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Recent progress of amino acid transporters as a novel antitumor target

  • Jiye Zhao , Jiayi Lv , Yang Chen , Qile Dong and Hao Dong EMAIL logo
Published/Copyright: November 16, 2022
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Open Chemistry
From the journal Open Chemistry Volume 20 Issue 1

Abstract

Glutamine transporters transport different amino acids for cell growth and metabolism. In tumor cells, glutamine transporters are often highly expressed and play a crucial role in their growth. By inhibiting the amino acid transport of these transporters, the growth of cancer cells can be inhibited. In recent years, more and more attention has been paid to the study of glutamine transporter. In this article, the differences between the ASC system amino acid transporter 2 (ASCT2), L-type amino acid transporter 1 (LAT1), and the cystine–glutamate exchange (xCT) transporters research progress on the mechanism of action and corresponding small molecule inhibitors are summarized. This article introduces 62 related small molecule inhibitors of different transporters of ASCT2, LAT1, and xCT. These novel chemical structures provide ideas for the research and design of targeted inhibitors of glutamine transporters, as well as important references and clues for the design of new anti-tumor drugs.

Keywords: glutamine transporter; ASCT2; LAT1; xCT; inhibitors

1 Introduction

At present, the global cancer mortality rate is increasing year by year. The incidence of breast cancer and lung cancer is high in the world (Figure 1a) [1]. According to the national cancer statistics in 2020, lung cancer possessed the highest incidence, accounting for about 17.9% of the country (Figure 1b), followed by colorectal cancer, gastric cancer, breast cancer, and liver cancer [2]. Therefore, combining global and national data on different cancer rates, it is an urgent need to design novel small molecule inhibitors that can inhibit the growth of malignant tumor cells.

Figure 1 The incidence of cancers in the world (a) and China (b).
Figure 1

The incidence of cancers in the world (a) and China (b).

One of the important features of tumor cells is metabolic abnormalities. In the process of in-depth research on tumor metabolism, the focus of research has gradually shifted from the original glucose metabolism to amino acid metabolism, especially the glutamine-dependent transport pathway. Compared with normal cellular metabolism, tumor cells need to consume far more nutrients than their own metabolism. The metabolic needs of tumor cells are met by providing nutrients through the collective action of angiogenesis [3]. The amino acid transporters are expressed at different levels in many tissues of ordinary humans and cancer patients, and amino acid-related transporters have very important effect on cancer cell metabolism. The abundant glutamine in the body provides the necessary carbon and nitrogen sources for the growth and proliferation of tumor cells [4,5], and ultimately synthesizes energy substances such as nucleotides, glutathione, amino sugars, and proteins to achieve the energy metabolism in the body [6]. Glutamine metabolism relies on amino acid transporters to pass through the cell membrane and enter the mitochondria through cell membranes to exert metabolic effects [7]. Related transporters consist of amino acid transporters, monocarboxylic acid transporters, and glucose transporters [8]. Due to the differences in biochemical and genetic factors, the genesis mechanisms of different cancers are different [9]. So, we think it is worthy to study further glutamine transporter target among the different cancer targets.

2 Glutamine transporter mechanism of action

2.1 Classification of glutamine transporters

Since most amino acids are hydrophilic, and the major site of glutamine metabolism is mitochondria, energy in the human body must cross the cell membrane via selective transporters [10,11]. Amino acid transporters in human cells can be classified into four classes according to whether they are dependent on Na+ transport: Na+-dependent transporter A, transporter ASC (alanine–serine–cysteine) (ASCT1 and ASCT2), transporter N (SN1 and SN2)E, and the Na+-independent transporter L (LAT1, LAT2, LAT3, and LAT4) [12]. Na+-dependent transporters mainly rely on Na+/K+-ATP enzyme for energy supply, whereas Na+-independent transporter LAT (large neutral amino acid transporter) does not depend on Na+ to supply energy [13,14] (Table 1). Na+-dependent transporter A mainly transports non-essential amino acids such as glutamine and alanine. The transporter ASC and transporter L are responsible for exchanging glutamine and alanine in the cell membrane and essential amino acids outside the membrane. Due to the affinity between glutamine transporter and the non-essential amino acid glutamine, this affinity of ASCT2 is involved in the uptake of glutamine [15]. The transporter N is responsible for regulating the concentration of glutamine in the cell membrane [16,17].

Table 1

Classification of ASCT, LAT, and cystine–glutamate exchange (xCT) transporters

Transporter Transporter system Na+-dependence Substrate
ASCT1 System ASC Na+-dependence Basic and small neutral amino acids
ASCT2 System ASC Na+-dependence Basic and small neutral amino acids
LAT1 System y Na+-independence Neutral amino acids/basic amino acids
LAT2 System y Na+-independence Neutral amino acids
LAT3 System L Na+-independence Large neutral amino acids
LAT4 System L Na+-independence Large neutral amino acids
xCT System xc- Na+-independence Acidic amino acids

2.2 Mechanism of action of glutamine transporter

Now the most frequently reported glutamine transporters in the literature are ASCT2, LAT1, and xCT [18,19]. The expression of ASCT2 protein is associated with poor prognosis in patients with colorectal cancer and prostate cancer [20]. The xCT transporter is responsible for the exchange of cystine–glutamate and is synthesized by the light chain (xCT) and the heavy chain (4F2hc). Human sample tissue analysis studies have shown that xCT is highly expressed in both lung and breast cancer patients. The LAT1 transporter is mainly responsible for the transport of macromolecular amino acids. The relationship between glutamine transporters LAT1, ASCT2, and xCT has not been reported so far. Therefore, we sort out the relationship between the three kinds of transporters and is shown in Figure 2 [21].

Figure 2 Mechanism of action of glutamine transporter. NEAA: non-essential amino acids; GLUD1: glutamate dehydrogenase 1; LAT2: alanine aminotransferase 2 recombinant protein; GPT2: glutamate pyruvic transaminase 2; TCA: cycle tricarboxylic acid cycle; and OAA: oxaloacetic acid.
Figure 2

Mechanism of action of glutamine transporter. NEAA: non-essential amino acids; GLUD1: glutamate dehydrogenase 1; LAT2: alanine aminotransferase 2 recombinant protein; GPT2: glutamate pyruvic transaminase 2; TCA: cycle tricarboxylic acid cycle; and OAA: oxaloacetic acid.

