New 1H-Benzo[f]indazole-4,9-diones Conjugated with C-Protected Amino Acids and Other Derivatives: Synthesis and in Vitro Antiproliferative Evaluation

Abstract

1H-Benzo[f ]indazole-4,9-dione derivatives conjugated with C-protected amino acids (glycine, L-alanine, L-phenylalanine and L-glutamic acid) 6a-l were prepared by chemically modifying the prenyl substituent of 3-methyl-7-(4-methylpent-3-enyl)-1H-benzo[f ]indazole-4,9-dione 2 through epoxidation, degradative oxidation, oxidation and N-acyl condensation reactions. The chemical structures of the synthesized compounds were elucidated by analyzing their IR, 1 H-NMR and 13 C-NMR spectral data together with elemental analysis for carbon, hydrogen and nitrogen. The preliminary in vitro antiproliferative activity of the synthesized derivatives was evaluated on KATO-III and MCF-7 cell lines using a cell proliferation assay. The majority of the derivatives exhibited significant antiproliferative activity with IC 50 values ranging from 25.5 to 432.5 µM. These results suggest that 1H-benzo[f ]indazole-4,9-dione derivatives are promising molecules to be researched for developing new anticancer agents.

Antiproliferative Benzoindazolequinones as Potential Cyclooxygenase-2 Inhibitors

“…In compounds 2a – c to 5a – c ( subseries a ), the substituent R 1 contains a 2-methylpropenyl radical or its epoxy derivative, or its degraded aldehyde or carboxylic groups. Compounds 6a – m ( subseries b ), are benzoindazolequinones conjugated with some C-protected amino acids as Gly, Ala, Phe, and Glu [11,14] (Figure 1).…”

“…Several of the synthesized BIZQs showed significant in vitro antiproliferative activity against KATO-III and MCF-7 cancer cells [14]. To establish any correlation between previous experimental results of in vitro antineoplastic cytotoxicity presented by BIZQs and the values obtained through docking and virtual screening, we carried out the evaluation of some physicochemical parameters, and the pharmacological and toxicological properties prediction for these derivatives.…”

“…The chemical procedures applied to obtain those here studied 1 H -benzo[ f ]indazole-4,9-dione (BIZQ) derivatives 2a – c to 5a – c and 6a – m was described in our previous article [11,14], while the route of synthesis for simple and conjugated BIZQs can be found in Supplementary Scheme S1. Briefly, the twenty-four benzoindazole derivatives, were synthesized by a direct cyclization reaction of 2-acetyl-6-(4-methyl-3-pentenyl)-1,4-naphthoquinone with hydrazines, followed by subsequent chemical modifications of the (4-methyl-3-pentenyl) chain through epoxidation, degradative oxidation, further oxidation, and N -acyl condensation reactions with protected amino acids, as previously described [14].…”

“…The cytotoxic effects of the 1 H -Benzo[ f ]indazole-4,9-dione derivatives were analyzed by in vitro assay on KATO-III human gastric cancer cells and MCF-7 human breast adenocarcinoma cells, obtained from American Type Culture as described. Briefly, the efficacy of antitumor activity of each BIZQs was determined using MTS (colorimetric test), and the half maximal inhibitory concentration (IC 50 ) was obtained from dose-response curves in both KATO-III and MCF-7 as previously described by Molinari et al (2015) [14].…”

“…Another critical consideration when synthesizing new anticancer drugs is to facilitate their transport across the cell membrane, which could be achieved by conjugation with amino acids [13]. Regarding this subject, we have reported on the synthesis of a series of twenty-four new BIZQs, including several conjugated with Gly, Ala, Phe, and Glu (Figure 1), and most of these derivatives showed antiproliferative activity on two types of human cancer cells as KATO-III gastric carcinoma (GC) and MCF-7 breast carcinoma (BC) [14].…”