoriasis. To assess the photodynamic properties of Sn-protoporphyrin, 31 subjects were investigated with regard to photosensitivity. In all subjects, phototesting using UVB, UVA, and visible light as well as photopatch testing was performed. Our investigations revealed that 16 of the 31 individuals treated with Sn-protoporphyrin developed a mild photosensitivity, mainly erythema of the hands and face, and in some cases a mild conjunctivitis. The duration of this sensitivity, which in no case caused discomfort, was dose-dependent and ranged from several weeks to 1-3 months. After administration of Sn-protoporphyrin, lower thresholds were found for both UVA and visible light, but the sensitivity for UVB was normal and photopatch tests were negative. In summary, the photosensitivity observed during Sn-protoporphyrin administration was of limited duration and magnitude and did not occur in all subjects. Thus, the combination of photoactive synthetic metalloporphyrins and artificial light might prove to be useful as a regimen for the treatment of skin disease.

Chemistry and biology of heme. Effect of metal salts, organometals, and metalloporphyrins on heme synthesis and catabolism, with special reference to clinical implications and interactions with cytochrome P-450.

Although free porphyrins occur in nature in small quantities, no known function has been assigned to them. In contrast, heme and cobalamin, which are Fe and Co chelates of porphyrins or porphyrin derivatives, respectively, carry out crucial biological functions. Heme is the prosthetic group for a number of hemoproteins. These include myoglobin and hemoglobin, which carry out oxygen binding or transport; mitochondrial cytochromes aa3, b, c, and c3, which are important in transferring electrons; microsomal cytochrome P-450, which catalyzes mixed-function oxidations; catalase, which decomposes H2O2; peroxidase, which activates H2O2; and tryptophan pyrrolase, which catalyzes the oxidation of tryptophan. Recently, heme has also been shown to be the prosthetic group of prostaglandin and peroxide synthetase and indoleamine dioxygenase. The elegant studies of the biochemical pathway for the formation of heme demonstrated the arrangement in the porphyrin macrocycle of the carbon and nitrogen atoms originating from the eight glycine and the succinic acid molecule that are the precursors of porphyrins. There are eight enzymes involved in the synthesis of heme. The first and last three of these enzymes are localized in mitochondria, while the intermediate enzymes are localized in cytosol. The catalytic site of HMOX recognizes metalloporphyrins with central metal atoms other than iron; it favors some of these metalloporphyrins over heme as a potential substrate, sometimes by a large factor, permitting the synthetic heme analogue to serve as a potent competitive inhibitor of HMOX reaction. Since these synthetic metalloporphyrins do not bind molecular oxygen, they are not metabolically degraded by ring rupture and do not add to the body pool of bile pigment. One possible consequence of this competitive inhibition of heme degradation is suppression of bile pigment formation to such a degree that excessive plasma levels of bilirubin may be diminished. The studies of Drummond and Kappas (1981) and later studies in rats, mice, monkeys, and man, and also our studies have proved the latter phenomenon. The compound does not appear to affect the metabolic disposition of preformed bilirubin but inhibits biliary bilirubin excretion derived from the metabolism of endogenous or exogenous heme. Whether some of the effect of Sn-PP on naturally occurring or experimentally induced jaundice in animals reflects diversion of heme to nonheme to oxygenase-dependent pathways of heme metabolism, or whether a pathway which is normally latent becomes activated concurrent with HMOX inhibition is not known.(ABSTRACT TRUNCATED AT 400 WORDS)

Tin-Protoporphyrin-Mediated Disruption In Vivo of Heme Oxygenase-2 Protein Integrity and Activity in Rat Brain

