Methyl Pheophorbide-a Research Articles

Synthesis of C3-substituted chlorophyll-a derivatives fused by a π-conjugated E-ring and their physical properties with unique near-infrared absorption

Chlorophylls (Chls) are one of the most important pigments for the light-harvesting systems in photosynthesis. Methyl pheophorbide-a derivative fused by a π-conjugated E-ring with the C131=C132 double bond was found as a synthetic example of the unique Chl-a derivatives, which showed split Soret absorption bands in the purple and ultraviolet-A regions and a broad absorption band at a near-infrared (NIR) region as its monomeric state, but not its self-aggregated species. The 3-vinyl group of the Chl-a derivative was chemically transformed into ethyl, formyl, hydroxymethyl, and dialkoxymethyl groups. All the resulting chlorins exhibited unique wide bands at a NIR region. The substitution effect on the peaks of their wide NIR bands was similar to that on the sharp redmost Qy maxima at a visible region of the corresponding pheophorbides with the C131–C132 single bond. Protons at the C5-, C10-, and C20-positions as well as of the peripheral C2-, C3-, C7-, and C8-substituents of methyl 3-substituted 131,132-didehydro-131-deoxo-pheophorbides-a were upfield-shifted in 1H nuclear magnetic resonance, compared with those of intact pheophorbides. The shifts were ascribed to the less ring current of the cyclic tetrapyrroles by π-conjugation of the E-ring. The non-fluorescent C3-substituted Chl-a derivatives could be useful as new materials absorbing NIR wavelength light.

Linker-length dependent intra/intermolecular coordination of synthetic zinc chlorophyll-a derivatives bearing a pyridine terminal in the C132-substituent

An ω-(m-pyridyl)alkyl group was introduced at the C132-methoxycarbonyl group of methyl pheophorbide-a as a chlorophyll-a derivative by exchange of the esterifying moiety. To avoid allomerization and epimerization of the C132-chiral center in the β-keto-ester moiety, a propyl group was substituted at the C132-position. The free bases were zinc-metalated to give zinc methyl 132-propyl-pheophorbides-a bearing an oligomethylene chain with a pyridyl terminal at the C132-position. Depending on the length of the alkyl chain between the terminal pyridine and C132-carboxylate moieties, the coordination of the m-pyridyl group with the central zinc atom in the stereochemically pure and fixed zinc chlorin–pyridine conjugates occurred in intra- or intermolecular fashions.

Synthesis of Red-Light-Responsive Pheophorbide-a Tryptamine Conjugated Photosensitizers for Photodynamic Therapy.

Six methyl pheophorbide-a derivatives were prepared by linking a tryptamine side chain at the C-131 , C-152 and C-173 positions of pheophorbide-a. Prepared conjugates were characterized and evaluated for their photocytotoxicity against A549 cells. The conjugate 6 a with strong absorption at 413 nm (Soret band), 663-671 nm (Q bands) and comparable fluorescence quantum yield (0.26) was found to exhibit significant cytotoxicity (659 nM). Molecular integration of pheophorbide-a and tryptamines showed synergistic effects as the most potent conjugate 6 a was identified with enhanced photocytotoxicity when compared to methyl pheophorbide-a. The conjugate 6 a was smoothly taken up by A549 cells and exhibited intracellular localization predominantly to lysosome in the cytoplasm. Upon photoirradiation 6 a generated singlet oxygen to show potent cytotoxicity toward A549 cells.

Pentacyclic triterpenoids and other constituents isolated from the leaves of Gambeya lacourtiana and their antibacterial activity

The phytochemical study was done on the leaves of Gambeya lacourtiana. This plant has been used in traditional medicine to treat of different ailments such as uterine heamorrhage, metritis and other vaginal infections. Chromatographic fractionation and purification on the leaves crude extract afforded lupeol acetate (1), lupenone (2), lupeol (3), taraxerol (4) stigmasterol (5), erythrodiol (6), chamaedrydiol (7), methyl pheophorbide-a (8), corosolic acid (9), tormentic acid (10), epicatechin (11) and 22-dihydrospinasterol 3-O-β-D-glucopyranoside (12). The structures of compounds 1–12 were elucidated on the basis of 1D and 2D NMR, mass spectrometric and the spectroscopic data as well as comparison with the literature. Compounds 4, 7–10 and 12 were isolated for the first time from Gambeya genus. Crude extract, fractions and compounds 6–12 were evaluated for their antibacterial activity. Methyl pheophorbide-a (8) demonstrated moderate activity against Salmonella typhi CPC with MIC values of 62.5 μg/mL. The chemophenetic significance of these compounds is also discussed.

