# Identification of Some Glutamic Acid Derivatives with Biological Potential by Computational Methods
## 1 Introduction
It has also been found that GS activity is important for the proangiogenic, immunosuppressive, and pro-metastatic function of M2-like macrophages [8]. The term \"glutamine addiction\" has been used to describe the enhanced usage of glutamine in cancer in an anaperiodic sense [15]. However, the inherent properties of tumour cells differ, as the specific mechanism that a tumour cell chooses is dictated by tumour type, oncogene/tumour suppressor status, tumour site, and stage of tumour development [9]. Some cancer types mainly depend on glutamine metabolism for tumour cell survival and proliferation. For example, pancreas cancer, lung cancer, colon cancer, glioblastoma, acute myeloid leukaemia, ovarian cancer or triple-negative breast cancer, which do not express oestrogen, progesterone receptors or human epidermal growth factor receptor 2, mainly depend on glutamine, in contrast with other types of cancer [8; 13; 16]. Human liver cancer has also been found to be dependent on extracellular glutamine [13]. Therefore, glutamine uptake and glutamine activity have been actively investigated as oncological targets [5]. Among the therapeutic strategies, one is targeting glutamine metabolism in tumours [13; 17; 18]. To date, the best-developed molecule is CB-839 (telaglenastat), which interferes with glutamine metabolism. This molecule is a potent, non-competitive allosteric inhibitor of the mitochondrial enzyme glutamine and the only one that is currently being used in Phase I clinical trials in cancer patients [9; 10; 13]. CB-839 shows antiproliferative properties in triple-negative breast cancer by reducing glutamine consumption, glutamate production, and levels of TCA intermediates [13; 15]. In addition, it exhibits significant efficacy in lung adenocarcinoma, chondrosarcoma and lymphoma cancer, but many liver cancer cell lines fail to respond to CB-839 treatment [13]. Besides CB-839, the compounds 968 (5-[3-bromo-4(dimethylamino)phenyl]-2,2-dimethyl-1,3,5,6-tetrahydrobenzo[a]phenanthridin-4-one) and BPTES (Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulphide) are other glutaminase inhibitors used in preclinical studies [10; 15; 19] (Figure 1). BPTES led to GSH depletion, making some lung cancer cells more sensitive to radiation treatment. At the same time, compound 968 blocked oncogenic transformation in fibroblasts and reduced the growth of cancer cells [11; 15]. Other potential therapeutic alternatives are glutamine mimics such as DON (6-dazo-5-oxo-L-norleucine), JHU-083 (ethyl 2-(2-amino-4-methylpentanamido)-DON), azasserine, and acivicin which are limited by their toxicity [10; 15; 20]. Similarly, the AOA (aminooxy-acetic acid) compound, an aminotransferase inhibitor, and L-asparaginase produce glutamine depletion [10]. EGCG (Epigallocatechin gallate) and R162 (2-allyl-1-hydroxy-9,10-anthraquinone) are glutamate dehydrogenase inhibitors that block the transformation of glutamic acid into \(\alpha\)-ketoglutate. For the moment, both of these are considered preclinical compounds [5; 10] (Figure 2). Additional pathways involving amino acid transport suggest effective therapies. Tumour cells achieve high intracellular concentrations of glutamine primarily through the upregulation of glutamine transporters, including AST2 (alanine, serine, cysteine transporter 2 or SLC1A5) [5]. Pharmacological blockade of SLC1A5 can be a successful alternative in some types of cancer. V-9302, an SLC1A5 antagonist (Figure 3), elicited a marked anti-tumour response in preclinical tumour models [10; 11]. It has blocked glutamine uptake in a broad spectrum of solid tumours (such as colorectal cancer cell lines) and several xenograft tumour models. This blocked glutamine uptake resulted in a profound alteration of tumour cell growth and survival [9; 21]. It has been observed that V-9302 was more productive in inducing triple-negative breast cancer cell death in several human and mouse cell culture models [16].