Design, Synthesis, and Investigation of the Pharmacokinetics and Anticancer Activities of Indenoisoquinoline Derivatives That Stabilize the G-Quadruplex in the MYC Promoter and Inhibit Topoisomerase I.

Autor:	Han Y; Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States., Buric A; Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States., Chintareddy V; Therachem Research Medilab LLC, 100 Jade Park, Chelsea, Alabama 35043, United States., DeMoss M; Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States., Chen L; Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States., Dickerhoff J; Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States., De Dios R; Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States., Chand P; Therachem Research Medilab LLC, 100 Jade Park, Chelsea, Alabama 35043, United States., Riggs R; Gibson Oncology, 7772 Fisher Island Drive, Miami, Florida 33109, United States., Yang D; Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States.; Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States.; Purdue Institute for Cancer Research, Purdue University, West Lafayette, Indiana 47907, United States., Cushman M; Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States.; Purdue Institute for Cancer Research, Purdue University, West Lafayette, Indiana 47907, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 May 09; Vol. 67 (9), pp. 7006-7032. Date of Electronic Publication: 2024 Apr 26.
DOI:	10.1021/acs.jmedchem.3c02303
Abstrakt:	G-quadruplexes are noncanonical four-stranded DNA secondary structures. MYC is a master oncogene and the G-quadruplex formed in the MYC promoter functions as a transcriptional silencer and can be stabilized by small molecules. We have previously revealed a novel mechanism of action for indenoisoquinoline anticancer drugs, dual-downregulation of MYC and inhibition of topoisomerase I. Herein, we report the design and synthesis of novel 7-aza-8,9-methylenedioxyindenoisoquinolines based on desirable substituents and π-π stacking interactions. These compounds stabilize the MYC promoter G-quadruplex, significantly lower MYC levels in cancer cells, and inhibit topoisomerase I. MYC targeting was demonstrated by differential activities in Raji vs CA-46 cells and cytotoxicity in MYC-dependent cell lines. Cytotoxicities in the NCI-60 panel of human cancer cell lines were investigated. Favorable pharmacokinetics were established, and in vivo anticancer activities were demonstrated in xenograft mouse models. Furthermore, favorable brain penetration, brain pharmacokinetics, and anticancer activity in an orthotopic glioblastoma mouse model were demonstrated.
Databáze:	MEDLINE
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