Methylene‐bearing sulfur‐containing cyanopyrimidine derivatives for treatment of cancer: Part‐II

Abstract

In continuation of our previous work on anticancer and anti-inflammatory agents, a series of 22 novel methylene-bearing sulfur-containing cyanopyrimidine derivatives was synthesized by Biginelli condensation reaction, which was followed by nucleophilic substitution of the chloro group with secondary or tertiary amines. Structural confirmation of these derivatives was attained through different spectral techniques. Then, anticancer evaluation of these compounds was done at the National Cancer Institute. Compounds 4g, 4j, 4k, and 4v demonstrated appreciable results against different cell lines. Among the synthesized compounds, 4g (NSC: 795475) exhibited a growth inhibition (GI) of 81.34% against the NCI-H460 lung cancer cell line, 72.64% against the ACHN renal cancer cell line, and 112.17% against the OVCAR-4 ovarian cancer cell line. Compound 4j (NSC: 795746) was active against U-251 CNS cancer, OVCAR-4 ovarian cancer, and 786-0 and ACHN renal cancer cell lines, with GI of 78.84%, 150.38%, 75.64%, and 86.45%, respectively. The literature supporting the association between cancer and underlying inflammation prompted us to evaluate the four compounds, 4g, 4j, 4k, and 4v, withappreciable anticancer activity for their in vitro anti-inflammatory activity. Cyclooxygenase (COX)-2 inhibition studies were also performed to study the molecular target. To validate the target study, molecular docking studies in the ligand-binding domain of COX-2 (PDB ID: 1CX2) were also performed. Compounds 4g, 4j, and 4k did not show cytotoxicity on RAW 264.7 cells up to 10 μM concentration; however, compound 4v showed cytotoxic effects at 10 μM concentration.

Synthesis and Characterization of 1,4-Benzodioxane-6-Carboxylic Acid Amide Analogs

“…while the protons of the methylene protons adjacent to the ether oxygen at position-8 appeared as a triplet at about 4.2 ppm. The methylene groups adjacent to the sulfur atom appeared as triplets at about 2.6 and 2.9 ppm [17]. In the C-13…”

New Pyrimidine-5-Carbonitriles as COX-2 Inhibitors: Design, Synthesis, Anticancer Screening, Molecular Docking, and In Silico ADME Profile Studies

“…On the other hand, 6-(4-methoxyphenyl)-dihydropyrimidine-5-carbonitrile derivative V has demonstrated significant COX-2 selectivity and also has a substantial effect on MDA-MB-231 (IC 50 = 3.43 µM) and MCF-7 (IC 50 = 2.56 µM) breast cancer cell lines [ 27 ]. Compound VI , which has a pyrimidine ring with cyano and p -methoxyphenyl moieties at the C-5 and C-6 positions, showed outstanding anticancer activity against most of the NCI60 cell lines, in addition to showing promising COX-2 inhibitory activities [ 28 ].…”

Synthesis, and reverse screening of 6‐(3,4,5‐trimethoxyphenyl)pyrimidine‐5‐carbonitrile derivatives as anticancer agents: Part‐II

“…Based on the reported literature [13] and our efforts devoted to the design and synthesis of cyanopyrimidine containing anticancer compounds, we have previously reported dihydropyrimidine-pyridazinone hybrids (1) with significant effect on breast cancer [14]. From the preliminary results obtained, we further designed cyanopyrimidine derivatives in which pyridazinone ring was replaced with methylene-bearing sulfur moiety in the form of isobutyl, isopropyl, and benzimidazole motif in addition to the " NH" or " N" placed at position ortho to the cyano group (2) based on the literature support [15,16]. In continuation to that, we further substituted methoxy group with fluoro (3) to observe the effect of electronic environment on anticancer activity [17].…”

“…Thus, encouraged by our previous work [9,[14][15][16][17]19] in the field of the synthesis of cyanopyrimidine derivatives as anticancer agents, we further designed, synthesized, and evaluated new 3,4,5-trimethoxy phenyl ring pendant sulfur-containing cyanopyrimidine derivatives (4a-m) with a particular lipophilic behavior. In this work, we further varied the chain length from isopropyl to isopentyl and evaluated their anticancer activities.…”