Synthesis of (+)-Thiersindole C

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.

indole diterpene alkaloids - thiersindole C - ent-halimic acid

References and Notes

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17a

Numbering for compound 4 agrees with that for the thiersindole C skeleton.

17b

Crystal data for 4: C₂₇H₃₅NO₄, monoclinic, space group P2₁ (no 4), a = 7.4100 (15) Å, b = 10.169 (2) Å, c = 16.045 (3) Å, α = γ = 90°, β = 97.11 (3)°, V = 1199.7 (4) ų, Z = 2, D_c = 1.211 Mg/m³, µ(Cu - K_α) = 0.640 mm^-1, F(000) = 472. The number of reflections collected was 1963, of which 937 were considered to be observed with I > 2σI. The structure was determined by direct methods using the SHELXTL^TM suite of programs. Hydrogen atoms were placed in calculated positions. Full-matrix least squares refinement based on F² with anisotropic thermal parameters for the non-hydrogen atoms led to agreement factors, R₁ = 0.0721 and ωR₂ = 0.1823. Crystallographic data (excluding structure factors) for the structure reported in this paper has been deposited at the Cambridge Crystallographic Data Centre as supplementary material no. CCDC-628164.

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20

(+)-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, H_A-10), 2.84 (d, J = 15.8 Hz, 1 H, H_B-10), 2.37 (m, 1 H, H_A-14), 2.25 (m, 1 H, H_B-14), 2.02 (m, 1 H, H_A-19), 2.00 (m, 1 H, H_A-22), 1.73 (m, 2 H, H_B-19, H_B-22), 1.71 (m, 1 H, H-12), 1.70 (m, 1 H, H_A-18), 1.68 (s, 3 H, Me-26), 1.60 (m, 1 H, H_A-21), 1.55 (s, 3 H, Me-25), 1.49 (m, 1 H, H_A-13), 1.39 (m, 1 H, H_B-13), 1.36 (m, 1 H, H_B-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.

21

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

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