Development of novel benzofuran-isatin conjugates as potential antiproliferative agents with apoptosis inducing mechanism in Colon cancer

Wagdy M Eldehna; Rofaida Salem; Zainab M Elsayed; Tarfah Al-Warhi; Hamada R Knany; Rezk R Ayyad; Thamer Bin Traiki; Maha-Hamadien Abdulla; Rehan Ahmad; Hatem A Abdel-Aziz; Radwan El-Haggar

doi:10.1080/14756366.2021.1944127

Development of novel benzofuran-isatin conjugates as potential antiproliferative agents with apoptosis inducing mechanism in Colon cancer

J Enzyme Inhib Med Chem. 2021 Dec;36(1):1424-1435. doi: 10.1080/14756366.2021.1944127.

Authors

Affiliations

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
² Scientific Research and Innovation Support Unit, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
³ Department of Chemistry, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.
⁴ Department of Pharmacognosy, College of Pharmacy, Mansoura University, Mansoura, Egypt.
⁵ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
⁶ Colorectal Research Chair, Department of Surgery, King Khalid University Hospital, King Saud University College of Medicine, Riyadh, Saudi Arabia.
⁷ Department of Applied Organic Chemistry, National Research Center, Dokki, Giza, Egypt.
⁸ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Helwan University, Cairo, Egypt.

Abstract

In the current work, a new set of carbohydrazide linked benzofuran-isatin conjugates (5a-e and 7a-i) was designed and synthesised. The anticancer activity for compounds (5b-d, 7a, 7b, 7d and 7g) was measured against NCI-55 human cancer cell lines. Compound 5d was the most efficient, and thus subjected to the five-dose screen where it showed excellent broad activity against almost all tested cancer subpanels. Furthermore, all conjugates (5a-e and 7a-i) showed a good anti-proliferative activity towards colorectal cancer SW-620 and HT-29 cell lines, with an excellent inhibitory effect for compounds 5a and 5d (IC₅₀ = 8.7 and 9.4 µM (5a), and 6.5 and 9.8 µM for (5d), respectively). Both compounds displayed selective cytotoxicity with good safety profile. In addition, both compounds provoked apoptosis in a dose dependent manner in SW-620 cells. Also, they significantly inhibited the anti-apoptotic Bcl2 protein expression and increased the cleaved PARP level that resulted in SW-620 cells apoptosis.

Keywords: Bcl2 inhibitors; Benzofuran hydrazide; Cleaved PARP; Colon cancer; Isatin.

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Benzofurans / chemistry*
Cell Line, Tumor
Cell Proliferation / drug effects*
Colonic Neoplasms / metabolism
Colonic Neoplasms / pathology*
Drug Development
Drug Screening Assays, Antitumor
Humans
Isatin / chemistry*
Molecular Structure
Proto-Oncogene Proteins c-bcl-2 / metabolism

Substances

Antineoplastic Agents
BCL2 protein, human
Benzofurans
Proto-Oncogene Proteins c-bcl-2
Isatin
benzofuran

Grants and funding

This research was funded by the Deanship of Scientific Research at Princess Nourah bint Abdulrahman University through the Fast-track Research Funding Program.