Selective [3 + 2] C-H/C-H Alkyne Annulation via Dual (Distal) C (β, δ) -H Bond Activation Relay: A Novel Therapeutic Quinazolone-Tethered Benzofulvenes for Oral Cancer.

Autor:	Satpute DP; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) - Ahmedabad, Palaj, Gandhinagar 382355, Gujarat, India., Narang G; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) - Ahmedabad, Palaj, Gandhinagar 382355, Gujarat, India., Rohit H; Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER) - Ahmedabad, Palaj, Gandhinagar382355, Gujarat, India., Manjhi J; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) - Ahmedabad, Palaj, Gandhinagar 382355, Gujarat, India., Kumar D; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) - Ahmedabad, Palaj, Gandhinagar 382355, Gujarat, India., Shinde SD; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) - Ahmedabad, Palaj, Gandhinagar 382355, Gujarat, India., Lokhande SK; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) - Ahmedabad, Palaj, Gandhinagar 382355, Gujarat, India., Vatsa PP; Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER) - Ahmedabad, Palaj, Gandhinagar382355, Gujarat, India., Upadhyay V; Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER) - Ahmedabad, Palaj, Gandhinagar382355, Gujarat, India., Bhujbal SM; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) - Ahmedabad, Palaj, Gandhinagar 382355, Gujarat, India., Mandoli A; Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER) - Ahmedabad, Palaj, Gandhinagar382355, Gujarat, India., Kumar D; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) - Ahmedabad, Palaj, Gandhinagar 382355, Gujarat, India.
Jazyk:	angličtina
Zdroj:	JACS Au [JACS Au] 2024 Oct 11; Vol. 4 (11), pp. 4474-4487. Date of Electronic Publication: 2024 Oct 11 (Print Publication: 2024).
DOI:	10.1021/jacsau.4c00802
Abstrakt:	In contrast to proximal C-H bond activations, distal C-H bond activation is fundamentally more challenging and requires distinctly specialized directing partners or techniques. In this context, we report an unprecedented dual (distal) β-C(benzylic)-H and δ-C(aryl)-H bond activation relay protocol for the chemo-, regio-, and stereoselective construction of heterocycle-tethered benzofulvenes via [3 + 2] CH/CH-alkyne annulation under palladium catalysis. The protocol overrides the more favorable [4 + 2] CH/NH annulation and does not follow the vinylic C-H bond activation pathway. Mechanistic studies provide insight into the favored cyclopalladation of key intermediates (resulting from β-C(benzylic)-H bond cleavage) through relay δ-C(aryl)-H cleavage (vs N-H cleavage) prior to reductive elimination, which is the key to desired annulation. The synthesized new chemical entities (NCEs) constitute a novel scaffold with favorable anticancer activity against oral squamous cell carcinoma (OSCC). Detailed biomolecular studies, including RNA-sequencing and analysis, indicate that these compounds ( 4e and 4w ) arrest the cell cycle at the S-phase and target multiple cancer hallmarks, such as the activation of apoptotic pathways and impairment of mitochondrial activity simultaneously, suggesting their chemotherapeutic potential for oral cancer by addressing the complexity and adaptability of cancer cells in chorus. Competing Interests: The authors declare the following competing financial interest(s): This innovation is the subject of an Indian patent application (application number: 202421073889). (© 2024 The Authors. Published by American Chemical Society.)
Databáze:	MEDLINE
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