Лаборатория медицинской химии (№17)

• Использование природных полиакоксибензолов в синтезе биологически активных веществ.
• Создание постоянно пополняемой коллекции химических соединений (около 200 000) и исследование их на противоопухолевую, антиоксидантную, антибактериальную, нейропротекторную  активности.  В рамках совместного проекта по поиску антимикробных веществ с Университетом Квинслэнда (г. Брисбен, Австралия) исследовано более 140 000 новых молекул и найдено более 300 веществ, представлющих интерес для дальнейших исследований.
• Биологические исследования лаборатория проводит совместно с ведущими мировыми университетами.
• Поиск ингибиторов полимеризации тубулина на модели зародышей морского ежа проводятся совместно с Институтом биологии развития им. Н.К. Кольцова РАН.
• Разработка технологии  получения лигандов для  99mTc-  содержащих радиофармпрепаратов,  применяющихся в нашей стране, на доступном отечественом сырье

✓  Разработана технология выделения  аллилполиалкоксибензолов из  семян петрушки и укропа методом экстракции жидким CO2

Эти  полупродукты использованы в синтезе аналогов природных ингибиторов полимеризации тубулина для химиотерапии онкологических заболеваний — комбретастатина, подофилотоксина, стеганоцина, глазиовианина А и др.,  находящихся на разных стадиях клинических испытаний в США, Японии и Европе.

✓  Free-radical-scavenging capacity antioxidant and membrane-protective properties of natural and related synthetic allylpolyalkoxybenzenes with different numbers of alkoxy/methoxy groups in the aromatic ring were evaluated using several in vitro models. These included the DPPH assay, inhibition of lipid peroxidation products accumulation, inhibition of H2O2-induced hemolysis, and oxidation of oxyhemoglobin. A synthetic protocol for the synthesis of natural nothoapiol (9) from a parsley seed metabolite, apiol (7), was developed. A structure−activity relationship study revealed that both the methylenedioxy fragment and methoxy groups in the aromatic ring are favorable for antioxidant activity. Hydroxyapiol (14), containing a hydroxy group in the aromatic core, was identified as the most potent compound. The pentaalkoxy-substituted nothoapiol (9) showed antioxidant activity in mouse brain homogenates, whereas in mouse erythrocytes it exhibited a marked pro-oxidant effect. Despite their low free-radical-scavenging capacity, allylpolyalkoxybenzenes can contribute to the total antioxidant potencies of plant essential oils.

✓  A series of both novel and reported combretastatin analogues including diarylpyrazoles, -isoxazoles, -1,2,3-triazoles and -pyrroles were synthesized via improved protocols in order to evaluate their antimitotic antitubulin activity using in vivo sea urchin embryo assay and a panel of human cancer cells. A systematic comparative structure-activity relationship studies of these compounds were conducted. Pyrazoles 1i and 1p, isoxazole 3a, and triazole 7b were found to be the most potent antimitotics across all tested compounds causing cleavage alteration of the sea urchin embryo at 1 nM, 0.25 nM, 1 nM, and 0.5 nM, respectively. These agents exhibited comparable cytotoxicity against human cancer cells. Structure-activity relationship studies revealed that compounds substituted with 3,4,5-trimethoxyphenyl ring A and 4-methoxyphenyl ring B displayed the highest activity. 3-Hydroxy group in the ring B was essential for the antiproliferative activity in the diarylisoxazole series, whereas it was not required for potency of diarylpyrazoles. Isoxazoles 3 with 3,4,5-trimethoxy substituted ring A and 3-hydroxy-4-methoxy substituted ring B were more active than the respective pyrazoles 1. Of the azoles substituted with the same set of other aryl pharmacophores, diarylpyrazoles 1, 4,5-diarylisoxazoles 3, and 4,5-diaryl-1,2,3-triazoles 7 displayed similar strongest antimitotic antitubulin effect followed by 3,4-diarylisoxazoles 5, 1,5-diaryl-1,2,3-triazoles 8, and pyrroles 10 that showed the lowest activity. Introduction of the amino group into the heterocyclic core decreased the antimitotic antitubulin effect of pyrazoles, triazoles, and to a lesser degree of 4,5-diarylisoxazoles, whereas potency of the respective 3,4-diarylisoxazoles was increased.

✓  A concise six-step protocol for the synthesis of isoflavone glaziovianin A (GVA) and its alkoxyphenyl derivatives starting with easily available plant metabolites from dill and parsley seeds was developed. The reaction sequence involved an efficient conversion of the key intermediate epoxides  into the respective -ketoaldehydes followed by their Cu(I)-mediated cyclization to result in the target series. Biological activity of GVA and its derivatives was evaluated using a panel of seven human cancer cell lines and in vivo sea urchin embryo assay. Both screening platforms confirmed antimitotic effect of the parent GVA  and its alkoxy derivatives. Structure-activity relationship studies suggested that compounds substituted with trimethoxy- and apiol-derived ring B, respectively, were less active than the parent compound. Of the evaluated human cancer cell lines, A375 melanoma cell line was the most sensitive to the tested molecules. Notably, the target compounds were not cytotoxic against human peripheral blood mononuclear cells up to 10 M concentration. Phenotypic readouts from the sea urchin assay unequivocally suggest a direct microtubule destabilizing effect of isoflavones

✓  Analogues of the bioactive natural alkoxynaphthalene pycnanthulignene D were synthesized by an efficient method. The starting plant allylalkoxybenzenes are easily available from the plant essential oils of sassafras, dill and parsley. The target 1-arylalkoxynaphthalenes exhibited antiproliferative activity in a phenotypic sea urchin embryo assay.

✓  A metal-free approach to 3,4-diarylpyrrole-2-carboxylate and pyrrolocoumarin cores of lamellarins and related natural products based on Barton–Zard reaction of nitrostilbenes with ethyl isocyanoacetate was developed. In the case of diarylpyrrole-2-carboxylates with a 3-(o-methoxyphenyl) fragment, treatment with 1 equiv. of  BBr3 resulted in selective O-demethylation of the ortho-methoxy group, while other methoxy groups in the molecule remained intact. The resulting 3-(2-hydroxyphenyl)pyrrole-2-carboxylates underwent baseinduced lactonization to form the target pyrrolocoumarins