Novel Chrysin-De-Allyl PAC-1 Hybrid Analogues as Anticancer Compounds: Design, Synthesis, and Biological Evaluation
Buthina A. Al-Oudat,
Hariteja Ramapuram,
Saloni Malla,
Suaad A. Audat,
Noor Hussein,
Jenna M. Len,
Shikha Kumari,
Mel F. Bedi,
Charles R. Ashby,
Amit K. Tiwari
Affiliations
Buthina A. Al-Oudat
Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordan
Hariteja Ramapuram
Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA
Saloni Malla
Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA
Suaad A. Audat
Department of Chemistry, College of Science and Arts, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordan
Noor Hussein
Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA
Jenna M. Len
Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA
Shikha Kumari
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA
Mel F. Bedi
Department of Medicinal and Biological Chemistry, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA
Charles R. Ashby
Department of Pharmaceutical Sciences, College of Pharmacy & Pharmaceutical Sciences, St. John’s University, Queens, NY 11439, USA
Amit K. Tiwari
Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA
New chrysin-De-allyl-Pac-1 hybrid analogues, tethered with variable heterocyclic systems (4a–4o), were rationally designed and synthesized. The target compounds were screened for in vitro antiproliferative efficacy in the triple-negative breast cancer (TNBC) cell line, MDA-MB-231, and normal human mammary epithelial cells (HMECs). Two compounds, 4g and 4i, had the highest efficacy and selectivity towards MDA-MB-231 cells, and thus, were further evaluated by mechanistic experiments. The results indicated that both compounds 4g and 4i induced apoptosis by (1) inducing cell cycle arrest at the G2 phase in MDA-MB-231 cells, and (2) activating the intrinsic apoptotic pathways in a concentration-dependent manner. Physicochemical characterizations of these compounds suggested that they can be further optimized as potential anticancer compounds for TNBC cells. Overall, our results suggest that 4g and 4i could be suitable leads for developing novel compounds to treat TNBC.