ASCT2, encoded by SLC1A5 gene, is a neutral amino acid, which is mainly responsible for transporting serine, threonine, valine, and other amino acids into the body. L-type amino acid transporter is a neutral amino acid transporter, which is independent of Na+ when transporting amino acids, including LAT1, LAT2, LAT3, and LAT4. The L-type amino acid transporter (LAT1) transports neutral amino acids, branched-chain amino acids, aromatic amino acids, and some essential amino acids. Amino acids are transported into cells. The different amino acids transported into the cell by ASCT2 and LAT1 are catalyzed by glutaminase (GLS) to produce glutamate and NH4+, which are then converted to α-ketoglutaric acid (α-kG) by glutamate dehydrogenase; α-KG enters the tricarboxylic acid (TCA) cycle [22,23,24], where oxalacetic acid produce acetic acid, acetyl-coa, and citric acid, providing a carbon source for the synthesis of fat [25]. Glutamine contains two amino groups, and amino nitrogen provides nitrogen source for the synthesis of other non-essential amino acids [26,27,28]. Glutamine also increases the production of glutathione to resist oxidative stress against cell death [29,30,31].

xCT (SLC7A11) is a cystine/glutamate antiporter that imports cystine into cells and exports glutamate [32,33]. It transports cystine into the cells, where it binds with glutamate and glycine in the body, and finally forms glutathione to resist redox stress and cell death [34,35].

Glutamine increases the production of glutathione to resist redox stress against cell death. Glutamate-ammonia ligase (GLUL) also exists in the cells, and glutamate synthesizes glutamine under the action of GLUL [36,37,38]. In tumor cells, the cellular utilization of glucose is carried out in a wasteful manner, regardless of the availability of oxygen, it utilizes glucose in aerobic glycolysis to produce adenosine triphosphate (ATP) (Warburg effect) [39,40,41]. Due to rapid proliferation, tumor cells must use an alternative energy supply method – through glutamine-driven oxidative phosphorylation and use glutamine to produce ATP by the glycolytic pathway [42]. Since the TCA cycle constantly consumes citric acid, it is necessary to supplement the TCA cycle intermediates, which significantly increases the consumption of glutamine [43]. The role of glutamine in tumor cells is mainly to supply the TCA cycle to provide nitrogen source for the synthesis of non-essential amino acids and nucleotides, and to resist redox stress by promoting the synthesis of glutathione.

3 Glutamine transporter inhibitors

3.1 ASCT2 inhibitors

3.1.1 ASCT2 positive control inhibitors

According to previous studies, high expression of glutamine transporter can lead to the large uptake of glutamine by lung cancer cells. Inhibition of glutamine transport is another more effective method to limit glutamine metabolism [44]. In the study of lung cancer patients, the inhibitor of ASCT2 receptor, l-γ-glutamine-p-nitroaniline (GPNA) (Figure 3a), only has a certain inhibitory effect on the glutamine uptake of ASCT2 cells. So, we used two experimental methods for comparison: the positron emission tomography technique and the glutamine analog labeling technique to study the uptake of glutamine by ASCT2. Evaluation analysis showed that glutamine transporter small molecule inhibitor GPNA had a certain inhibitory effect on lung cancer patients. Preclinical pharmacology studies have shown that V-9302 is another novel inhibitor of transmembrane transport glutamine (Figure 3b). The therapeutic effect of V-9302 not only showed significant inhibitory effect on tumor cell growth and proliferation, but also induced tumor cell death and oxidative stress, ultimately leading to tumor cell apoptosis. Since glutamine is transported from outside the cell membrane to the cell membrane, it has a certain limiting effect, which will not only affect the glutamine metabolism process but also reduce the mTORC1 signal transduction effect, and eventually reduce the proliferation of lung cancer cells. Through experimental studies, the comparative study of inhibitor V-9302 and GPNA inhibitor shows that V-9302 has a stronger inhibitory effect on tumor cells and a more effective therapeutic effect [45].

Figure 3 Structure of GPNA (a) and V-9302 (b).
Figure 3

Structure of GPNA (a) and V-9302 (b).

Current ASCT2 inhibitors are mainly non-selective small molecule compounds, such as serine biphenyl-4-carboxylate, benzylserine, and glutamine structure-related inhibitors [46]. GPNA has a weak inhibitory effect on ASCT2 (IC50 = 1,000 μM) [47]. Competitive inhibitors of ASCT2 have been developed, including 2-amino-4-bis (aryloxybenzyl) aminobutyric acid and benzylproline, if hydroxyl or amide group is introduced into the structure of these inhibitors, increasing the hydrophilicity of the compound will significantly increase the affinity of the inhibitor for ASCT2 [48]. Schulte’s team reported that competitive antagonist V-9302 (IC50 = 9.6 μM), which strongly inhibits ASCT2, slows the proliferation and growth of cancer cells, and increases the number of cancer cells. The number of cell death and the incidence of oxidative stress increased [49].

3.1.2 2-Substituted Nc-glutamyl anilide series derivatives

Manning’s research group discussed the structure–activity relationship of a series of derivatives containing glutamine structure, designed and synthesized 20 new small molecule inhibitors, and about 12 compounds were inactive. Compound a first obtains b under the conditions of CbzCl, NEt3, and MeOH, and b under the conditions of SOCI2 and CH2CI2 obtains compound c, and c under the conditions of lithium hydroxide and hydrogen synthesize 2-substituted Nc-glutamyl anilides (Figure 4).

Figure 4 Synthetic route towards 2-substituted Nc-glutamyl anilides (Compound a as initial material, b and c as synthetic intermediates).
Figure 4

Synthetic route towards 2-substituted Nc-glutamyl anilides (Compound a as initial material, b and c as synthetic intermediates).

