Design, Synthesis, Anticancer Activity, and Solid Lipid Nanoparticle Formulation of Indole-and Benzimidazole-Based Compounds as Pro-Apoptotic Agents Targeting Bcl-2 Protein

Authors

Shady Swidan, The British University in EgyptFollow
Ali Nasr, Department of Pharmaceutics, Faculty of Pharmacy, Port Said University, Port Said 42526, Egypt
Mona K. Qushawy, Department of Pharmaceutics, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia
Manar Nagy, Department of Medicinal Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, EgyptFollow
Khalid Darwish, Department of Medicinal Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, EgyptFollow
Samia Mostafa, Department of Medicinal Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, EgyptFollow
Ismail Salama, Department of Medicinal Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, EgyptFollow
Mohaamed Tantawy, National Research Center, Hormones Department, Medical Research Division, Dokki, Giza 12622, EgyptFollow

Document Type

Article

Publication Date

2-1-2021

Abstract

Cancer is a multifactorial disease necessitating identification of novel targets for its treatment. Inhibition of Bcl-2 for triggered pro-apoptotic signaling is considered a promising strategy for cancer treatment. Within the current work, we aimed to design and synthesize a new series of benzimidazole- and indole-based derivatives as inhibitors of Bcl-2 protein. The market pan-Bcl-2 inhibitor, obatoclax, was the lead framework compound for adopted structural modifications. The obatoclax’s pyrrolylmethine linker was replaced with straight alkylamine or carboxyhydrazine methylene linkers providing the new compounds. This strategy permitted improved structural flexibility of synthesized compounds adopting favored maneuvers for better fitting at the Bcl-2 major hydrophobic pocket. Anti-cancer activity of the synthesized compounds was further investigated through MTT-cytotoxic assay, cell cycle analysis, RT-PCR, ELISA and DNA fragmentation. Cytotoxic results showed compounds 8a, 8b and 8c with promising cytotoxicity against MDA-MB-231/breast cancer cells (IC₅₀ = 12.69 ± 0.84 to 12.83 ± 3.50 µM), while 8a and 8c depicted noticeable activities against A549/lung adenocarcinoma cells (IC₅₀ = 23.05 ± 1.45 and 11.63 ± 2.57 µM, respectively). The signaling Bcl-2 inhibition pathway was confirmed by molecular docking where significant docking energies and interactions with key Bcl-2 pocket residues were depicted. Moreover, the top active compound, 8b, showed significant upregulated expression levels of pro-apoptotic/anti-apoptotic of genes; Bax, Bcl-2, caspase-3, -8, and -9 through RT-PCR assay. Improving the compound’s pharmaceutical profile was undertaken by introducing 8b within drug-solid/lipid nanoparticle formulation prepared by hot melting homogenization technique and evaluated for encapsulation efficiency, particle size, and zeta potential. Significant improvement was seen at the compound’s cytotoxic activity. In conclusion, 8b is introduced as a promising anti-cancer lead candidate that worth future fine-tuned lead optimization and development studies while exploring its potentiality through in-vivo preclinical investigation.

Recommended Citation

Nagy, M.I.; Darwish, K.M.; Kishk, S.M.; Tantawy, M.A.; Nasr, A.M.; Qushawy, M.; Swidan, S.A.; Mostafa, S.M.; Salama, I. Design, Synthesis, Anticancer Activity, and Solid Lipid Nanoparticle Formulation of Indole- and Benzimidazole-Based Compounds as Pro-Apoptotic Agents Targeting Bcl-2 Protein. Pharmaceuticals 2021, 14, 113. https://doi.org/10.3390/ph14020113