Styryl quinazolinones and its ethynyl derivatives induce myeloid differentiation

• Published in: Bioorganic & medicinal chemistry letters Vol. 29; no. 16; pp. 2286 - 2289
• Main Authors: Radhakrishnan, Sridhar, Syed, Riyaz, Takei, Hisashi, Kobayashi, Ikei S., Nakamura, Eugene, Sultana, Farheen, Kamal, Ahmed, Tenen, Daniel G., Kobayashi, Susumu S.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15-08-2019
• Subjects: Alkynes - chemistry; Alkynes - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; CCAAT-Enhancer-Binding Protein-alpha - antagonists & inhibitors; CCAAT-Enhancer-Binding Protein-alpha - genetics; CCAAT-Enhancer-Binding Protein-alpha - metabolism; CCAAT/enhancer binding protein; Cell Differentiation - drug effects; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HL-60 Cells; Humans; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - metabolism; Molecular Structure; Myeloid differentiation; Quinazolinones - chemical synthesis; Quinazolinones - chemistry; Quinazolinones - pharmacology; Structure-Activity Relationship; Styryl quinazolinones; Thienopyrimidinone; Thienopyrimidinone; Styryl quinazolinones; Myeloid differentiation; CCAAT/enhancer binding protein; Apoptosis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2019.06.024

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The tumor suppressor transcription factor CCAAT enhancer-binding protein α (C/EBPα) expression is downregulated in myeloid leukemias and enhancement of C/EBPα expression induces granulocytic differentiation in leukemic cells. Previously we reported that Styryl quinazolinones induce myeloid differentiation in HL-60 cells by upregulating C/EBPα expression. To identify more potent molecule that can induce leukemic cell differentiation we synthesized and evaluated new series of styryl quinazolinones, ethynyl styryl quinazolinones, styryl quinolinones and thienopyrimidinones. Thienopyrimidinones were found toxic and styryl quinolinones were found inactive. Ethynyl styryl quinazolinone 39 and styryl quinazolinone 5 were found active on par with the earlier reported analogues 1 and 2 suggesting that the 5-nitro furan-2-yl styryl quinazolinones find a real promise in leukemic cell differentiation. The improved potency of 5 suggested that further modifications in the 5-nitro furan-2-yl styryl quinazolinones can be at the phenyl substitution at the 3-position of the quinazolinone ring apart from the 5-position of the heteroaryl ring.