Synthesis of demethoxy-amino-substituted hypocrellins: novel photosensitizers for photodynamic therapy

Gastric cancer was one of the most common malicious diseases around the world1. Photodynamic therapy (PDT) has been applied to the treatment of gastric tumors since 1980’s and desirable results has been obtained. Hypocrellin B (HB), the natural perylenequinone pigment (PQP), was found to be new effective sensitizer in the photodynamic therapy by virtue of its photophysical, photochemical and photobiological properties2. Scheme 1. The structures of AHBDs AHBDsNevertheless, natural PQP…     

Water soluble distyryl-boradiazaindacenes as efficient photosensitizers for photodynamic therapy

We introduce a novel class of water soluble, extended conjugation boradiazaindacene dyes which are efficient singlet oxygen generators and have spectacular photoinduced cytotoxicity when excited in the "therapeutic window" of the electromagnetic spectrum.     

Structure-activity relationship of new octaethylporphyrin-based benzochlorins as photosensitizers for photodynamic therapy

An in vitro and in vivo structure-activity relationship study was carried out on a series of benzochlorins with variable lipophilicity. The structural features evaluated in this study include the length of the alkyl or fluoroalkyl groups attached to the six-member exocyclic ring either by an ether or by a carbon-carbon bond. In preliminary in vitro (radiation-induced fibrosarcoma [RIF] cells) and in vivo screening (C3H mice, bearing RIF tumors), all Zn (II) benzochlorins were found to be effective. However, benzochlorins bearing alkyl groups with carbon-carbon bonds showed enhanced efficacy compared with the related alkyl ether analogs. A comparative intracellular localization study of the newly synthesized benzochlorins with Rhodamine-123 indicated that the effective photosensitizers localize in mitochondria, and a displacement study with PK11195 showed their partial affinity for the peripheral benzodiazepine receptor (PBR). Interestingly, compared with the Zn(II) benzochlorin that was found to be quite effective in vivo, the corresponding free-base analog produced less photosensitizing activity and was found to localize in lysosomes. A comparative study with dansyl-proline confirmed the binding of the effective benzochlorins to Site II of human serum albumin (HSA). However, no direct correlation was observed between the binding constant values (to HSA or to PBR) of benzochlorins and their photosensitizing ability.     

Synthesis of eight-membered ring compounds using enyne metathesis

[reaction: see text] A novel procedure for synthesizing eight-membered ring compounds was developed using ruthenium-catalyzed enyne metathesis. When a CH2Cl2 solution of enyne connected with catechol, o-amino phenol, or o-phenylenediamine was stirred in the presence of benzylidene ruthenium carbene complex (10 mol %) at room temperature overnight, an eight-membered ring compound was obtained in high yield. In a similar manner, monocyclic 1,4-diaza- or 1-oxa-4-azacyclooctene derivative was obtained in high yield.     

Synthesis of styrenes using ruthenium-catalyzed ring-closing enyne metathesis

The synthesis of substituted styrenes was achieved by ring-closing enyne metathesis (RCEM)/elimination of enyne substrates 12. The synthetic approach was also effective for a different type of enyne substrate 14, yielding corresponding styrene 15.     

meso-tetraphenylporphyrin dimer derivatives as potential photosensitizers in photodynamic therapy. Part 2

Studies on the synthesis, singlet oxygen and fluorescence yields and pharmacokinetic properties of three different dimeric porphyrins with an amide linkage (D2-D4) are described and compared with the results recently reported for a dimeric porphyrin (D1). The pharmacokinetic behavior of all dimers were examined in Balb/c mice bearing MS-2 fibrosarcomas. The maximal efficiency and selectivity of photosensitizer accumulation in each tumor tissue takes place at 24 h after drug administration of 1.0 mg kg-1 into DL-alpha-dipalmitoylphosphatidylcholine liposomes by intravenous injection. Since the dimeric porphyrins exhibit high quantum yields of singlet oxygen generation, long triplet lifetimes and high photostability, the results obtained suggest that the evaluated dimeric structures may be promising candidates for further use in PDT experiments. The results also allow the possibility to establish a correlation between the chemical structure of the dyes and the efficiency/selectivity of the tumor accumulation and can be used for building up optimal photosensitizing agents for tumors.     