The ability of synthetic metalloporphyrins to suppress heme oxygenase activity and bilirubin formation has recently become of considerable clinical and experimental interest for suppression of jaundice in humans, including neonatal hyperbilirubinemia. The present investigation compares the biochemical effects of Sn- and Zn-protoporphyrins on the predominant heme oxygenase isozyme present in the brain (HO-2) at activity, protein, and transcript levels and describes the ability of Sn-protoporphyrin to adversely affect this isozyme. Specifically, 6 h after a modest dose (50 mumol/kg, i.v.) of Sn-protoporphyrin, heme oxygenase activity in rat brain was nearly undetectable. In addition, as revealed by Western blot analysis, HO-2 protein level was decreased by 20% and the electrophoretic behavior of the protein in the microsomal membranes was altered. Moreover, the activity of NADPH-cytochrome P-450 reductase, which is required for the oxidation of heme molecule, was markedly decreased (60% of control). Western immunoblot analysis revealed also a pronounced decrease in the reductase protein level. The inducible form of heme oxygenase, HO-1, was not detectable by immunoblotting in brain microsomes of either control or Sn-protoporphyrin-treated animals. Northern blot analyses did not reveal decreases in the levels of the single HO-1 mRNA (1.8 kb) or the two HO-2 transcripts (1.3 and 1.9 kb), suggesting that Sn-protoporphyrin mediates its effects on heme oxygenase isozymes at the protein level. Zn-protoporphyrin, on the other hand, had no deleterious effect on brain parameters presently investigated.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential regulation of heme oxygenase isozymes by Sn- and Zn-protoporphyrins: Possible relevance to suppression of hyperbilirubinemia

Synthetic metalloporphyrins decrease heme oxygenase (HO)-dependent bilirubin formation. Presently, the effects in vivo and in vitro of Sn- and Zn-protoporphyrins on HO-1 (HSP-32) and HO-2 at the protein and transcript levels were examined. Western blot analysis of HO-2 in testes microsomes of Sn-protoporphyrin-treated rats revealed a dramatic disruption of the integrity of the HO-2 protein. Similar observations were made with the liver and adrenal HO-2 and the NADPH-cytochrome P-450 reductase of treated rats. Northern blot analysis, however, suggested unaltered tissue levels of HO-2 transcripts (∼ 1.9 and ∼ 1.3 kb). The HO-1 protein integrity in organs of treated rats was less dramatically affected by the metalloporphyrin and an increase in its 1.8 kb mRNA level in the testes was detected. Zn-protoporphyrin also increased HO-1 mRNA level in the testes, but did not affect HO-2 protein integrity. In in vitro studies with purified HO-1 and HO-2, both Sn- and Zn-protoporphyrins were equally inhibitory to HO-1 activity; Sn-protoporphyrin, however, was by far more inhibitory to HO-2-dependent activity than to that of HO-1. Together, these findings and the fact that HO-2 under normal conditions is the predominant form of the enzyme in most organs suggest that loss of HO-2 protein integrity may to a significant degree account for suppression of bilirubin formation by Sn-protoporphyrin. These in turn may reflect differences between HO-1 and HO-2, both at the transcriptional level with HO-2 being noninducible, and in structure/composition of the isozymes, with HO-2 being more labile.

Intestinal heme oxygenase inhibition and increased biliary iron excretion by metalloporphyrins

The effects of synthetic metalloporphyrins on heme oxygenase activity in the epithelium of the proximal region of the small intestine were examined both in vitro and in vivo in male Sprague-Dawley rats. Metalloporphyrins, which inhibit hepatic heme oxygenase in vitro, also inhibit intestinal heme oxygenase. Chromium and tin porphyrins are the most potent inhibitors of the intestinal enzyme in vitro. Oral administration of Sn-protoporphyrin (25 μmol/kg body weight) resulted in inhibition of intestinal heme oxygenase, however, no effect was observed on the splenic, hepatic, or renal enzymes. Metal analyses in these tissues showed essentially no intestinal absorption of the metalloporphyrin. Oral administration of Cr-mesoporphyrin (25 μmol/kg body wt) also resulted in inhibition of intestinal heme oxygenase activity. Zinc and manganese mesoporphyrin did not inhibit intestinal heme oxygenase activity when administered orally. Microsomal intestinal heme oxygenase activity was inhibited in a dose-dependent manner by antiserum raised in rabbit against rat hepatic heme oxygenase. The parenteral administration of metalloporphyrin inhibitors of heme oxygenase to bile ductcannulated rats resulted in a significant increase in iron levels in the bile.