It mainly includes compounds 3–9 (Figure 5), among which compound 7 has better activity. Biological experiments found that N-(2-(morpholino methyl) phenyl)-l-glutamine had the best effect on inhibiting glutamine absorption [50]. The introduction of a morpholine ring group significantly enhanced the inhibitory effect on glutamine uptake. This level of inhibition is three times higher than the previous levels of GPNA inhibition. In addition, the chemical properties of other compounds in this series need to be further studied and explored. This series of compounds provides a useful reference for the design of ASCT2 small molecule inhibitors.

Figure 5 Structures of compounds 1, 3–9.
Figure 5

Structures of compounds 1, 3–9.

3.1.3 Amino acid and l-glutamine nitroaniline inhibitors

Singh’s team designed and synthesized a series of derivatives and reported the derivatives, and modified the structure of l-alanine inhibitor, and l-proline and l-glutamyl nitroaniline inhibitors including serine derivatives (Figure 6). The structure of benzylproline was analyzed and studied. Finally, the structure of benzylproline was modified at the position of 2,3,4 substitution on the benzene ring of proline structure [51]. The study showed that the substituents on the benzene ring had little effect on the inhibitory effect, but the more hydrophobic groups in the structure, the stronger the binding ability to the ASCT2 transporter [52]. Benzylproline skeleton further enhances the binding capacity of ASCT2 inhibitors

Figure 6 Structures of compounds 10–14.
Figure 6

Structures of compounds 10–14.

3.2 LAT1 inhibitors

3.2.1 LAT1 positive control inhibitors

Inhibitors of LAT1 transporters are known to block their protein synthesis and cell proliferation processes. Leucine stimulates protein synthesis and cell growth through mammalian target of rapamycin (mTOR). LAT1 transporter inhibitors continue to inhibit mTOR signaling, thereby inhibiting tumor growth. However, the detailed mechanism by which leucine activates the mTOR signaling pathway in this nutrient is still unclear. At present, inhibitors of LAT1 are relatively few. 2-Aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) (Figure 7a) and (S)-2-amino-3-(4-((5-amino-2-phenylbenzo[d]oxazole-7-yl) methoxy)-3,5-dichlorophenyl)-propionic acid 2 (JPH-203 or KYT-0353) JPH-203 are the main inhibitors of LAT1 transporters [53,54,55].

Figure 7 (a) Structure of BCH and (b) schematic diagram of BCH binding sites.
Figure 7

(a) Structure of BCH and (b) schematic diagram of BCH binding sites.

BCH is an L-system inhibitor that inhibits the growth and apoptosis of cancer cells, including breast, prostate, and lung cancer [56]. A schematic diagram of the BCH inhibitor binding site is shown in Figure 7b (BCH density and isoline as shown in the blue grid), where the amino and carboxyl groups in the parent nucleus bind to G255, G65, and S66 (BCH, pdb: 6IRT).

In 2010, Oda’s team published another inhibitor JPH-203 (Figure 8), which is based on the structure of the thyroid hormone triiodothyronine (T3). T3 is a substrate of LAT1 and LAT2. As a result, JPH-203 inhibited the proliferation of human colon cancer-derived HT-29 cells and human oral cancer cells with IC50 values of 4.1 and 69 μM, significantly reducing tumor growth in vivo [57,58].

Figure 8 Chemical structures of inhibitor 15 (BCH) and inhibitor 16 (JPH 203).
Figure 8

Chemical structures of inhibitor 15 (BCH) and inhibitor 16 (JPH 203).

The researchers then tested JPH-203 in other cancers and the results showed that JPH-203 reduced survival in brain, stomach, head and neck cancer, leukemia, prostate cancer, kidney cancer, thymic cancer, and thyroid cancer cell lines. Furthermore, it was observed that the inhibitory effect of JPH-203 on tumor cells in vitro was highly dependent on LAT1 substrate concentration [59]. In order to make the inhibitory effect of JPH-203 on tumor cells more obvious, it is necessary to solve the problem whether the concentration of LAT1 substrate in tumor cells affects the in vivo efficacy of JPH-203.

JPH-203 first entered phase I clinical trials in humans, primarily for the treatment of patients with advanced solid tumors. For 17 patients diagnosed with advanced solid tumors, the performance of some patients was relatively stable. Of the six samples tested, four were diagnosed with biliary cancer, and plasma levels of the LAT1 substrate remained high. JPH-203 was found to be effective in biliary tract cancer [60]. It is currently undergoing a clinical trial to evaluate phase II clinical trial in patients with advanced biliary tract cancer (UMIN Clinical Trial Registry, UMIN000034080) [61]. By comparing the chemical structures of BCH and JPH-203, it can be speculated that phenylalanine in the structure of JPH-203 may have a stronger inhibitory effect on cancer cells.

3.2.2 Phenylalanine series inhibitors

MF Wempe’s group designed and synthesized a series of derivatives according to the structure of JPH-203. As shown in Figure 9, compound 17 (IC50 = 0.42 µM) is currently undergoing clinical studies and experiments. They also introduced the characteristics of the inhibitor; its biological activity is not as good as JPH-203. Compound 18 (IC50 = 14 µM) is currently under the biological test stage and is a large neutral amino acid transporter small subunit 1 (SLC7A5; LAT1) inhibitor. Published by MF Wempe’s group and colleagues, it is mainly used to study the treatment, diagnosis, or monitoring of some cancer diseases. Compound 19 (IC50 = 11.5 µM) is a large neutral amino acid transporter small subunit 1 (LAT1) inhibitor. It is used to treat some cancer diseases and has been ineffective in biological trials. At present, the clinical research is in the stage of biological test. Compound 20 (IC50 = 9.20 µM) is currently under biological testing. The introduction of trifluoromethyl and chlorine atom groups on the benzene ring significantly improves the inhibitory effect on glutamine uptake. The MF Wempe’s team described the properties of these inhibitors, which target their respective cancer diseases [62].

Figure 9 Chemical structures of compounds 17–20.
Figure 9

Chemical structures of compounds 17–20.

