Side chain modifications of (indol-3-yl)glyoxamides as antitumor agents

Figures & data

Figure 1 Structure of D-24851.

Figure 2 General structure of new synthesized indolylglyoxamides with our numbering of the hydrogens for the NMR spectra in the experimental section.

Scheme 1 Preparation of analogues of D-24851 with an amino spacer 13-15. (a) i) NaH, DMSO, rt, 1 h ii) 4-chlorobenzyl chloride, DMSO, rt, 6 h (b) ClCOCOCl, Et₂O, rt, 1 h (c) DCP, Et₃N, CH₂Cl₂, rt, 2 days (R = H, CH₃) or CNMPI, Et₃N, CH₂Cl₂, Δ, 5 h (R = CH(CH₃)CH₂CH₃) (d) H₂, Pd/C 5%, MeOH, rt, 1 h (e) Et₃N, THF, Δ, 10 h.

Scheme 2 Preparation of key intermediates for the synthesis of analogues of D-24851 with the glyoxamide chain in positions 4 and 5 of indole ring. (a) HCl, MeOH, Δ, 48 h (b) DMFDMA, DMF, 110°C, 8 h (c) H₂, Pd/C 5%, benzene, rt, 6 h (d) LiAlH₄, THF, 0°C or rt, 20 h (e) MnO₂, CH₂Cl₂, rt, 24 h (f) 4-chlorobenzyl chloride, Cs₂CO₃, CH₃CN, Δ, 3 h (g) i) NaH, DMSO, rt, 1 h ii) 4-chlorobenzyl chloride, DMSO, rt, 4 h (h) PDC, CH₂Cl₂, rt, 6 h.

Scheme 3 Synthesis of analogue of D-24851 with the glyoxamide chain in position 5 of the indole ring. (a) PhSO₂Cl, Et₃N, (CH₂)₂Cl₂, rt, 12 h (b) ClCOCOOEt, AlCl₃, CH₂Cl₂, rt, 6 h (c) Mg, MeOH, rt, 2 h (d) MnO₂, toluene, Δ, 2 h (e) i) NaH, DMSO, rt, 1 h ii) 4-chlorobenzyl chloride, DMSO, rt, 4 h (f) NaOH 1 M, EtOH, Δ, 3 h (g) CNMPI, Et₃N, CH₂Cl₂, Δ, 4 days

Table I.  Anticancer activity of indolylgloxamides in cancer cell lines.

		Cell lines
N°	Structure	KB IC50 (μg/mL)	SK-OV-3 IC50 (μg/mL)	NCI-H460 IC50 (μg/mL)	SF-268 IC50 (μg/mL)
D-24851		0.017	0.030	0.064	0.077
13		0.216	0.017	0.136	0.015
14		6.44	8.07	1.49	2.15
15		270.8	0.224	1.11	0.004
39		ND	18.49	0.331	67.0

^aAll values are the mean of at least 2 determinations.