Intestinal heme oxygenase inhibition and increased biliary iron excretion by metalloporphyrins

The effects of synthetic metalloporphyrins on heme oxygenase activity in the epithelium of the proximal region of the small intestine were examined both in vitro and in vivo in male Sprague-Dawley rats. Metalloporphyrins, which inhibit hepatic heme oxygenase in vitro, also inhibit intestinal heme oxygenase. Chromium and tin porphyrins are the most potent inhibitors of the intestinal enzyme in vitro. Oral administration of Sn-protoporphyrin (25 mumol/kg body weight) resulted in inhibition of intestinal heme oxygenase; however, no effect was observed on the splenic, hepatic, or renal enzymes. Metal analyses in these tissues showed essentially no intestinal absorption of the metalloporphyrin. Oral administration of Cr-mesoporphyrin (25 mumol/kg body wt) also resulted in inhibition of intestinal heme oxygenase activity. Zinc and manganese mesoporphyrin did not inhibit intestinal heme oxygenase activity when administered orally. Microsomal intestinal heme oxygenase activity was inhibited in a dose-dependent manner by antiserum raised in rabbit against rat hepatic heme oxygenase. The parenteral administration of metalloporphyrin inhibitors of heme oxygenase to bile duct-cannulated rats resulted in a significant increase in iron levels in the bile. (Gastroenterology 1992 Apr;102(4 Pt 1):1170-5)

Photochemical formation of oxochromium(IV) tetraphenylporphyrin from nitritochromium(III) tetraphenylporphyrin in benzene

It has been well recognized that synthetic metalloporphyrins with central metals Fe, Co, Rh, and Mn react with simple diatomic molecules O{sub 2}, CO, and NO to yield their adducts. Laser photolysis studies have revealed that these adducts readily liberate the diatomic molecules to give metalloporphyrins upon photoexcitation. The photoreaction is simply interpreted in terms of the photoindiced dissociation of the axial diatomic molecules from the central metal. In the present work, the authors have carried out photochemical studies of nitritochromium(III) tetraphenylporphyrin, ONO-Cr{sup III}TPP, which is considered to be an adduct of a triatomic molecule NO{sub 2} of chromium(II) tetraphenylporphyrin, Cr{sup II}TPP.

Biocompatible catalysis. Forging a link between redox enzymes and synthetic metalloporphyrin catalysts in phospholipid bilayers

Biocompatible catalysis. Forging a link between redox enzymes and synthetic metalloporphyrin catalysts in phospholipid bilayers

ChemInform Abstract: Oxyfunctionalization of Alkanes with Hydrogen Peroxide on Titanium Silicalite.

BECAUSE of the chemical inertness of alkanes, the introduction of functional groups into them by oxidation has tended to require severe and thus unselective conditions. The homogeneous and heterogeneous catalysts used for alkene oxidation are ineffective for alkanes1,2. Cleavage of carbon–carbon bonds in the presence of transition metal complexes effects mainly complete oxidation to acids2, although some selectivity is occasionally possible3. Oxyfunctionalization without C–C bond cleavage has also been achieved2,4,5, and high selectivity may be obtained from natural or synthetic metalloporphyrin systems6,7. Here we show that titanium silicalite, a microporous crystalline Ti-silica8, is able to activate secondary and tertiary carbon atoms in alkanes, so that they may be oxidized to alcohols and subsequently to ketones using aqueous H2O2. The catalyst has low regioselectivity for alcohol formation but high reactant selectivity in the formation of ketones.

