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Synlett 2007(13): 2017-2022  
DOI: 10.1055/s-2007-984893
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of (+)-Thiersindole C

Isidro S. Marcos*a, Miguel A. Escolaa, Rosalina F. Moroa, Pilar Basabea, David Dieza, Faustino Mollinedob,c, Julio G. Uronesa
a Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad de Salamanca, Plaza de los Caídos 1-5, 37008 Salamanca, Spain
Fax: +34(923)294574; e-Mail: ismarcos@usal.es;
b Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas, Universidad de Salamanca, Campus Miguel de Unamuno, 37007 Salamanca, Spain
c APOINTECH, Campus Miguel de Unamuno, 37007 Salamanca, Spain
Further Information

Publication History

Received 26 February 2007
Publication Date:
12 July 2007 (online)

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Abstract

The indole diterpene alkaloid (+)-thiersindole C has been synthesised from ent-halimic acid. Firstly was elaborated the bi­cyclic system, secondly a Fischer indolization was used to obtain the north side chain and finally elongation of the south side chain was achieved with an isoprene unit. The synthesis of (+)-thiersindole C has corroborated the absolute configuration for the natural product (-)-thiersindole C. The synthesized (+)-thiersindole C showed antitumor activity against a number of human tumor cell lines with an IC50 in the range of 10-5 M.

Key words

indole diterpene alkaloids - thiersindole C - ent-halimic acid

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(+)-Thiersindole C(37): [α]D 22 +54.0 (c = 0.20, CH2Cl2). IR (film): 3411, 3056, 2927, 1457, 1375, 1261, 1094, 1046, 1012, 995, 740 cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.89 (br s, 1 H, H-1), 7.60 (d, J = 7.9 Hz, 1 H, H-5), 7.32 (d, J = 8.1 Hz, 1 H, H-8), 7.16 (ddd, J = 1.1, 7.2, 8.1 Hz, 1 H, H-7), 7.10 (ddd, J = 1.1, 7.2, 7.9 Hz, 1 H, H-6), 7.05 (s, 1 H, H-2), 5.10 (br t, J = 6.0 Hz, 1 H, H-23), 3.82 (dd, J = 3.7, 11.1 Hz, 1 H, H-17), 2.92 (d, J = 15.8 Hz, 1 H, HA-10), 2.84 (d, J = 15.8 Hz, 1 H, HB-10), 2.37 (m, 1 H, HA-14), 2.25 (m, 1 H, HB-14), 2.02 (m, 1 H, HA-19), 2.00 (m, 1 H, HA-22), 1.73 (m, 2 H, HB-19, HB-22), 1.71 (m, 1 H, H-12), 1.70 (m, 1 H, HA-18), 1.68 (s, 3 H, Me-26), 1.60 (m, 1 H, HA-21), 1.55 (s, 3 H, Me-25), 1.49 (m, 1 H, HA-13), 1.39 (m, 1 H, HB-13), 1.36 (m, 1 H, HB-21), 1.03 (s, 3 H, Me-27), 0.98 (s, 3 H, Me-29), 0.86 (d, J = 6.8 Hz, 3 H, Me-28). 13C NMR (100 MHz, CDCl3): δ = 121.4 (C-2), 113.1 (C-3), 128.9 (C-4), 118.7 (C-5), 119.1 (C-6), 121.6 (C-7), 110.8 (C-8), 135.4 (C-9), 31.2 (C-10), 42.1 (C-11), 33.3 (C-12), 27.2 (C-13), 24.8 (C-14), 134.7 (C-15), 43.1 (C-16), 80.0 (C-17), 27.5 (C-18), 24.9 (C-19), 135.0 (C-20), 35.6 (C-21), 23.1 (C-22), 124.8 (C-23), 131.1 (C-24), 25.6 (C-25), 17.7 (C-26), 21.7 (C-27), 16.7 (C-28), 20.4 (C-29). HRMS (ESI): m/z [M+ + Na] calcd for C28H39NONa: 428.2924; found: 428.2928.

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The in vitro antitumor activity for compound 37, (+)-thiersindole C, was determined by measurement of its cytostatic and cytotoxic properties in human tumor cell lines by the XTT assay, in which the metabolic activity of viable cells was assessed. Cells were incubated in RPMI-1640 (HL-60) or DMEM (HeLa, A549, HT-29) culture medium containing 10% fetal calf serum, in the absence and in the presence of the indicated compound at a concentration range of 10-4 to 10-8 M in 96-well plates, and following a 72-h incubation at 37 °C in a humidified atmosphere of air-CO2 (19:1) the XTT assay was performed. Measurements were done in triplicate, and the IC50 value, defined as the drug concentration required to cause 50% inhibition in the cellular proliferation with respect to the untreated controls, were determined. Values shown are means ±SE of four independent determinations.22