Synthesis and evaluation of the antiproliferative activity of novel isoindolo[2,1-a]quinoxaline and indolo[1,2-a]quinoxaline derivatives

Figures & data

Figure 1.  Structure of compounds I, II and new synthesized substituted isoindolo- or indoloquinoxaline derivatives 1a-h.

Scheme 1.  Reagents and conditions: (i) DBU, THF/t-BuOH, 50°C; (ii) 1-fluoro-2-nitrobenzene, Cs₂CO₃, DMF, Δ; (iii) Fe, CH₃COOH, Δ; (iv) 1) o-iodotrifluoroacetanilide, K₂CO₃, CuI, L-proline, DMSO, 80°C; 2) H₂O, 60°C (v) POCl₃, Δ; (vi) OHC-C₆H₄-B(OH)₂, Pd[P(C₆H₅)₃]₄, K₂CO₃, toluene, EtOH, Δ; (vii) 4-(2-ketobenzimidazolin-1-yl)piperidine or 4-(5-fluorobenzimidazolin-2-yl)piperidine, NaBH₃CN, MeOH, Δ.

Figure 2.  The ORTEP drawing of 1,3-dihydro-1-{1-[4-(pyrrolo[1,2-a]quinoxalin-4-yl)benzyl]piperidin-4-yl}-2H-benzimidazol-2-ones 1a and 1c with thermal ellipsoids at 30% level.

Scheme 2.  Reagents and conditions: (i) NaHSO₃, KCN, H₂O, 70°C; (ii) CH₃COOH, Δ; (iii) KOH, tert-BuOH, 80°C.

Table 1.  In vitro activity of compounds 1a-h on U937, K562, HL60, Jurkat, U266, and MCF7 cells, and cytotoxicity on human peripheral blood mononuclear cells PBMNC + PHA.

IC50 values (µM)^a
Compound	U937	K562	HL60	Jurkat	U266	MCF7	Cytotoxicity on activated human peripheral blood mononuclear cells (PBMNC)
							PBMNC + PHA
LY-294002	14 ± 0.3	38 ± 1	14 ± 0.3	22 ± 1	46 ± 2	7 ± 0.5	>50
1a	>50	46.5 ± 1	13.5 ± 0.3	44 ± 1	>50	11 ± 0.5	>50
1b	>50	45.5 ± 1	>50	>50	>50	9 ± 0.5	>50
1c	>50	45.5 ± 1	>50	>50	>50	>50	41 ± 1
1d	>50	11 ± 0.5	9 ± 0.4	5 ± 0.2	> 50	> 50	>50
1e	3.5 ± 0.3	3 ± 0.2	4 ± 0.2	3.5 ± 0.2	3.5 ± 0.3	4 ± 0.3	6 ± 0.3
1f	4 ± 0.3	4 ± 0.3	3 ± 0.5	3 ± 0.2	4 ± 0.3	3 ± 0.4	7 ± 0.5
1g	4 ± 0.3	3.5 ± 0.2	4 ± 0.3	3.5 ± 0.3	3 ± 0.2	4 ± 0.4	4 ± 0.3
1h	42 ± 1	13 ± 0.5	18 ± 0.5	12 ± 0.5	14 ± 0.5	33 ± 1	>50

^aThe IC₅₀ (µM) values correspond to the mean ± standard deviation from three independent experiments.

Figure 3.  Structure of compound LY-294002.