دورية أكاديمية
أعرض في EDS

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.

التفاصيل البيبلوغرافية
العنوان: 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.
المؤلفون: 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.
المصدر: Journal of medicinal chemistry [J Med Chem] 2024 May 09; Vol. 67 (9), pp. 7006-7032. Date of Electronic Publication: 2024 Apr 26.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE
أسماء مطبوعة: Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
مواضيع طبية MeSH: G-Quadruplexes*/drug effects , Promoter Regions, Genetic* , Drug Design* , Antineoplastic Agents*/pharmacology , Antineoplastic Agents*/chemical synthesis , Antineoplastic Agents*/pharmacokinetics , Antineoplastic Agents*/chemistry , Antineoplastic Agents*/therapeutic use , Isoquinolines*/pharmacology , Isoquinolines*/chemistry , Isoquinolines*/pharmacokinetics , Isoquinolines*/chemical synthesis , Proto-Oncogene Proteins c-myc*/genetics , Proto-Oncogene Proteins c-myc*/metabolism , Topoisomerase I Inhibitors*/pharmacology , Topoisomerase I Inhibitors*/chemical synthesis , Topoisomerase I Inhibitors*/pharmacokinetics , Topoisomerase I Inhibitors*/chemistry , Topoisomerase I Inhibitors*/therapeutic use, Humans ; Animals ; Cell Line, Tumor ; Mice ; Structure-Activity Relationship ; DNA Topoisomerases, Type I/metabolism ; Xenograft Model Antitumor Assays
مستخلص: 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.
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معلومات مُعتمدة: P30 CA023168 United States CA NCI NIH HHS; R01 CA177585 United States CA NCI NIH HHS; T32 GM132024 United States GM NIGMS NIH HHS; U01 CA240346 United States CA NCI NIH HHS
المشرفين على المادة: 0 (Antineoplastic Agents)
0 (Isoquinolines)
0 (Proto-Oncogene Proteins c-myc)
0 (Topoisomerase I Inhibitors)
EC 5.99.1.2 (DNA Topoisomerases, Type I)
تواريخ الأحداث: Date Created: 20240426 Date Completed: 20240509 Latest Revision: 20240605
رمز التحديث: 20240605
مُعرف محوري في PubMed: PMC11134171
DOI: 10.1021/acs.jmedchem.3c02303
PMID: 38668707
قاعدة البيانات: MEDLINE
الوصف
تدمد:1520-4804
DOI:10.1021/acs.jmedchem.3c02303