D. V. Belykh

Novel boronated chlorin e6-based photosensitizers: synthesis, binding to albumin and antitumour efficacy.

Chlorins, a class of plant porphyrins, are perspective as photosensitizing agents due to light absorption in the long wavelength spectral region and deeper photodamage of tissues. Aiming at optimization of antitumour properties of chlorins, we synthesized a series of boronated derivatives of chlorin e(6) and their complexes containing Zn(II), Pd(II) or Sn(IV). The compounds were synthesized by alkylation of amino or hydroxy derivatives of chlorin e(6) with 1-trifluoromethanesulfonylmethyl-o-carborane. Chlorin e(6) 13(1)-N-{2-[N-(o-carboran-1-yl)methyl]aminoethyl}amide-15(2), 17(3)-dimethyl ester (compound 5) formed complexes with serum albumin, a major porphyrin carrier. The binding constant of these complexes was approximately 4 times bigger than the respective value for the complexes of albumin with boron-free aminochlorin e(6). Compound 5 potently sensitized rat fibroblasts to illumination with monochromatic red light: >98% of cells were necrotic by 24h post-illumination with 1 microM of 5. This compound demonstrated high efficacy in photodynamic therapy of rat M-1 sarcoma. After PDT with 25mg/kg of 5 the residual tumours were significantly smaller than in animals subjected to PDT with equal concentration of boron-free aminochlorin e(6). No signs of general toxicity were detectable after PDT with 5. Thus, boronation can enhance the potency of chlorins in PDT, in particular, due to an increased binding to albumin. Our data expand the therapeutic applicability of boronated chlorins beyond boron neutron capture therapy; these agents emerge as dual efficacy photoradiosensitizers.

Comparative study of redox characteristics and antioxidant activity of porphyrins with 2,6-dialkylphenol groups

152 The oxidative stress of an organism is a result of the acceleration of lipid peroxidation (LPO) in cells and the formation of reactive oxygen species and free rad icals. This process leads to destruction of membranes, the emergence of numerous pathologies, and prema ture aging of the organism. The search for new antiox idants, as well as for methods to assess the antioxidant activity, is an important and interesting task [1]. Of particular interest are synthesis and study of properties of polyfunctional compounds with several pharma cophoric centers in the molecule, because such a com bination is able not only to enhance the known physi ological activity but also to cause the appearance of new types of physiological activity [2–4]. Ionol I (2,6 di tert butyl 4 methylphenol) is a known anti oxidant used in the manufacture of foodstuffs (food additive E321). 2,6 Diisobornyl 4 methylphenol (dibornol) IV is currently undergoing preclinical tri als as a promising drug [5]. CHEMISTRY

Simple synthesis of a terpenophenol—chlorin conjugate with an amide bond

A terpenophenol with a butylaminomethyl group was synthesized and conjugated to a chlorin macrocycle through formation of an amide bond without using activating reagents.

Synthesis of novel terpenophenol-chlorin conjugates and evaluation of their membranotropic and membrane-protecting properties

A series of conjugates has been synthesized by the reaction of methylpheophorbide a with ortho-alkylaminomethyl derivatives of 2-isobornyl-4-methylphenol; the terpenophenol fragment in the conjugates is attached to the methylpheophorbide a macrocycle by an amide bond formed upon the amidation of the 13(2)-ester group. A scanning electron microscopy study of the surface structure of erythrocytes incubated with these compounds confirmed their ability to interact with the cell membrane. It was found, based on the ability of the conjugates to inhibit the H2O2-induced hemolysis of erythrocytes and slow down the accumulation of the secondary lipid peroxidation products, that they possess membrane-protecting and antioxidant properties.

Oxidation of 1-methyl-1H-imidazole-2-thiol with chlorine dioxide

Oxidation of 1-methyl-1H-imidazole-2-thiol with chlorine dioxide was performed for the first time, and the results were shown to depend on the oxidation conditions. Optimal conditions were found for the preparation of 1-methylimidazole-2-sulfonic acid, 2,2′-disulfanediylbis(1-methylimidazole) hydrochlorite, and 1-methyl-3-sulfo-3H-imidazolium chloride. A new salt, 4-methylanilinium 1-methyl-1H-imidazole-2-sulfonate, was isolated.

Membrane protective properties of diastereomers of methylpheophorbide a 13(2)-N-n-octyl-N-(2-hydroxy-3-isobornyl-5-methylbenzyl)amide

Two diastereomers of methylpheophorbide a 13(2)-N-n-octyl-N-(2-hydroxy-3-isobornyl-5-methylbenzyl)amide were obtained from (+)- and (−)-enantiomers of 2-isobornyl-4-methylphenol. The evaluation of the membrane protective and antioxidant activity of the individual diastereomers on the model of H2O2-induced hemolysis of blood erythrocytes showed that the stereochemistry of the isobornyl substituent in the synthesized conjugates did not influence their biological activity.

Conjugates of natural chlorins and isobornylphenols with a different length of the spacer between the chlorin and terpenephenolic fragments: synthesis and antioxidant activity

Conjugates containing chlorine and isobornylphenolic fragments, which are connected by spacers of different lengths, were synthesized from methyl pheophorbide a. The toxicity and antioxidant activity of the obtained compounds were studied. Derivatives of pyropheophorbide a containing the most distant from the macrocycle terpenephenolic fragment combine a low toxicity with the high antioxidant activity, and are the most promising for further designing of new medicinal agents for the treatment of diseases associated with a disorder in oxidation-reduction processes in the body.

First macrocycle based on chlorin and isosteviol structural elements

Acylation by suberic acid chloride of chlorin with two oximated isosteviol groups on its periphery produced for the first time a macrocyclic system containing a porphyrin ring and two tetracyclic ent-beyerane frameworks.

Reaction of methylpheophorbides d and b with amines

A series of formyl analogs of chlorin e6 13-amides were synthesized in high yields by reaction under mild conditions of primary and secondary amines with methylpheophorides b and d. In contrast with the secondary 13-amides, tertiary 13-amides were found as two isomers differing in the orientation of the amide plane relative to the plane of the chlorin ring. Methylpheophorbides b and d were more reactive toward the amines than methylpheophorbide a.

Synthesis of conjugates based on chlorin and isosteviol building blocks

Conjugates containing ent-beyerane carbocyclic frameworks on the periphery of a porphyrin macrocycle were prepared by acylation of chlorin e6 derivatives with hydroxyl and amino groups using ent-16-ketobeyeran19-oic acid chloride (diterpenoid isosteviol).