Novel spirooxindole based benzimidazole scaffold: In vitro, nanoformulation and in vivo studies on anticancer and antimetastatic activity of breast adenocarcinoma

Assem Barakat; Saeed Alshahrani; Abdullah Mohammed Al-Majid; Abdullah Saleh Alamary; Matti Haukka; Marwa M Abu-Serie; Alexander Dömling; Eman A Mazyed; Farid A Badria; Fardous F El-Senduny

doi:10.1016/j.bioorg.2022.106124

Novel spirooxindole based benzimidazole scaffold: In vitro, nanoformulation and in vivo studies on anticancer and antimetastatic activity of breast adenocarcinoma

Bioorg Chem. 2022 Dec:129:106124. doi: 10.1016/j.bioorg.2022.106124. Epub 2022 Sep 5.

Affiliations

¹ Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia. Electronic address: ambarakat@ksu.edu.sa.
² Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia.
³ Department of Chemistry, University of Jyväskylä, P.O. Box 35, FI-40014 Jyväskylä, Finland.
⁴ Medical Biotechnology Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Egypt.
⁵ Department of Drug Design, Groningen Research Institute of Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands.
⁶ Department of Pharmaceutical Technology, Faculty of Pharmacy, Kaferelsheikh University, Kaferelsheikh P.O. Box 33516, Egypt.
⁷ Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address: faridbadria@gmail.com.
⁸ Department of Chemistry, Faculty of Science, Mansura University, Mansura 35516, Egypt.

PMID: 36174446
DOI: 10.1016/j.bioorg.2022.106124

Abstract

The present work provided in vitro anticancer investigation of novel spirooxindole based benzimidazole scaffold SP1 and its nanoformulation with in vivo evaluation of anticancer and antimetastatic activity as potential drug for breast adenocarcinoma. The synthesized compound SP1 exhibited potent growth inhibitory efficacy against four types of human cancer (breast, prostate, colon and lung) cell lines with IC₅₀ = 2.4, 3.4, 7.24 and 7.81 µM and selectivity index 5.79, 4.08, 1.93 and 1.78 respectively. Flow cytometric analysis illustrated that SP1 exhibited high apoptotic effect on all tested cancer cell lines (38.22-52.3 %). The mode of action of this promising compound was declared by its ability to upregulate the gene expression of p21 (2.29-3.91 folds) with suppressing cyclin D (1.9-8.93 folds) and NF-κB (1.26-1.44 fold) in the treated cancer cells. Also, it enhanced the protein expression of apoptotic marker p53 and moderate binding affinity for MDM2 (K_D;7.94 μM). Notwithstanding these promising impressive findings, its selectivity against cancer cell lines and safety on normal cells were improved by nanoformulation. Therefore, SP1 was formulated as ultra-flexible niosomal nanovesicles (transethoniosomes). The ultra-deformability is attributable to the synergism between ethanol and edge activators in improving the flexibility of the nanovesicular membrane. F8 exhibited high deformability index (DI) of (23.48 ± 1.4). It was found that % SP1 released from the optimized transethoniosomal formula (F8) after 12 h (Q_12h) was 84.17 ± 1.29 % and its entrapment efficiency (%EE) was 76.48 ± 1.44 %. Based upon the very encouraging and promising in vitro results, an in vivo study was carried out in female Balb/c mice weighing (15-25 g). SP1 did halt the proliferation of breast cancer cells as well as suppressed the metastasis in other organs like liver, lung and heart.

Keywords: BLC2; Benzimidazole; Drug delivery; MDM2 inhibitors; Metastasis; NF-κB; Nanoformulation; Spirooxindole; p53.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma* / drug therapy
Animals
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Benzimidazoles / pharmacology
Breast Neoplasms* / drug therapy
Cell Line
Cell Line, Tumor
Cell Proliferation
Drug Screening Assays, Antitumor
Female
Humans
Mice
NF-kappa B

Substances

NF-kappa B
Benzimidazoles
Antineoplastic Agents