An Amidochlorin-Based Colorimetric Fluorescent Probe for Selective Cu(2+) Detection.

The design and synthesis of selective and sensitive chemosensors for the quantification of environmentally and biologically important ionic species has attracted widespread attention. Amidochlorin p6 (ACP); an effective colorimetric and fluorescent probe for copper ions (Cu2+) in aqueous solution derived from methyl pheophorbide-a (MPa) was designed and synthesized. A remarkable color change from pale yellow to blue was easily observed by the naked eye upon addition of Cu2+; and a fluorescence quenching was also determined. The research of fluorescent quenching of ACP-Cu2+ complexation showed the detection limit was 7.5 × 10−8 mol/L; which suggested that ACP can act as a high sensitive probe for Cu2+ and can be used to quantitatively detect low levels of Cu2+ in aqueous solution. In aqueous solution the probe exhibits excellent selectivity and sensitivity toward Cu2+ ions over other metal ions (M = Zn2+; Ni2+; Ba2+; Ag+; Co2+; Na+; K+; Mg2+; Cd2+; Pb2+; Mn2+; Fe3+; and Ca2+). The obvious change from pale yellow to blue upon the addition of Cu2+ could make it a suitable “naked eye” indicator for Cu2+.

The Excitation Spectra of Singlet Oxygen and Photoluminescence of Methyl Pheophorbide-a

The correlation between the photoluminescence intensity of a dye-sensitizer (methyl pheophorbide-a, MPP-a) and the efficiency of the singlet oxygen (1O2) generation is studied. The excitation spectrum of 1O2 emission at 1270 nm has one strong band at 403 nm that coincides with the Soret band of MPP-a and only a weak peak at 667 nm, which practically coincides with the strongest band of the MPP-a excitation spectrum. Therefore, the choice of an excitation wavelength for the efficient 1O2 generation should be based on direct measurements of the excitation spectra of the sensitized 1O2 emission.

Phototoxic effects of pyropheophorbide-a from chlorophyll-a on cervical cancer cells

Photodynamic therapy (PDT) is a promising modality in both the curative and palliative treatment against a variety of experimental and naturally occurring human cancers. At present, chlorophyll a derivatives are extensively used for the synthesis of photosensitizers (PSs) for PDT of tumors. In the present study, chlorophyll-a was extracted from the blue-green algae Spirulina platensis by refluxing with acetone. The extract was further acid treated to obtain methylpheophorbide-a (MPa), which was then refluxed in collidine and methylpyropheophorbide-a (Mppa) was obtained. After that, Mppa was converted to pyropheophorbide-a (Ppa) by treatment with 50% sulfuric acid. Finally, phototoxicity and dark toxicity of purified Ppa in two different cell lines, TC-1 and CaSki, were examined by MTT assay. The results suggest that Ppa is more toxic to TC-1 cell line than CaSki cell line. In vivo, the photosensitizing efficiency of Ppa was also higher than those of unloaded PS. These results indicate the potential of Ppa in PDT.

Synthesis of Chlorins Fused with Nitrogen-Containing Heterocycle by the Modification along TheirN21-N23axis

Quinoxalinodeoxopyropheophorbide-a and benzimidazolopurpurin-18 imide were obtained from methyl pheophorbide-a by one-pot method. The synthesis of a series of chlorins fused with nitrogen-containing heterocycle was fulfilled by chemical modifications along their N21–N23 axis such as LiOH-promoted allomerization of C12-methyl group, electrophilic addition to C3-vinyl group, substitution at 20-meso-position and 1, 3-dipolar cycloaddition with diazomethane at 3-position. The structures of new chlorins were characterized by UV–vis, MS, 1H NMR spectra, and elemental analysis.