Pharmacologic Approaches to the Prevention and Treatment of Neonatal Hyperbilirubinemia

Because of the high frequency, serious sequelae, and complex and costly management, neonatal jaundice is a good candidate for preventive treatment. In this respect the clinical problem of neonatal jaundice has many similarities with the problem of hemorrhagic disease of the newborn. Both conditions are transient peculiarities of newborn metabolism. Most neonates exhibit the biochemical abnormality, but a small minority is placed in jeopardy of life or suffers serious sequelae. In both conditions a loose relationship exists between the degree of biochemical abnormality and the clinical manifestations that are poorly predicted by monitoring the abnormalities. The administration of vitamin K at birth corrected the biochemical abnormalities and eliminated clinical hemorrhagic disease. The simplicity, efficacy, and safety of vitamin K prevention of hemorrhagic disease of the newborn is the prototype in the search for the solution to the problem of neonatal jaundice. For most neonates, antenatal phenobarbital comes close to this prototype in terms of efficacy and simplicity. The combination of antenatal and postnatal therapy seems suitable for use in preterm labor in combination with tocolysis. This recommendation is conditional on the demonstration of safety by long-term follow-up. The competitive inhibition of HO by synthetic metalloporphyrins offers an even simpler solution, but the level of efficacy achieved with the doses and compounds used so far are not comparable with that of phenobarbital. For the time being, phenobarbital is recommended for population groups with high risk of severe neonatal jaundice, or scarcity of resources for the management of neonatal jaundice with phototherapy and exchange transfusion.

Oxyfunctionalization of alkanes with hydrogen peroxide on titanium silicalite

BECAUSE of the chemical inertness of alkanes, the introduction of functional groups into them by oxidation has tended to require severe and thus unselective conditions. The homogeneous and heterogeneous catalysts used for alkene oxidation are ineffective for alkanes1,2. Cleavage of carbon–carbon bonds in the presence of transition metal complexes effects mainly complete oxidation to acids2, although some selectivity is occasionally possible3. Oxyfunctionalization without C–C bond cleavage has also been achieved2,4,5, and high selectivity may be obtained from natural or synthetic metalloporphyrin systems6,7. Here we show that titanium silicalite, a microporous crystalline Ti-silica8, is able to activate secondary and tertiary carbon atoms in alkanes, so that they may be oxidized to alcohols and subsequently to ketones using aqueous H2O2. The catalyst has low regioselectivity for alcohol formation but high reactant selectivity in the formation of ketones.

In vitro Generation of Carbon Monoxide from Organic Molecules and Synthetic Metalloporphyrins Mediated by Light

Tin protoporphyrin (SnPP) and analogs are being studied as possible agents for the prevention of neonatal hyperbilirubinemia through inhibition of heme oxygenase. Because SnPP is a photosensitizer, we studied its role in the photogeneration of carbon monoxide (CO) from organic compounds in vitro. Generation of CO occurred in the presence of 5 microM SnPP and cool white light (19 muW/cm2/nm or 29 W/m2) from SnPP alone, human serum albumin, glucose, histidine, ethanolamine, medium-chain triglycerides, the reduced form of nicotinamide-adenine dinucleotide phosphate (NADPH), and human plasma. More detailed studies with human serum albumin and NADPH established that the photogeneration of CO is nearly linear with time and irradiance. It is curvilinear with respect to the SnPP concentration at the concentrations tested, and it is dependent on the presence of O2 in the reactor headspace. Cool white light generated less CO from human serum albumin and NADPH than equidistantly placed blue and green phototherapy light sources. Comparison of SnPP with other metalloporphyrin heme oxygenase inhibitors indicates that tin mesoporphyrin is most and zinc protoporphyrin least photoreactive.

Solvent Effects upon the Conformational Equilibrium for the Cofacial Zinc(II) Tetraphenylporphyrin Cage Molecule