3.2.3 Aryloxyalkylamines, butanediol acid derivatives

Zhang’s group reported compound 21, which is currently in the biological trial stage (Figure 10). Compound 21 targeted epidermal growth factor receptor (EGFR) and used monoclonal antibodies and EGFR-mediated tumor cell endocytosis to improve PAMAM Vector response. Compound 22 (IC50 = 3.00 ± 0.020 µM) is currently undergoing biological testing. Compound 23 (IC50 = 0.339 µM) inhibitor is currently under the biological trial stage, and its biological activity data is worse. Compound 24 is currently under the preclinical research stage, and other related studies have not been reported in detail. Compared with the arrangement of other positions, the three-dimensional structure of the benzene ring from the outside to the inside significantly weakens the inhibitory effect on glutamine uptake. Compound 25 is currently under biological trials, which is another molecular structure of the inhibitor [63].

Figure 10 Chemical structures of compounds 21–25.
Figure 10

Chemical structures of compounds 21–25.

3.2.4 Indole alanine derivatives

Based on the l-tryptophan structural backbone, Julien Graff’s group evaluated a series of new l-tryptophan derivatives indole ring backbone benzene moiety substituents as potential inhibitory groups of L-type amino acid transporter LAT1. The structural skeleton of compound 26 was structurally modified and transformed (Figure 11), compounds 27, 28, and 29 were designed, and the degree of inhibition of 3H-l-Leu entering HT-29 cells was tested by a biological activity test. The results showed that the IC50 value of compound 26 was 18.8 μM and the IC50 values of compounds 27, 28, and 29 were all greater than 100 μM. The experimental data showed that compound 26 had the best inhibitory effect on l-glutamine uptake, and the modification of amino groups in the structure of compound 26 did not improve the inhibitory effect on glutamine uptake [64]. The indole alanine group increases the hydrophilicity of the inhibitor, making it more effective in inhibiting glutamine uptake.

Figure 11 Chemical structures of compounds 26–29.
Figure 11

Chemical structures of compounds 26–29.

3.2.5 N,N dichloroethyl-phenylbutanine derivatives

Jandeleit’s group reported the bioactivity data of compounds 30–36. Compound 30 (IC50 < 0.100 mM) is currently under the stage of biological testing and is a large inhibitor of amino acid transporters (Figure 12). Compounds 31 (IC50 < 0.100 mM), 32, 33, 34, and 35 (IC50 < 0.100 mM) are currently under the biological test stage and are large neutral amino acid transporter inhibitors. Jandeleit’s group reported compound 36 (IC50 < 0.100 mM) and is currently in the stage of biological testing. In summary, most of the different LAT1 inhibitors are currently in the stage of biological testing, and their biological activity data are not very good [65]. A related inhibitor of JPH-203 (IC50 = 0.12 µM) is currently in phase II clinical development by J-Pharma for the treatment of ending biliary tract cancer disease. This inhibitor has a more potent effect than other inhibitors.

Figure 12 Chemical structures of compounds 30–36.
Figure 12

Chemical structures of compounds 30–36.

3.2.6 Phenylalanine derivatives

Compound 37 is currently in the biological test stage and is a large neutral amino acid transporter inhibitor. No other data on this structural type of inhibitor has been reported, and further studies are needed. The introduction of m-2 phenol and cyano groups improves the hydrophilicity of the inhibitor, making it more effective in inhibiting glutamine uptake. The structure of Dopa-CBT is shown in Figure 13. Compound 38 (Dopa-CBT) (IC50 = 27.7 ± 1.04 µM) is currently in biological test, and Thiele’s group has presented the structure of the inhibitor [66]. Compound 39 (IC50 = 18.2 ± 1.20 µM) is currently in preclinical testing stage, and it is an inhibitor of a large neutral amino acid transporter.

Figure 13 Chemical structures of compounds 37–39.
Figure 13

Chemical structures of compounds 37–39.

3.2.7 Benzocyclohexane derivatives

Yoshikatsu Kanai’s group screened out candidate compound 40 through computer virtual screening and docking, they modified the structure of compound 40, and designed and synthesized compounds 41 and 42 (Figure 14). These compounds were tested for biological activity, and the IC50 values of compounds 40, 41, and 42 were 0.121, 0.165, and 0.234 μM, respectively. Comparing the biological activity data, compound 40 had the strongest inhibitory effect. It shows that after the introduction of biphenyl ring, compound 40 was better than naphthalene ring and benzoxazole ring [67].

Figure 14 Chemical structures of compounds 40–42.
Figure 14

Chemical structures of compounds 40–42.

In addition, several research groups have demonstrated that LAT1-targeting nanoparticles are highly effective against tumors that overexpress LAT1. In conclusion, currently available LAT1 inhibitors and LAT1-targeting nanoparticles have made some progress in different preclinical and clinical research experiments. Future research questions will predict which type of cancer patients are most sensitive to LAT1 inhibition. This is important for competitive LAT1 inhibitors, as it is unclear whether the level of LAT1 substrate in the tumor microenvironment will be affected.

3.3 xCT (SLC7A11) inhibitor

At present, the inhibitors of xCT transporters are rare. The inhibitors sulfasalazine (SAS) and Erastin are effective inhibitors of xCT transporters. As a small molecule inhibitor, SAS is widely used in the treatment of arthritis and enteritis. It induces cytotoxic effects by inhibiting cystine or glutamate anti-transporters in cancer cells [68,69,70].

Nuclear factor kappa B (NFKB) is a nuclear transcription factor of all cell types and plays an important role in regulating the immune response to infection. SAS is an inhibitor of NFKB activation. It is speculated that the metabolites of SAS, 5-aminosalicylic acid (5-ASA) and sulfadiazine can inhibit the activation of NFKB. The experimental results of SAS in the treatment of enteritis and rheumatism showed that the number of proliferating cells gradually decreased significantly in several cell lines and mice, suggesting that SAS had a certain inhibitory effect on tumor cells. These results provide reference for the study of cystine–glutamate transporters [71,72].

Erastin mainly acts on mitochondrial voltage-dependent anion channel (VDAC) to induce iron death in tumor cells. Erastin has the same effect as glutamate, which inhibits cystine uptake by the cystine/glutamate transporter. Finally, Erastin disrupts the cellular oxidative defense system and induces iron-dependent oxidative death.

