Synthesis and Anticancer Activity of Functionalized Thieno[2,3- d ]pyrimidine Compounds and Their Triazinyl and Tetrazin

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ynthesis and Anticancer Activity of Functionalized Thieno[2,3-d]pyrimidine Compounds and Their Triazinyl and Tetrazinyl Derivatives Walaa I. El-Sofanya, b, 1, Dalia Ahmed A. Othmana, Asma M. Mahrana, El-Manawaty A. Mayc, and Wael A. El-Sayeda, d, 2 aPhotochemistry

Department, National Research Centre, Dokki, Cairo, 12622 Egypt Department of Chemistry, College of Science, University of Hail, Ha’il 81451 Kingdom of Saudi Arabia c Department of Pharmacology, National Research Centre, Dokki, Cairo, 12622 Egypt dDepartment of Chemistry, College of Science, Qassim University, Qassim, 51431 Kingdom of Saudi Arabia b

Received August 30, 2019; revised November 16, 2019; accepted December 24, 2019

Abstract—New thienopyrimidine derivatives substituted with amino and hydrazinyl side chains were synthesized starting with 2-hydrazinyl substituted thienopyrimidine as a key compound. The newly synthesized compounds were studied for their anticancer activity against prostate cancer (PC3), lung carcinoma (A549), and hepatocellular carcinoma (HepG2) cell lines. Benzothienopyrimidine derivatives incorporating thioxoethanethioamide, pyrimidotetrazine carbothioamide, and hydrazinylglycine moieties exhibited high activities against PC3 or A549 cell lines. In addition, the thienopyrimidotriazine derivatives and their thienopyrimidinone analogues were preferentially active against the two cell lines. A number of the synthesized compounds also revealed moderate activities against PC3 and A549 cell lines. Keywords: thienopyrimidine, pyrimidotetrazine, pyrimidotriazine, anticancer, PC3, A549, HepG2 DOI: 10.1134/S106816202003005X

INTRODUCTION Many fused pyrimidine scaffolds have been designed and synthesized as drug candidates with different pharmacological applications [1]. The presence of purine and pyrimidine ring systems in nucleic acids prompts the research of incorporation of fused pyrimidines as therapeutic agents in recent extended medicinal chemistry research. Interestingly, various fused heterocycles, such as pteridines, purines, and pyrimidines, have been reported to show various pharmacological activities by themselves [2]. Thieno[2,3d]pyrimidine rigid scaffold is a bicyclic heterocycle considered as one of the most important fused pyrimidines. The variety of developed synthetic strategies hearten the availability of new leads with significant and versatile bioactivities and pharmacological properties, including anticancer [3, 4], kinase inhibition [5], antioxidant [6], anti-inflammatory [7], antimicrobial [8], antiviral [9], anti-tuberculosis [10], and CNS protection activities. GNE-490 and GNE-493 (Fig. 1) are two thienopyrimidine derivatives that have been designed as a structural alteration of GDC-0941. These two candidates revealed good pharmacokinetic (PK) parame1 Corresponding author: e-mail: [email protected]. 2 Corresponding author: e-mail: [email protected].

ters and high potency to inhibit selectively the PI3K pathway. They are currently in phase II clinical trials for the treatment of breast cancer [11]. Re