Discovery of New Apoptosis-Inducing Agents for Breast Cancer Based on Ethyl 2-Amino-4,5,6,7-Tetra Hydrobenzo[ b ]Thiophene-3-Carboxylate: Synthesis, In Vitro, and In Vivo Activity Evaluation

• Published in: Molecules (Basel, Switzerland) Switzerland), 2020-05, Vol.25 (11), p.2523
• Main Authors: Gad, Emad M, Nafie, Mohamed S, Eltamany, Elsayed H, Hammad, Magdy S A G, Barakat, Assem, Boraei, Ahmed T A
• Format: Article
• Language: English
• Subjects: Alkylation; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; benzo[b]thiophene; Breast Neoplasms - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Hep G2 Cells; HepG-2; Humans; JAK2 inhibitor; MCF-7; MCF-7 Cells; pyrimidinone; Pyrimidinones - chemistry; Pyrimidinones - pharmacology; Structure-Activity Relationship; Thiophenes - chemistry; Thiophenes - pharmacology
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules25112523

A multicomponent synthesis was empolyed for the synthesis of ethyl 2-amino-4,5,6,7-tetrahydrobenzo[ ]thiophene-3-carboxylate . An interesting cyclization was obtained when the amino-ester reacted with ethyl isothiocyanate to give the benzo[4,5]thieno[2,3- ][1,3]thiazin-4-one . Acylation of the amino-ester with chloroacetyl chloride in DCM and Et N afforded the acylated ester . The amino-ester was cyclized to benzo[4,5]thieno[2,3- ]pyrimidin-4(3 )-one which was reacted with some alkylating agents leading to alkylation at nitrogen . Hydrazide was utilized as a synthon for the synthesis of the derivatives - . Chloro-thieno[2,3- ]pyrimidine was synthesized and reacted with the hydrazine hydrate to afford the hydrazino derivative which was used as a scaffold for getting the derivatives - . Nucleophilic substitution reactions were used for getting the compounds - from chloro-thieno[2,3- ]pyrimidine . In the way of anticancer therapeutics development, the requisite compounds were assessed for their cytotoxicity in vitro against MCF-7 and HepG-2 cancer cell lines. Twelve compounds showed an interesting antiproliferative potential with IC from 23.2 to 95.9 µM. The flow cytometric analysis results showed that hit induces the apoptosis in MCF-7 cells with a significant 26.86% reduction in cell viability. The study revealed a significant decrease in the solid tumor mass (26.6%) upon treatment with compound . Moreover, study as an agonist for inhibitors of JAK2 and prediction study determined their binding energies and predicted their physicochemical properties and drug-likeness scores.