3.3.1 SAS derivatives

Davide Cirillo’s team screened some xCT anti-transporter inhibitors in the molecular library. Using SAS (compound 43) as lead compound, compounds 44–46 were synthesized (Figure 15). The bioactivity of compound 43 in U87MG cells was IC50 = 30 μM. The EC50 value of compound 44 is 18 μM in HT1080 cells. The toxicity test of compounds 45 and 46 in normal human astrocytes showed that the bioactivity data of compound 45 was IC50 = 74.6 μM and compound 46 was IC50 = 110.30 μM.

Figure 15 Chemical structures of compounds 43–46.
Figure 15

Chemical structures of compounds 43–46.

Compound 45 had a strong inhibitory effect on glutamine uptake and less cytotoxicity. At present, it is in progress and can be used as a candidate compound for further biological studies in vitro and in vivo testing and evaluation. The introduction of hydroxyl and carboxylic acid groups improved the hydrophilicity of the inhibitor, which made the inhibition of glutamine uptake more obvious. It is hoped that compound 45 will have a better inhibitory effect on tumor cells than compound 43 in future clinical trials [73].

3.3.2 4-Ketobenzopyrimidine derivatives

Brents’s group designed the synthetic routes of compound g. Compound g is synthesized through a three-step reaction. The process is as follows: compound e is obtained by reducing compound d with iron powder, then compound e is synthesized under the action of N,N-diisopropylethylamine and PCI3, and f is synthesized under the action of 4-dimethylaminopyridine and dichloromethane. The parent nucleus of the target structure g (Figure 16).

Figure 16 Structure g synthetic route map.
Figure 16

Structure g synthetic route map.

Compounds 47–52 were all obtained by structural modification of the target structure g (Figure 17). In this series of compounds, most of the small molecule inhibitors are currently in the stage of biological activity testing. Nicholas’s teams have researched and launched a series of small molecule inhibitors, and their bioactivity data vary widely. By summing and comparing, the introduction of imidazole ring or piperazine ring will improve its biological activity, it was found that the biological activity of compound 47 was superior to other similar compounds.

Figure 17 Chemical structures of compounds 47–52.
Figure 17

Chemical structures of compounds 47–52.

3.3.3 4-Ketobenzopyrimidopiperazine derivatives

Dixon’s group selected benzopyrimidine 4-ketone from compound 53 as the basic parent nucleus and designed compounds 54–58 through structural modification, and tested the inhibitory effect of different compounds on glutamate uptake in CCF-STTG1 cells (Figure 18). The IC50 values of compounds 53–58 were 0.09, 0.14, 0.54, 0.042, 0.074, and 0.15 μM. Compounds 54, 57, and 58 were found to have stronger inhibitory effects on glutamate uptake in CCF-STTG1 cells. Introducing chlorine atoms into the benzene ring or keeping the structure of the benzene ring unchanged could inhibit the uptake of glutamate in CCF-STTG1 l-glutamine. These candidate compounds provide more reference for the subsequent compound design and screening [74].

Figure 18 Chemical structures of compounds 53–58.
Figure 18

Chemical structures of compounds 53–58.

3.3.4 Erastin derivatives

Erastin (compound 59) is the most active small molecule inhibitor of all xCT inhibitors studied till date (Figure 19). The IC50 value of compound 59 is 625 nM. It is a ferroptosis activator that acts on mitochondrial VDACs and selectively acts on tumor cells containing the oncogene RAS [75]. It selectively kills and causes oncogenic Ras mutant cell lines and triggers a unique Fe-dependent non-apoptotic cell death called ferroptosis.

Figure 19 Chemical structures of compounds 59–62.
Figure 19

Chemical structures of compounds 59–62.

Erastin binds directly to VDAC2 and causes mitochondrial damage by reactive oxygen species (ROS) production in a nicotinamide adenine dinucleotide-dependent manner. Furthermore, Erastin strongly enhanced the effect of wild-type EGFR cells by inducing caspase-independent cell death mediated by ROS. Compounds 60, 61, and 62 are currently in biological testing. For the same series of compounds, the biological activity data varied according to their structure–activity relationship [76].

4 Conclusion

At present, the death rate caused by cancer is increasing year by year. With the deepening of understanding of tumor metabolism, the focus of tumor metabolism research has gradually shifted from glucose metabolism to amino acid metabolism [77,78,79], especially the glutamine pathway [80,81,82,83]. Changes in cellular metabolism are one of the important features of tumors [84,85,86,87]. The glutamine transport pathway mainly includes three transport modes: ASCT2, LAT1, and xCT [88,89,90,91]. Therefore, altering the metabolism of tumor cells by inhibiting the l-glutamine pathway is relatively new [92,93]. This article reviews the different types of l-glutamine transporters and their mechanisms of action, as well as the characteristics of reported small molecule inhibitors (Table 2).

Table 2

Different inhibitors of transporters

Target Mechanism Inhibitor Remarks
ASCT2 Inhibition of glutamine transport GPNA Animal experiments and lung cancer cell lines
(SCL1A5) V-9302
LAT1 Inhibition of glutamine–EAA transport BCH Lung cancer cell lines
(SCL7A5)
xCT Inhibition of cysteine–glutamate transport SAS Animal experiments and lung cancer cell lines
(SCL7A11)

In addition, by understanding and summarizing the information from the currently reported literature, some practical design ideas for glutamine transporter inhibitors were proposed, which involved the structural characteristics of the reported inhibitors. By detailed introduction and analysis of the small molecule inhibitors reported so far, it is believed that they will play an important role in future drug development and overcome the difficulties better. Thus, the future of designing better inhibitors can be helped by combining the different strengths and weaknesses of the existing small molecule inhibitors. It is hoped that this review can provide reference information for other studies to further understand and provide more ideas to develop new glutamine transporter inhibitors.

Acknowledgment

The authors are grateful to the Fundamental Research Funds for the Central Universities (2632022ZD01).

  1. Funding information: This work was supported by the Fundamental Research Funds for the Central Universities (2632022ZD01).

  2. Author contributions: Jiye Zhao: methodology, writing, and editing; Jiayi Lv: revised and checked for writing and grammar; Yang Chen: revised and checked the concept; Dong Qile: conceptualization and supervision; Dong Hao: software and validation.

