Discovery of benzochromene derivatives first example with dual cytotoxic activity against the resistant cancer cell MCF-7/ADR and inhibitory effect of the P-glycoprotein expression levels

Lali M Al-Harbi; Eman A Al-Harbi; Rawda M Okasha; R A El-Eisawy; Mohammed A A El-Nassag; Hany M Mohamed; Ahmed M Fouda; Ahmed A Elhenawy; Ahmed Mora; Ahmed M El-Agrody; Heba K A El-Mawgoud

doi:10.1080/14756366.2022.2155814

Discovery of benzochromene derivatives first example with dual cytotoxic activity against the resistant cancer cell MCF-7/ADR and inhibitory effect of the P-glycoprotein expression levels

J Enzyme Inhib Med Chem. 2023 Dec;38(1):2155814. doi: 10.1080/14756366.2022.2155814.

Authors

Affiliations

¹ Chemistry Department, Faculty of Science, King Abdul-AzizUniversity, Jeddah, Saudi Arabia.
² Chemistry Department, Faculty of Science, Taibah University, Medina, Saudi Arabia.
³ Chemistry Department, Faculty of Science, Al-Azhar University, Cairo, Egypt.
⁴ Chemistry Department, Faculty of Science and Art, Al-Baha University, Al-Baha, Saudi Arabia.
⁵ Chemistry Department, Faculty of Science, Jazan University, Jazan, Saudi Arabia.
⁶ Chemistry Department, Faculty of Science, King Khalid University, Abha, Saudi Arabia.
⁷ Chemistry Department, Faculty of Science and Art, AlBaha University, Al Bahah, Saudi Arabia.
⁸ Chemistry Department, Faculty of Women for Arts, Science, and Education, Ain Shams University, Cairo, Egypt.

Abstract

A series of 1H-benzo[f]chromene moieties (4a-z) were synthesised under Ultrasonic irradiation and confirmed with spectral analyses. Derivative 4i solely possessed an X-ray single crystal. The anti-proliferative efficacy of the desired molecules has been explored against three cancer cells: MCF-7, HCT-116, and HepG-2 with the cytotoxically active derivatives screened against MCF-7/ADR and normal cells HFL-1 and WI-38. Furthermore, compounds 4b-d, 4k, 4n, 4q, and 4w, which possessed good potency against MCF-7/ADR, were tested as permeability glycoprotein (P-glycoprotein [P-gp]) expression inhibitors. The attained data confirmed that 4b-d, 4q, and 4w exhibited strong expression inhibition against the P-gp alongside its cytotoxic effect on MCF-7/ADR. The western blot results and Rho123 accumulation assays showed that compounds 4b-d, 4q, and 4w effectively inhibited the P-gp expression and efflux function. Meanwhile, 4b-d, 4q, and 4w induced apoptosis and accumulation of the treated MCF-7/ADR cells in the G1 phase and 4k and 4n in the S phase of the cell cycle.

Keywords: 1H-Benzo[f]chromenes; MCF-7/ADR; P-glycoprotein; SAR; Ultrasound synthesis; antitumor activity; cell cycle arrest; western blot.

MeSH terms

ATP Binding Cassette Transporter, Subfamily B / pharmacology
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Benzopyrans / pharmacology
Doxorubicin / pharmacology
Drug Resistance, Neoplasm
Humans
MCF-7 Cells
Neoplasms*

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
Antineoplastic Agents
ATP Binding Cassette Transporter, Subfamily B
Benzopyrans
Doxorubicin

Grants and funding

The authors would like to express gratitude to the Deanship of Science Research at King Khalid University, Saudi Arabia for funding this work through General Research Project under Grant Number [RGP.1/245/43] and also, to Malak T. Mahmoud for editing and revising the manuscript.