Diastereoselective approach to rationally design tetrahydro-β-carboline-isatin conjugates as potential SERMs against breast cancer

Abstract

A series of tetrahydro-β-carboline-isatin conjugates, with varying substituents as well as stereochemistry at C-1 and C-5 position of tetrahydro-β-carboline (THβC) and isatin ring, were prepared and assayed for anti-proliferative efficacy on Estrogen Responsive ER(+) (MCF-7) and ER(-ve) MDA-MB-231 cell-lines. The synthesized scaffolds displayed selective anti-proliferative efficacy against MCF-7 cell-line with the most active conjugate 8b exhibiting an IC₅₀ value of 37.42 μM, comparable to that of peganumine A, a tetrahydro-β-carboline analogue, isolated from Peganum harmala. The synthesized compound 8b was also more potent than the standard drug tamoxifen (IC₅₀ = 50 μM against MCF-7). The observed activities were further corroborated via docking studies in ER-α (PDB ID: 3ERT).

Fig. 1. Natural and synthetic structural motifs with a tetrahydro-β-carboline core.

Fig. 2. Designed tetrahydro-β-carboline–isatin conjugates.

Scheme 1. Synthesis of N-propargylated tetrahydro-β-carboline ethyl ester. (i) 30% formaldehyde, NaOH, H₂O, 8 h, reflux, or (ii) 40% acetaldehyde, H₂SO₄,, 6–8 h, rt, or (iii) benzaldehyde, acetic acid, 2 h, reflux (iv) SOCl₂, EtOH, 6 h, reflux (v) propargyl bromide, acetonitrile, rt, 6–8 h. (vi) CuSO₄·5H₂O, sodium ascorbate, EtOH, rt, 8 h.

Scheme 2. Synthesis of substituted N-alkyl-azido-isatin (i) NaH, dibromoalkane, anhy. DMF, 60 °C, 6–8 h (ii) NaN₃, DMF, 60 °C, 2 h.

Scheme 3. Synthesis of 1H-1,2,3-triazole-linked tetrahydro-β-carboline–isatin conjugates 8a–r (i) CuSO₄, sodium ascorbate, EtOH, 6–8 h, rt.

Fig. 3. Representative graph of percentage growth inhibition on MCF7 and MDA-MB-231 cells at selected concentrations of test compounds 8a–r. 40 μM plumbagin was used as a positive control. Data shows mean ± standard deviation S.D. (n = 3), where *p < 0.05, **p < 0.01 and ***p < 0.001 significance compared to untreated control.

Fig. 4. Three-dimensional illustration of docked ligands interacting in the binding site of the estrogen receptor (PDB: 3ERT).