  3. Conflict of interest: All the authors have no conflicts of interest and agree to the publication of the article.

  4. Ethical approval: The conducted research is not related to either human or animal use.

  5. Data availability statement: All data generated or analyzed during this study are included in this published article [and its supplementary information files].

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Received: 2022-09-14
Revised: 2022-10-26
Accepted: 2022-10-27
Published Online: 2022-11-16

© 2022 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  41. Isolation and identification of unstable components from Caesalpinia sappan by high-speed counter-current chromatography combined with preparative high-performance liquid chromatography
  42. Quantification of biomarkers and evaluation of antioxidant, anti-inflammatory, and cytotoxicity properties of Dodonaea viscosa grown in Saudi Arabia using HPTLC technique
  43. Characterization of the elastic modulus of ceramic–metal composites with physical and mechanical properties by ultrasonic technique
  44. GC-MS analysis of Vespa velutina auraria Smith and its anti-inflammatory and antioxidant activities in vitro
  45. Texturing of nanocoatings for surface acoustic wave-based sensors for volatile organic compounds
  46. Insights into the molecular basis of some chalcone analogues as potential inhibitors of Leishmania donovani: An integrated in silico and in vitro study
  47. (1R,2S,5R)-5-Methyl-2-(propan-2-yl)cyclohexyl 4-amino-3-phenylbutanoate hydrochloride: Synthesis and anticonvulsant activity
  48. On the relative extraction rates of colour compounds and caffeine during brewing, an investigation of tea over time and temperature
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  50. Rapeseed oil-based hippurate amide nanocomposite coating material for anticorrosive and antibacterial applications
  51. Chemically modified Teucrium polium (Lamiaceae) plant act as an effective adsorbent tool for potassium permanganate (KMnO4) in wastewater remediation
  52. Efficiency analysis of photovoltaic systems installed in different geographical locations
  53. Risk prioritization model driven by success factor in the light of multicriteria decision making
  54. Theoretical investigations on the excited-state intramolecular proton transfer in the solvated 2-hydroxy-1-naphthaldehyde carbohydrazone
  55. Mechanical and gamma-ray shielding examinations of Bi2O3–PbO–CdO–B2O3 glass system
  56. Machine learning-based forecasting of potability of drinking water through adaptive boosting model
  57. The potential effect of the Rumex vesicarius water seeds extract treatment on mice before and during pregnancy on the serum enzymes and the histology of kidney and liver
  58. Impact of benzimidazole functional groups on the n-doping properties of benzimidazole derivatives
  59. Extraction of red pigment from Chinese jujube peel and the antioxidant activity of the pigment extracts
  60. Flexural strength and thermal properties of carbon black nanoparticle reinforced epoxy composites obtained from waste tires
  61. A focusing study on radioprotective and antioxidant effects of Annona muricata leaf extract in the circulation and liver tissue: Clinical and experimental studies
  62. Clinical comprehensive and experimental assessment of the radioprotective effect of Annona muricata leaf extract to prevent cellular damage in the ileum tissue
  63. Effect of WC content on ultrasonic properties, thermal and electrical conductivity of WC–Co–Ni–Cr composites
  64. Influence of various class cleaning agents for prosthesis on Co–Cr alloy surface
  65. The synthesis of nanocellulose-based nanocomposites for the effective removal of hexavalent chromium ions from aqueous solution
  66. Study on the influence of physical interlayers on the remaining oil production under different development modes
  67. Optimized linear regression control of DC motor under various disturbances
  68. Influence of different sample preparation strategies on hypothesis-driven shotgun proteomic analysis of human saliva
  69. Determination of flow distance of the fluid metal due to fluidity in ductile iron casting by artificial neural networks approach
  70. Investigation of mechanical activation effect on high-volume natural pozzolanic cements
  71. In vitro: Anti-coccidia activity of Calotropis procera leaf extract on Eimeria papillata oocysts sporulation and sporozoite
  72. Determination of oil composition of cowpea (Vigna unguiculata L.) seeds under influence of organic fertilizer forms
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  74. Treatment of rat brain ischemia model by NSCs-polymer scaffold transplantation
  75. Lead and cadmium removal with native yeast from coastal wetlands
  76. Characterization of electroless Ni-coated Fe–Co composite using powder metallurgy
  77. Ferrate synthesis using NaOCl and its application for dye removal
  78. Antioxidant, antidiabetic, and anticholinesterase potential of Chenopodium murale L. extracts using in vitro and in vivo approaches
  79. Study on essential oil, antioxidant activity, anti-human prostate cancer effects, and induction of apoptosis by Equisetum arvense
  80. Experimental study on turning machine with permanent magnetic cutting tool
  81. Numerical simulation and mathematical modeling of the casting process for pearlitic spheroidal graphite cast iron
  82. Design, synthesis, and cytotoxicity evaluation of novel thiophene, pyrimidine, pyridazine, and pyridine: Griseofulvin heterocyclic extension derivatives
  83. Isolation and identification of promising antibiotic-producing bacteria
  84. Ultrasonic-induced reversible blood–brain barrier opening: Safety evaluation into the cellular level
  85. Evaluation of phytochemical and antioxidant potential of various extracts from traditionally used medicinal plants of Pakistan
  86. Effect of calcium lactate in standard diet on selected markers of oxidative stress and inflammation in ovariectomized rats
  87. Identification of crucial salivary proteins/genes and pathways involved in pathogenesis of temporomandibular disorders
  88. Zirconium-modified attapulgite was used for removing of Cr(vi) in aqueous solution
  89. The stress distribution of different types of restorative materials in primary molar
  90. Reducing surface heat loss in steam boilers
  91. Deformation behavior and formability of friction stir processed DP600 steel
  92. Synthesis and characterization of bismuth oxide/commercial activated carbon composite for battery anode
  93. Phytochemical analysis of Ziziphus jujube leaf at different foliar ages based on widely targeted metabolomics
  94. Effects of in ovo injection of black cumin (Nigella sativa) extract on hatching performance of broiler eggs
  95. Separation and evaluation of potential antioxidant, analgesic, and anti-inflammatory activities of limonene-rich essential oils from Citrus sinensis (L.)
  96. Bioactivity of a polyhydroxy gorgostane steroid from Xenia umbellata
  97. BiCAM-based automated scoring system for digital logic circuit diagrams
  98. Analysis of standard systems with solar monitoring systems
  99. Structural and spectroscopic properties of voriconazole and fluconazole – Experimental and theoretical studies
  100. New plant resistance inducers based on polyamines
  101. Experimental investigation of single-lap bolted and bolted/bonded (hybrid) joints of polymeric plates
  102. Investigation of inlet air pressure and evaporative cooling of four different cogeneration cycles
  103. Review Articles
  104. Comprehensive review on synthesis, physicochemical properties, and application of activated carbon from the Arecaceae plants for enhanced wastewater treatment
  105. Research progress on speciation analysis of arsenic in traditional Chinese medicine