Synthesis of (+)-anatoxin-a using enyne metathesis

Synthesis of N-tosylanatoxin-a was achieved by metathesis of enyne in cis-substituents on a pyrrolidine derivative. Metathesis reactions of enyne having terminal alkyne using various ruthenium-carbene complexes did not give a good results. However, when the terminal alkyne was protected with a TMS group, the reaction proceeded smoothly using a second-generation ruthenium-carbene complex to give the desired cyclized compound in high yield. Oxymercuration followed by Dess-Martin oxidation afforded N-tosylanatoxin-a.     

Synthesis of spiro-pyridopyridine analogues by Grubbs' catalyst mediated alkene and enyne metathesis reaction

A practical synthesis of spiro-naphthyridinone derivatives is described by the combination of the Claisen rearrangement and ring-closing metathesis/ring-closing enyne metathesis process. The RCM or RCEM proceeded smoothly in the presence of Grubbs' first generation catalyst at room temperature under a nitrogen atmosphere.     

Cycloheptadiene ring synthesis by tandem intermolecular enyne metathesis

[reaction: see text] The tandem intermolecular enyne metathesis between 1-alkynes and cyclopentene is reported, providing 2-substituted 1,3-cycloheptadienes. The success of the intermolecular reaction hinges on an appropriate balance between cycloalkene ring strain and reactivity of the alkyne.     

Synthesis of fused imidazo azepine derivatives by sequential van Leusen/enyne metathesis reactions

A facile synthesis of fused imidazo azepine derivatives by a van Leusen/intramolecular enyne metathesis synthetic sequence is reported. The two-step reaction sequence generates compounds of significant molecular complexity from simple starting materials in an expedient fashion with good overall yields.     

Research advances in the use of tetrapyrrolic photosensitizers for photodynamic therapy

Photodynamic therapy (PDT) is a promising new treatment modality for several diseases, most notably cancer. In PDT, light, O2, and a photosensitizing drug are combined to produce a selective therapeutic effect. Lately, there has been active research on new photosensitizer candidates, because the most commonly used porphyrin photosensitizers are far from ideal with respect to PDT. Finding a suitable photosensitizer is crucial in improving the efficacy of PDT. Recent synthetic activity has created such a great number of potential photosensitizers for PDT that it is difficult to decide which ones are suitable for which pathological conditions, such as various cancer species. To facilitate the choice of photosensitizer, this review presents a thorough survey of the photophysical and chemical properties of the developed tetrapyrrolic photosensitizers. Special attention is paid to the singlet-oxygen yield (PhiDelta) of each photosensitizer, because it is one of the most important photodynamic parameters in PDT. Also, in the survey, emphasis is placed on those photosensitizers that can easily be prepared by partial syntheses starting from the abundant natural precursors, protoheme and the chlorophylls. Such emphasis is justified by economical and environmental reasons. Several of the most promising photosensitizer candidates are chlorins or bacteriochlorins. Consequently, chlorophyll-related chlorins, whose PhiDelta have been determined, are discussed in detail as potential photosensitizers for PDT. Finally, PDT is briefly discussed as a treatment modality, including its clinical aspects, light sources, targeting of the photosensitizer, and opportunities.     

A first comparative study of purpurinimide-based fluorinated vs. nonfluorinated photosensitizers for photodynamic therapy

A first report on the synthesis and comparative in vitro-in vivo photosensitizing efficacy of various fluorinated and the corresponding nonfluorinated, purpurinimide-based photosensitizers is discussed. In preliminary in vivo screening, compared with the nonfluorinated analogs, purpurinimides bearing trifluoromethyl substituents showed enhanced photosensitizing efficacy. Among compounds (isomers) with similar lipophilicity, the position of the substituents was found to play a decisive role in biological efficacy.     

Endo-selective enyne ring-closing metathesis promoted by stereogenic-at-W mono-pyrrolide complexes

The utility of W-alkylidene complexes for enyne ring-closing metathesis is demonstrated in a direct comparison with Mo-based analogs. Tungsten complexes lead to less alkyne oligomerization and higher levels of endo-selectivity and enantioselectivity.     

Ring synthesis by stereoselective, methylene-free enyne cross metathesis

Tandem enyne metathesis between 1-alkynes and 1,5-cyclooctadiene or all-cis-1,4-polybutadiene resulted in a direct, one-step ring synthesis of cyclohexadienes by methylene-free metathesis. The use of methylene-free metathesis conditions provided apparent Z-selectivity in the intermolecular enyne metathesis step.     

