Cheminformatics-based design and biomedical applications of a new Hydroxyphenylcalix[4] resorcinarene as anti-cancer agent

Abstract

The distinct conformational characteristics, functionality, affordability, low toxicity, and usefulness make calixarene-based compounds a promising treatment option for cancer. The aim of the present study is to synthesize a new calixarene-based compound and assess of its anticancer potential on some human cancer cells. The synthesized C-4-Hydroxyphenylcalix[4] resorcinarene (HPCR) was characterized by several spectroscopic techniques such as 1HNMR, 13CNMR, and X-ray crystallographic analysis to confirm its purity and identity. IC₅₀ values were identified for cancer cell lines (U-87, MCF-7, A549) and human dermal fibroblasts cell line (HDF) after treatment with HPCR and the standard drug Cisplatin. A significant selective growth inhibitory activity against U-87 and A549 cell lines was obtained at an HPCR concentration of 100 μM. The MOE docking module (version 2015) was utilized to assess the extent of inhibition for HPCR compound against four cancer-related proteins (3RJ3, 7AXD, 6DUK, and 1CGL).

Keywords: Anti-cancer agent; Anti-proliferative activity; Calix[n]arenes; MTT assay; Molecular docking.

Fig. 1

Structure of HPCR.

Fig. 2

Synthesis of C-4-Hydroxyphenylcalix[4] resorcinarene (HPCR).

Fig. 3

(A) The HPCR structure (capped sticks), and (B) Projection of the structure along a, b and c axis. Black, red, and snowballs correspond to carbon, oxygen and hydrogen atoms.

Fig. 4

¹H-NMR spectrum of HPCR (400 MHz, DMSO-d₆).

Fig. 5

¹³C-NMR spectrum of HPCR (100 MHz, DMSO-d₆).

Fig. 6

DEPT-90 spectrum of HPCR (DMSO-d₆).

Fig. 7

DEPT-135 spectrum of HPCR (DMSO-d₆).

Fig. 8

Anti-proliferative activity of HPCR on normal cells; human dermal fibroblast (HDF) and cancerous cell lines including breast cancer (MCF-7), non-small cell lung cancer (A549) and glioblastoma (U-87 MG). Cells were treated with HPCR at various concentrations ranging from 1–1000 μM for 96 h.

Fig. 9

Cytotoxic effects of HPCR and Cisplatin against normal cells; human dermal fibroblast (HDF) and cancerous cell lines including breast cancer (MCF-7), non-small cell lung cancer (A549) and glioblastoma (U-87 MG) upon 96 h treatment period. The treatment was carried out at the respective IC₅₀ of HPCR for each cell line (HDF; 146.7 ± 12, MCF-7; 112.3 ± 5.4, A549; 92.3 ± 7.3 and U- 87 MG; 71 ± 10) as well as cisplatin (HDF; 40.9 ± 5.4, MCF-7; 26.9 ± 4.7, A549; 30.4 ± 5.2and U- 87 MG; 28.3 ± 5.3) (40 × objective lens, total magnification = 400x).

Fig. 10

Best interaction patterns for HPCR tested complexes against 3RJ3 (A), 7AXD (B), 6DUK (C), 1CGL (D) and cisplatin (inhibitor) with 1CGL.

Fig. 11

Optimized structure (a), HOMO (b), LUMO (c), ESP_map (d), Fukui functions indices of the HPCR molecule derived by using the DFT/GGA tool.

Fig. 12

Electron localization functions (ELF), and localized orbital locator (LOL) of the HPCR molecule found by using DFT/GGA technology.

Fig. 13

(a) top view and (b) zoomed view of the NCI isosurface, as well as (c) the RDG isosurface of the HPCR@1CGL protein compound adsorption.