  106. Recent modified air-assisted liquid–liquid microextraction applications for medicines and organic compounds in various samples: A review
  107. An insight on Vietnamese bio-waste materials as activated carbon precursors for multiple applications in environmental protection
  108. Antimicrobial activities of the extracts and secondary metabolites from Clausena genus – A review
  109. Bioremediation of organic/heavy metal contaminants by mixed cultures of microorganisms: A review
  110. Sonodynamic therapy for breast cancer: A literature review
  111. Recent progress of amino acid transporters as a novel antitumor target
  112. Aconitum coreanum Rapaics: Botany, traditional uses, phytochemistry, pharmacology, and toxicology
  113. Corrigendum
  114. Corrigendum to “Petrology and geochemistry of multiphase post-granitic dikes: A case study from the Gabal Serbal area, Southwestern Sinai, Egypt”
  115. Corrigendum to “Design of a Robust sliding mode controller for bioreactor cultures in overflow metabolism via an interdisciplinary approach”
  116. Corrigendum to “Statistical analysis on the radiological assessment and geochemical studies of granite rocks in the north of Um Taghir area, Eastern Desert, Egypt”
  117. Corrigendum to “Aroma components of tobacco powder from different producing areas based on gas chromatography ion mobility spectrometry”
  118. Corrigendum to “Mechanical properties, elastic moduli, transmission factors, and gamma-ray-shielding performances of Bi2O3–P2O5–B2O3–V2O5 quaternary glass system”
  119. Erratum
  120. Erratum to “Copper(ii) complexes supported by modified azo-based ligands: Nucleic acid binding and molecular docking studies”
  121. Special Issue on Applied Biochemistry and Biotechnology (ABB 2021)
  122. Study of solidification and stabilization of heavy metals by passivators in heavy metal-contaminated soil
  123. Human health risk assessment and distribution of VOCs in a chemical site, Weinan, China
  124. Preparation and characterization of Sparassis latifolia β-glucan microcapsules
  125. Special Issue on the Conference of Energy, Fuels, Environment 2020
  126. Improving the thermal performance of existing buildings in light of the requirements of the EU directive 2010/31/EU in Poland
  127. Special Issue on Ethnobotanical, Phytochemical and Biological Investigation of Medicinal Plants
  128. Study of plant resources with ethnomedicinal relevance from district Bagh, Azad Jammu and Kashmir, Pakistan
  129. Studies on the chemical composition of plants used in traditional medicine in Congo
  130. Special Issue on Applied Chemistry in Agriculture and Food Science
  131. Strip spraying technology for precise herbicide application in carrot fields
  132. Special Issue on Pharmacology and Metabolomics of Ethnobotanical and Herbal Medicine
  133. Phytochemical profiling, antibacterial and antioxidant properties of Crocus sativus flower: A comparison between tepals and stigmas
  134. Antioxidant and antimicrobial properties of polyphenolics from Withania adpressa (Coss.) Batt. against selected drug-resistant bacterial strains
  135. Integrating network pharmacology and molecular docking to explore the potential mechanism of Xinguan No. 3 in the treatment of COVID-19
  136. Chemical composition and in vitro and in vivo biological assortment of fixed oil extracted from Ficus benghalensis L.
  137. A review of the pharmacological activities and protective effects of Inonotus obliquus triterpenoids in kidney diseases
  138. Ethnopharmacological study of medicinal plants in Kastamonu province (Türkiye)
  139. Protective effects of asperuloside against cyclophosphamide-induced urotoxicity and hematotoxicity in rats
  140. Special Issue on Essential Oil, Extraction, Phytochemistry, Advances, and Application
  141. Identification of volatile compounds and antioxidant, antibacterial, and antifungal properties against drug-resistant microbes of essential oils from the leaves of Mentha rotundifolia var. apodysa Briq. (Lamiaceae)
  142. Phenolic contents, anticancer, antioxidant, and antimicrobial capacities of MeOH extract from the aerial parts of Trema orientalis plant
  143. Chemical composition and antimicrobial activity of essential oils from Mentha pulegium and Rosmarinus officinalis against multidrug-resistant microbes and their acute toxicity study
  144. Special Issue on Marine Environmental Sciences and Significance of the Multidisciplinary Approaches
  145. An insightful overview of the distribution pattern of polycyclic aromatic hydrocarbon in the marine sediments of the Red Sea
  146. Antifungal–antiproliferative norcycloartane-type triterpenes from the Red Sea green alga Tydemania expeditionis
  147. Solvent effect, dipole moment, and DFT studies of multi donor–acceptor type pyridine derivative
  148. An extensive assessment on the distribution pattern of organic contaminants in the aerosols samples in the Middle East
  149. Special Issue on 4th IC3PE
  150. Energetics of carboxylic acid–pyridine heterosynthon revisited: A computational study of intermolecular hydrogen bond domination on phenylacetic acid–nicotinamide cocrystals
  151. A review: Silver–zinc oxide nanoparticles – organoclay-reinforced chitosan bionanocomposites for food packaging
  152. Green synthesis of magnetic activated carbon from peanut shells functionalized with TiO2 photocatalyst for Batik liquid waste treatment
  153. Coagulation activity of liquid extraction of Leucaena leucocephala and Sesbania grandiflora on the removal of turbidity
  154. Hydrocracking optimization of palm oil over NiMoO4/activated carbon catalyst to produce biogasoline and kerosine
  155. Special Issue on Pharmacology and metabolomics of ethnobotanical and herbal medicine
  156. Cynarin inhibits PDGF-BB-induced proliferation and activation in hepatic stellate cells through PPARγ
  157. Special Issue on The 1st Malaysia International Conference on Nanotechnology & Catalysis (MICNC2021)
  158. Surfactant evaluation for enhanced oil recovery: Phase behavior and interfacial tension
  159. Topical Issue on phytochemicals, biological and toxicological analysis of aromatic medicinal plants
  160. Phytochemical analysis of leaves and stems of Physalis alkekengi L. (Solanaceae)
  161. Phytochemical and pharmacological profiling of Trewia nudiflora Linn. leaf extract deciphers therapeutic potentials against thrombosis, arthritis, helminths, and insects
  162. Pergularia tomentosa coupled with selenium nanoparticles salvaged lead acetate-induced redox imbalance, inflammation, apoptosis, and disruption of neurotransmission in rats’ brain
  163. Protective effect of Allium atroviolaceum-synthesized SeNPs on aluminum-induced brain damage in mice
  164. Mechanism study of Cordyceps sinensis alleviates renal ischemia–reperfusion injury
  165. Plant-derived bisbenzylisoquinoline alkaloid tetrandrine prevents human podocyte injury by regulating the miR-150-5p/NPHS1 axis
  166. Network pharmacology combined with molecular docking to explore the anti-osteoporosis mechanisms of β-ecdysone derived from medicinal plants
  167. Chinese medicinal plant Polygonum cuspidatum ameliorates silicosis via suppressing the Wnt/β-catenin pathway
  168. Special Issue on Advanced Nanomaterials for Energy, Environmental and Biological Applications - Part I
  169. Investigation of improved optical and conductivity properties of poly(methyl methacrylate)–MXenes (PMMA–MXenes) nanocomposite thin films for optoelectronic applications
  170. Special Issue on Applied Biochemistry and Biotechnology (ABB 2022)
  171. Model predictive control for precision irrigation of a Quinoa crop
https://doi.org/10.1515/chem-2022-0239
Keywords for this article
glutamine transporter; ASCT2; LAT1; xCT; inhibitors
Creative Commons
BY 4.0