Experimental values for conformational equilibrium constants of the zinc(II) tetraphenylporphyrin cage molecule in seventeen nonaqueous solvents have been published recently. That data collection has now been critically re-examined in order to identify the characteristics of the solvent associated with the observed changes in the distribution of the solute between the introverted and extroverted forms of the porphyrin-quinone. Based on a linear solvation energy analysis for a wide range of solvent types, it now appears that the primary influences which are attributable to the solvent environment include the dipolarity, inductive polarizability, and hydrogen bonding by the solvent species. The biochemical metalloporphyrins have been studied extensively as chemical agents in oxygen transfer and storage and in electron transfer processes. A number of synthetic metalloporphyrins have been examined as well in order to isolate and more fully identify particular structural features contributing to photochemical, mechanistic and catalytic properties of their more complex natural analogues. Among these synthetic compounds, zinc(II) tetraphenyl-porphyrin (ZnTPP) and its derivatives have served as model structures for the investigation of the influence of axial ligation on electronic spectra (Nappa and Valentine, 1978) and thermodynamic changes which accompany modifications in the side-chain substituents on the porphyrin (Walker and Benson, 1980). Of the many ZnTPP derivatives, one structurally unique and interesting porphyrin-quinone cage molecule has been recently synthesized and fully characterized by Lisicki et al. (1988). This molecule can most easily be pictured as having an overall hemispherical shape with the base of the hemisphere being the Zn-porphyrin planar structure and the quinone portion located at the polar position above the center of the porphyrin ring. Thus, the quinone portion is attached to the perimeter of the ZnTPP plane by four bridging arms or spacer groups.

Sensitivity of human tissue heme oxygenase to a new synthetic metalloporphyrin.

Heme oxygenase, the rate-limiting enzyme for heme degradation, can be inhibited by several new synthetic metalloporphyrins. Under certain conditions, a depression in heme oxygenase activity has important clinical significance in the treatment of hyperbilirubinemia, and, in this regard, tin-protoporphyrin has been shown to decrease the production of bilirubin in vitro as well as in vivo. Similarly, our study was concerned with finding a new metalloporphyrin which will inhibit heme oxygenase. Many of the synthetic heme analogs that we analyzed were quite effective inhibitors of heme oxygenase, but the most powerful inhibitor was found to be zinc-deuteroporphyrin IX, 2,4-bisglycol. This metalloporphyrin almost completely inhibits liver heme oxygenase at concentrations as low as 0.5 microM. Its potency as an inhibitor was found to be greater than that of tin-protoporphyrin; the Ki of zinc-deuteroporphyrin IX, 2,4-bisglycol was calculated to be 0.003 microM. In conclusion, we demonstrated that zinc-deuteroporphyrin IX, 2,4-bisglycol has potent inhibitory effects on human liver, kidney and brain heme oxygenase so that this metalloporphyrin can be considered as an alternative to tin-protoporphyrin in the treatment of hyperbilirubinemia.

Potentiation of radiation-induced cell kill by synthetic metalloporphyrins

The effects of the combination of several meso-substituted, water soluble metalloporphyrins with ionizing radiation on hypoxic and oxic monolayers of Chinese hamster fibroblast (V79N) cells were studied. The metalloporphyrins tested included a series of cationic metalloporphyrins complexed with Co(III), Zn(II), Fe(III), Cu(II), Pd(II) or Mn(III) and a series of anionic porphyrins chelated with Co(III), Fe(III), Cu(II), Rh(III), Mn(III) or Sn(IV). Both cationic and anionic free porphyrins were also tested. Cationic ligands were tetrakis(4N-methylpyridyl)porphine [TMPyP], tetrakis(4N-trimethylamino phenyl)porphine [TMAP], tetrakis(4N-butylpyridyl)porphine [TBPyP] and tetmkis(3N-meth3+lpyridyl)porphine [3TMPyP]. Anionic ligands tested were tetmkis(4-sulfonato phenyl)porphine [TPPS], tetrakis(biphenyl)porphine sulfonate [TBPS] and tetrakis(4-carboxyphenyl)porphine rFCPP]. SER calculated from survival curves and SFR from one radiation dose were used to assess the relative effectiveness of this class as non-cytotoxic hypoxic and oxic cell-kill potentiators. Comparisons were made at 100 μM, which was essentially non-toxic (>70% survival) for all porphyrins tested except for Co]TMPyP] (approximately 50% survival after 1 hour at 37°C under oxic conditions). The greatest effects on radiation-induced cell kill were achieved with Co[TPPS] and Co[TMPyP] with SER values of 2.3 and 2.4 respectively. Porphyrin analogs with no coordinated metal were found to be less active than the same compound with metal. The overall charge on the molecule did not systematically relate to the biological activity of the compounds tested.