Advance in Photosensitizers and Light Delivery for Photodynamic Therapy

The brief history of photodynamic therapy (PDT) research has been focused on photosensitizers (PSs) and light delivery was introduced recently. The appropriate PSs were developed from the first generation PS Photofrin (QLT) to the second (chlorins or bacteriochlorins derivatives) and third (conjugated PSs on carrier) generations PSs to overcome undesired disadvantages, and to increase selective tumor accumulation and excellent targeting. For the synthesis of new chlorin PSs chlorophyll a is isolated from natural plants or algae, and converted to methyl pheophorbide a (MPa) as an important starting material for further synthesis. MPa has various active functional groups easily modified for the preparation of different kinds of PSs, such as methyl pyropheophorbide a, purpurin-18, purpurinimide, and chlorin e6 derivatives. Combination therapy, such as chemotherapy and photothermal therapy with PDT, is shortly described here. Advanced light delivery system is shown to establish successful clinical applications of PDT. Phtodynamic efficiency of the PSs with light delivery was investigated in vitro and/or in vivo.

Synthesis of purpurin-18 imide derivatives from chlorophyll-a and -b by modifications and functionalizations along their peripheries

The methyl pheophorbide-a and methyl pheophorbide-b were used as starting materials and converted to purpurin-18 ester by ring-opening and rearrangement reaction in their exocyclic ring. N-Substituted purpurin-18 imides were obtained from purpurin-18 ester through amidation reaction of six-membered cyclic anhydride. Further chemical modifications along their peripheries were carried out by a variety of common reactions, including electrophilic substitution, Wittig reaction, allomerization and Vilsmeier reaction, to afford the title compounds with long-wavelength absorption. The structures of all new chlorins were characterized by elemental analysis, IR, UV–vis and 1H NMR spectra.

Two New Phloroglucinol Derivatives and Five Photosensitizing Pheophorbides from Syzygium polyanthum Leaves (Salam)

Two new phloroglucinol derivatives, identified as anthuminoate (1) and anthuminone (2), were isolated from the ichthyotoxic ethyl acetate fraction of Syzygium polyanthum leaves. In addition, bioassay-guided fractionation followed by dereplication of the photocytotoxic fraction of this plant part has resulted in the identification of five known pheophorbides as the bioactive constituents. The compounds were identified as pheophorbide-a, methyl pheophorbide-a, methyl hydroxypheophorbide-a, pheophorbide-b and hydroxypheophorbide-b. Inhibition of cell viability shown by the compounds ranged from 83.3 to 86.1% at a test concentration of 5 microg/mL. This shows that Syzygium polyanthum leaves are a potential new source in the studies of photocytotoxicity for photodynamic therapy.

ChemInform Abstract: Synthesis of 3‐Pyrazolinyl Chlorins Related to Chlorophyll by 1,3‐Dipolar Cycloaddition Reaction from Methyl Pheophorbide‐a

Abstract8 examples

Synthesis of 3-Pyrazolinyl Chlorins Related to Chlorophyll by 1,3-Dipolar Cycloaddition Reaction from Methyl Pheophorbide-a

The synthesis of a series of 3-pyrazolinyl-substituted chlorins, possessing different basic skeletons of chlorophyll degradation products such as pheophorbide-a, pyropheophorbide-a, purpurin-18, purpurin-7, purpurin-5, chlorin-p 6, and chlorin-e 6, was fulfilled from methyl pheophorbide-a by chemical modification and 1,3-dipolar cycloaddition with diazomethane. The structures of new chlorins were characterized by ultraviolet (UV), infrared (IR), 1H NMR, and mass spectra and elemental analysis.

Acetylation of Chlorophyll-a Degradation Products and Synthesis of Chlorin Derivatives

Methyl pheophorbide-a (MPa) was used as starting material and converted to Ni(II) complexes by modifying for chemical structures and metallizing with Ni(acac)2. Their Vilsmerier reactions with phosphoryl chloride and 3-(dimethylamino)-acrolein or N,N-dimethylformamide were performed regioselectively to introduce formyl or formylvinyl group on the periphery of chlorin. The formylmethyl group also was established by oxidation reaction of the C(3)-vinyl group with thallium nitrate. The hydroxyalkyloxyl or hydroxyalkylamino group on the macrocycle was constructed based on the chemical activities of the vinyl group at 3-position and ketone group in E-ring and subsequently the hydroxyl group was oxidized with the conbination of tetrapropylammonium perruthenate (TPAP) and N-methylmorpholine N-oxide to the corresponding formyl group, respectively. The structures of all the new chlorins containing acyl structure were characterized by UV, IR, H NMR spectra and elemental analysis.

