Synthesis and study of cytotoxicity of 3β-acetoxyurs-12-en-28-oyl-thiourea derivatives

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Resumo

The interaction of 3β-acetoxyurs-12-en-28-oyl chloride with potassium rhodanide afforded 3β-acetoxyurs-12-en-28-oyl isothiocyanate. A series of substituted 3β-acetoxy-urs-12-en-28-oyl-thioureas was synthesised in yields of 69–88% by condensation of triterpene acyl isothiocyanate with a series of amino derivatives. The CuAAC cycloaddition reaction of N-(2-azidoethylcarbamothioyl)-3-acetoxyurs-12-en-28-oyl-amide with propargyl alcohol and 3-(prop-2-inyloxy)-4,5-((R,S)-methoxymethylenedioxy)-benzoate led to the formation of hybrid acylthioureas containing a 1,2,3-triazole linker in 72 and 75% yields. In CuAAC reactions of N-(prop-2-ynylcarbamothioyl)-3β-acetoxyurs-12-en-28-oylamide with substituted acylthiourea azides containing 1,2,3-triazole were isolated in moderate yields of 48–62%. The use of one-pot-reactor version of the synthesis with the preparation of substituted (1H-1,2,3-triazol-4-yl)methanamines in the reaction of propargylamine with substituted azides followed by condensation with 3β-acetoxyurs-12-en-28-oyl isothiocyanate increased the yield of 1,2,3-triazole-containing acylthioureas to 65–85%. Polar triterpene acylthioureas containing carboxyl or alcohol groups exhibited high inhibitory activity against HepG2 cells, significantly superior to the parent compound ursolic acid, and were also more selective than the drug doxorubicin. Among the acylthioureas, products of CuAAC cycloaddition, the most active was the polar derivative with (1H-1,2,3-triazol-4-yl)methanol substituent, which was cytotoxic to all cells tested, including the non-tumour control, but superior in selectivity to doxorubicin. Ursane hybrids with acylthiourea derivatives are of interest for further investigation as promising antitumour agents.

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Sobre autores

S. Popov

Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences

Autor responsável pela correspondência
Email: spopov@nioch.nsc.ru
Rússia, prosp. Akad. Lavrentyevа 9, Novosibirsk, 630090

T. Borisova

Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences; Novosibirsk State Technical University

Email: spopov@nioch.nsc.ru
Rússia, prosp. Akad. Lavrentyevа 9, Novosibirsk, 630090; prosp. K. Marksa 20, Novosibirsk 630073

E. Shults

Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences

Email: spopov@nioch.nsc.ru
Rússia, prosp. Akad. Lavrentyevа 9, Novosibirsk, 630090

М. Marenina

Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences

Email: spopov@nioch.nsc.ru
Rússia, prosp. Akad. Lavrentyevа 9, Novosibirsk, 630090

Yu. Meshkova

Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences

Email: spopov@nioch.nsc.ru
Rússia, prosp. Akad. Lavrentyevа 9, Novosibirsk, 630090

T. Tolstikova

Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences

Email: spopov@nioch.nsc.ru
Rússia, prosp. Akad. Lavrentyevа 9, Novosibirsk, 630090

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2. Scheme 1. Synthesis of acyl isothiocyanate (III) andN-acyl-Nʹ-substituted thioureas (IV). Conditions: i – Ac2O, Et3N, CHCl3, room. t., 15 h; (COCl)2, CH2Cl2, room. t., 15 h.; ii –KSCN, Me2CO, room. t., 2–4 p.m.; iii – connections (IVa), (IVb), (IVc), (IVe), (IVa), (IVg), (IVh) – THF, room. t., 2–4 p.m.; iv – compounds (IVd), (IVi), (IVj) – pyridine, THF, 14–16 h.

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3. Scheme 2. CuAAC reaction ofN-3β-acetoxyurs-12-ene-28-oil-Nʹ-propargyl-thiourea (IVd)with substituted azides. Conditions: v –CuSO4× 5H2O, sodium ascorbate, t-BuOH-H2O, room. t., 15 h.

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4. Scheme 3. CuAAC reaction of propargylamine and substituted azides (IV) and interaction of aminotriazoles (VII) with acyl isothiocyanate (III). Conditions: v – CuSO4 × 5H2O, sodium ascorbate, t-BuOH-H2O, rt, 15 h; vi – CHCl3–t-BuOH-H2O, rt, 0.5 h; iii – CHCl3–t-BuOH-H2O, rt. t., 14-16 h.

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5. Scheme 4. Cycloaddition reaction ofN-3β-acetoxyurs-12-ene-28-oil-N'-azidoethylthiourea (IVe) and propargyl derivatives. Conditions: v –CuSO4× 5H2O, sodium ascorbate, t-BuOH-H2O, room. t., 15 h.

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