Synthesis, Molecular Structure, Anticancer Activity, and QSAR Study of N-(aryl/heteroaryl)-4-(1 H-pyrrol-1-yl)Benzenesulfonamide Derivatives

Abstract

A series of N-(aryl/heteroaryl)-4-(1H-pyrrol-1-yl)benzenesulfonamides were synthesized from 4-amino-N-(aryl/heteroaryl)benzenesulfonamides and 2,5-dimethoxytetrahydrofuran. All the synthesized compounds were evaluated for their anticancer activity on HeLa, HCT-116, and MCF-7 human tumor cell lines. Compound 28, bearing 8-quinolinyl moiety, exhibited the most potent anticancer activity against the HCT-116, MCF-7, and HeLa cell lines, with IC₅₀ values of 3, 5, and 7 µM, respectively. The apoptotic potential of the most active compound (28) was analyzed through various assays: phosphatidylserine translocation, cell cycle distribution, and caspase activation. Compound 28 promoted cell cycle arrest in G2/M phase in cancer cells, induced caspase activity, and increased the population of apoptotic cells. Relationships between structure and biological activity were determined by the QSAR (quantitative structure activity relationships) method. Analysis of quantitative structure activity relationships allowed us to generate OPLS (Orthogonal Projections to Latent Structure) models with verified predictive ability that point out key molecular descriptors influencing benzenosulfonamide's activity.

Keywords: OPLS; anticancer; apoptosis; benzenesulfonamide; synthesis.

Figure 1

The structures of obatoclax mesylate, sunitinib, and ulixertinib.

Figure 2

Sulfonamides used as antitumor drugs.

Scheme 1

Synthesis of 4-(1H-pyrrol-1-yl)-N-(aryl/heteroaryl)benzenesulfonamides. (a) Ar/Het-NH₂, dry pyridine, r.t. or 105 °C, 2‒20 h; (b) Ar/Het-NH₂, dry acetone, dry pyridine, r.t., 18‒48 h; (c) 8% NaOH in H₂O, ethanol, 100 °C, 1 h; (d) HCl aq, ethanol, 100 °C, 1 h; (e) 2,5-dimethoxytetrahydrofuran, p-dioxane, glacial acetic acid, reflux, 24‒26 h; Ar = aryl, Het = heteroaryl; * sulfamethoxazole (I), sulfapyridine (II), sulfadiazine (III), sulfamerazine (IV), sulfamethazine (V), sulfadimethoxine (VI), sulfamethoxypyridazine (VII).

Figure 3

Atom numbering scheme for 25, hydrogen atoms not labelled for clarity. Selected bond lengths [Å] and angles [°]: S1–O2 1.4287(14), S1–O3 1.4336(14), S1–N1 1.6300(17), S1–C13 1.7646(19), N1–C1 1.427(3), C2–O1 1.392(2), C7–O1 1.406(2); O2–S1–O3 120.24(9), O2–S1–N1 105.80(9), O3–S1–N1 107.69(8), S1–N1–C1 123.68(13), C13–S1–O2 107.80(8), C13–S1–O3 107.79(8), C13–S1–N1 106.83(8), C2–O1–C7 115.53(14).

Figure 4

Chain of molecules linked by hydrogen bonding NH···O and CH···O, spreading along the b axis with no internal symmetry.

Figure 5

Crystal packing diagram for 25, hydrogen atoms omitted.

Figure 6

Observed versus predicted values for OPLS-based QSAR models for activity against (A) HCT-116; (B) HeLa; and (C) MCF-7 cell line. R²Y—coefficient of determination, Q²—cross-validated coefficient of determination, RMSE—root mean squared error, RMSEqv—root mean squared error for cross-validation procedure.

Figure 7

Effects of 28 on the viability of HCT-116, HeLa, and MCF-7 cells. The cells were treated with 28 in the concentration range of 1–25 µM. After 24, 48, and 72 h of incubation, cell viability was assessed with the MTT assay. Values represent mean ± SD of three independent experiments.

Figure 8

Induction of apoptosis by 28 in HCT-116, HeLa, and MCF-7 cells. Cells were treated with the indicated concentrations of 28 for 48 h (HCT-116) and 72 h (HeLa and MCF-7). Cells were stained with Annexin V-PE and 7-AAD and analyzed with flow cytometry. Dotplots show early apoptotic (bottom right quadrant), late apoptotic (upper right quadrant), viable (lower left quadrant), and necrotic cell populations (upper left quadrant). Values represent mean ± SD of three independent experiments.

Figure 9

Induction of caspase activity by 28 in HCT-116, HeLa, and MCF-7 cells. Cells were treated with the indicated concentrations of 28 for 24 h (HCT-116) and 48 h (HeLa and MCF-7). Enzyme activity was determined using flow cytometry with the use of a caspase inhibitor, FAM-VAD-FMK. Values represent mean ± SD of three independent experiments.

Figure 10

Effects of 28 on G2/M arrest in HCT-116, HeLa, and MCF-7 cells. Cells were treated with the indicated concentrations of 28 for 48 h (HCT-116) and 72 h (HeLa and MCF-7), and cell cycle distribution was analyzed using flow cytometry. Values represent mean ± SD of three independent experiments.