Allomerization of Methyl Pheophorbide-a and Synthesis of Chlorin Derivatives

Allomerization of Methyl Pheophorbide-a and Synthesis of Chlorin Derivatives

The synthesis of chlorophyll-a skeleton homologs bearing linear six-carbon chain from methyl pheophorbide-a

The synthesis of chlorins bearing 6C-straight chain was accomplished from methyl pheophorbide-a. A series of chemical modifications were employed for the construction of active functional groups, such as bromine atom or aldehyde group, on the periphery of chlorins. These functionalized chlorins further reacted with the reagent containing straight carbon-chain by common chemical reactions to produce target compounds. The structures of all new chlorins were characterized by elemental analysis, IR, UV-Vis and 1H NMR spectra.

The regioselective Synthesis of bromochlorins related to chlorophyll-a from methyl pheophorbide-a

An efficient methodology has been developed for the regioselective synthesis of brominated chlorins related to chlorophyll-a from methyl pheophorbide-a. Several regioselective bromination reactions were accomplished by some particular reaction conditions and a series of conversion of functional group from methyl pheophorbide-a to synthesize mono-, bis- and tri-brominated chlorines. The possible mechanisms for the debromination were tentatively proposed and the structures of all new chlorins were characterized by elemental analysis, IR, UV-Vis and 1H NMR spectra.

Photodynamic and Antioxidant Activities of Divalent Transition Metal Complexes of Methyl Pheophorbide-a

E-mail: yoonil71@inje.ac.kr (I. Y.); ykshim@inje.ac.kr (Y. K. S.)Received March 14, 2011, Accepted April 8, 2011A comparative study of the photodynamic and antioxidant activities of methyl pheophorbide-a (MPa, 1) andits transition metal(II) complexes ( 2-5) is described. Four transition metal complexes (palladium(II): 2, zinc(II):3, cobalt(II): 4 and copper(II): 5) of MPa were prepared by reaction between the corresponding transition metaland 1, respectively, and were characterized by

Synthesis of oligomethylene-strapped chlorophyll derivatives and optical properties of their stereoisomers in a solution

Methyl pheophorbide-a/a' derivatives covalently linked with oligomethylene chains at the 3-CH(2)OCO- and 13(2)-COO- moieties in a molecule were prepared by modifying chlorophyll-a through intramolecular ring-closing metathesis of vinyl groups. At least, a C10-length between the 3(3)- and 13(4)-positions was necessary for the cyclization and connection of a C12-strap was the most suitable to achieve the highest closure yield. The oligomethylene chain in 13(2) R-epimers derived from methyl pheophorbide-a covered the α-face of the chlorin π-plane and the strap in the corresponding 13(2) S-epimers protected the β-face. Synthetic 13(2) R-epimer with a dodecamethylene chain gave a flat chlorin π-plane, while the decamethylene chain in the 13(2) R-epimer distorted the π-system due to its shorter linkage. The distortion by strapping in the 13(2) R-epimer induced a slight blue-shift of Qy peak in dichloromethane. CD spectra of the 13(2) R-epimers were similarly dependent on the chain length, i.e., the distortion of π-plane. Visible absorption and CD spectra of all the strapped 13(2) S-epimers were almost identical and only slightly different from those of the unstrapped. The strapping in the 13(2) S-epimers shifted the Qy peak bathochromically.

Photodynamic inactivation of wound-associated bacteria with new troponyl (pyro)pheophobides

In this study, the effect of light activated agent, methyl (pyro)pheophorbide-a, which bears non-aromatic cyclic compound, excited with red light from a LED on the viability of S. aureus, S. epidermidis, and E. coli was investigated. All species were susceptible to killing by photosensitization and photodynamic effect was dependent on both the chemical structure and concentration. However, E. coli was not susceptible to concentrations used to obtain a significant kill with the Gram-positive bacteria upon irradiation. To more closely mimic the conditions of wounds, photodynamic therapy was carried out on S. aureus, which is the most important organism that can cause a range of mild to severe infections in skin and burn wounds, in the presence of human blood plasma and human serum albumin, representing a wound fluid model. Results indicate that microorganisms could be successfully photoinactivated by tropolone methyl (pyro)pheophorbide-a derivatives when suspended in phosphate buffered saline. However, changing the medium into 4.5% and 7% HSA/PBS solutions reduced the effectiveness of lethal photosensitization of bacteria. The same results were obtained with human blood plasma. Also, the mechanism of bacterial cell inactivation by a sensitizer and light was studied with reactive oxygen species scavengers. Further evidence of the involvement of singlet oxygen is provided by the protective effect of the singlet oxygen scavenger, sodium azide.