Journal Article

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

Gad, Emad M., Barakat, Assem, Hammad, Magdy S. A. G., Nafie, Mohamed S., Eltamany, Elsayed H., Boraei, Ahmed T. A.

2020

Overview

A multicomponent synthesis was empolyed for the synthesis of ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate 1. An interesting cyclization was obtained when the amino-ester 1 reacted with ethyl isothiocyanate to give the benzo[4,5]thieno[2,3-d][1,3]thiazin-4-one 3. Acylation of the amino-ester 1 with chloroacetyl chloride in DCM and Et3N afforded the acylated ester 4. The amino-ester 1 was cyclized to benzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one 8, which was reacted with some alkylating agents leading to alkylation at nitrogen 9–13. Hydrazide 14 was utilized as a synthon for the synthesis of the derivatives 15–19. Chloro-thieno[2,3-d]pyrimidine 20 was synthesized and reacted with the hydrazine hydrate to afford the hydrazino derivative 21, which was used as a scaffold for getting the derivatives 22–28. Nucleophilic substitution reactions were used for getting the compounds 29–35 from chloro-thieno[2,3-d]pyrimidine 20. 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 IC50 from 23.2 to 95.9 µM. The flow cytometric analysis results showed that hit 4 induces the apoptosis in MCF-7 cells with a significant 26.86% reduction in cell viability. The in vivo study revealed a significant decrease in the solid tumor mass (26.6%) upon treatment with compound 4. Moreover, in silico study as an agonist for inhibitors of JAK2 and prediction study determined their binding energies and predicted their physicochemical properties and drug-likeness scores.

• Publisher: MDPI,MDPI AG
• Subject: 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