State of the art in the delivery of photosensitizers for photodynamic therapy

In photodynamic therapy, one of the problems limiting the use of many photosensitizers (PS) is the difficulty in preparing pharmaceutical formulations that enable their parenteral administration. Due to their low water solubility, the hydrophobic PS cannot be simply injected intravenously. Different strategies, including polymer-PS conjugation or encapsulation of the drug in colloidal carriers such as oil-dispersions, liposomes and polymeric particles, have been investigated. Although these colloidal carriers tend to accumulate selectively in tumour tissues, they are rapidly taken up by the mononuclear phagocytic system. In order to reduce this undesirable uptake by phagocytic cells, long-circulating carriers that consist of surface modified carriers have been developed. Moreover, considerable effort has been directed towards using other types of carriers to improve tumour targeting and to minimize the side effects. One of the approaches is to entrap PS into the lipophilic core of low-density lipoproteins (LDL) without altering their biological properties. The LDL receptor pathway is an important factor in the selective accumulation of PS in tumour tissue owing to the increased number of LDL receptors on the proliferating cell surface. Specific targeting can also be achieved by binding of monoclonal antibodies or specific tumour-seeking molecules to PS or by the coating of PS loaded carriers.     

Combinatorial synthesis and characterization of new asymmetric porphyrins as potential photosensitizers in photodynamic therapy

Porphyrins play a major role as active photosensitizers in noninvasive optical photodynamic therapy (PDT). In a modular approach, this paper presents a short review of the recent developments of porphyrin structures and materials with improved photosensitizing properties and then presents the synthesis and characterization of a series of new second generation asymmetrical meso-tetraphenylporphyrins varied by substituent in the meta positions of the phenyl rings with either -OH or -OCH3 groups, whereas in the para positions only with -OCH3 groups. The new series of differentially functionalized porphyrins were obtained by a combinatorial multicomponent synthesis (Adler-Longo method) by simultaneously using two different aldehydes: 3,4-dimethoxybenzaldehyde and 3-hydroxybenzaldehyde. The porphyrins were isolated, purified and characterized by HPLC, TLC, UV-vis, fluorescence, MS, 1H-NMR, and 13C-NMR analysis, accompanied by DEPT 135 experiments. Because of the fact that the medium in cancerous tissues is often more acidic than in normal tissues, the capacity of these porphyrins to exist simultaneously in aggregated and protonated forms was also investigated, in tetrahydrofuran (THF) and acid THF-water systems, underlying the changes in the photophysical behaviour. The relative fluorescence quantum yields (Phif) were calculated in comparison with meso-tetraphenylporphyrin (TPP), and the values between 0.14-0.26 were found to be promising for further trials. The series of asymmetrically substituted tetraphenylporphyrins, as the new class of supramolecular materials, are suitable for further functionalization in order to improve their photophysical properties, and they could represent interesting potential PDT photosensitizers.     

Meso-substituted porphyrin photosensitizers with enhanced near-infrared absorption: Synthesis,characterization and biological evaluation for photodynamic therapy

Porphyrin derivatives are widely explored and used in photodynamic therapy, for their marvelous therapeutic properties. In order to fill in the gaps of insufficient photosensitizers with near-infrared absorption, three porphyrin molecules, 5,10,15,20-tetrakis(3,4-bis(2-(-2-(2-hydroxyethoxy)ethoxy)ethoxy)benzyl)zinc porphyrin(P1), 5,15-bis(3,4-bis(2-(-2-(2-hydroxyethoxy)ethoxy)ethoxy)benzyl)-10,20-bis(2-(2-(2-(4-ethynylphenoxy)ethoxy)ethoxy)ethanol)zincporphyrin(P2),5,15-bis(3,4-bis(2-(-2-(2-hydroxyethoxy)ethoxy)ethoxy)benzyl)-10,20-N,N-dibutyl-4-ethynylaniline zinc porphyrin(P3), were designed and synthesized targeting for more efficient cancer treatment. Excellent photophysical properties were illustrated by UV–vis absorption and emission spectra with enhanced absorbance between 650 and 750?nm and fluorescence emission within 600–800?nm. Besides, with high ¹O₂ quantum yield, especially P2 (0.89), all porphyrins were further evaluated in vitro by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay against Hela cells and exhibited negligible dark toxicity and robust phototoxicity. Fluorescence confocal laser microscopy confirmed cellular uptake and diffusion of these porphyrins, therefore demonstrated their potential and promising applications in photodynamic therapy.