Articles in the same Issue

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  42. Quantification of biomarkers and evaluation of antioxidant, anti-inflammatory, and cytotoxicity properties of Dodonaea viscosa grown in Saudi Arabia using HPTLC technique
  43. Characterization of the elastic modulus of ceramic–metal composites with physical and mechanical properties by ultrasonic technique
  44. GC-MS analysis of Vespa velutina auraria Smith and its anti-inflammatory and antioxidant activities in vitro
  45. Texturing of nanocoatings for surface acoustic wave-based sensors for volatile organic compounds
  46. Insights into the molecular basis of some chalcone analogues as potential inhibitors of Leishmania donovani: An integrated in silico and in vitro study
  47. (1R,2S,5R)-5-Methyl-2-(propan-2-yl)cyclohexyl 4-amino-3-phenylbutanoate hydrochloride: Synthesis and anticonvulsant activity
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  52. Efficiency analysis of photovoltaic systems installed in different geographical locations
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  54. Theoretical investigations on the excited-state intramolecular proton transfer in the solvated 2-hydroxy-1-naphthaldehyde carbohydrazone
  55. Mechanical and gamma-ray shielding examinations of Bi2O3–PbO–CdO–B2O3 glass system
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  57. The potential effect of the Rumex vesicarius water seeds extract treatment on mice before and during pregnancy on the serum enzymes and the histology of kidney and liver
  58. Impact of benzimidazole functional groups on the n-doping properties of benzimidazole derivatives
  59. Extraction of red pigment from Chinese jujube peel and the antioxidant activity of the pigment extracts
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  61. A focusing study on radioprotective and antioxidant effects of Annona muricata leaf extract in the circulation and liver tissue: Clinical and experimental studies
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  78. Antioxidant, antidiabetic, and anticholinesterase potential of Chenopodium murale L. extracts using in vitro and in vivo approaches
  79. Study on essential oil, antioxidant activity, anti-human prostate cancer effects, and induction of apoptosis by Equisetum arvense
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  81. Numerical simulation and mathematical modeling of the casting process for pearlitic spheroidal graphite cast iron
  82. Design, synthesis, and cytotoxicity evaluation of novel thiophene, pyrimidine, pyridazine, and pyridine: Griseofulvin heterocyclic extension derivatives
  83. Isolation and identification of promising antibiotic-producing bacteria
  84. Ultrasonic-induced reversible blood–brain barrier opening: Safety evaluation into the cellular level
  85. Evaluation of phytochemical and antioxidant potential of various extracts from traditionally used medicinal plants of Pakistan
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  89. The stress distribution of different types of restorative materials in primary molar
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  93. Phytochemical analysis of Ziziphus jujube leaf at different foliar ages based on widely targeted metabolomics
  94. Effects of in ovo injection of black cumin (Nigella sativa) extract on hatching performance of broiler eggs
  95. Separation and evaluation of potential antioxidant, analgesic, and anti-inflammatory activities of limonene-rich essential oils from Citrus sinensis (L.)
  96. Bioactivity of a polyhydroxy gorgostane steroid from Xenia umbellata
  97. BiCAM-based automated scoring system for digital logic circuit diagrams
  98. Analysis of standard systems with solar monitoring systems
  99. Structural and spectroscopic properties of voriconazole and fluconazole – Experimental and theoretical studies
  100. New plant resistance inducers based on polyamines
  101. Experimental investigation of single-lap bolted and bolted/bonded (hybrid) joints of polymeric plates
  102. Investigation of inlet air pressure and evaporative cooling of four different cogeneration cycles
  103. Review Articles
  104. Comprehensive review on synthesis, physicochemical properties, and application of activated carbon from the Arecaceae plants for enhanced wastewater treatment
  105. Research progress on speciation analysis of arsenic in traditional Chinese medicine
  106. Recent modified air-assisted liquid–liquid microextraction applications for medicines and organic compounds in various samples: A review
  107. An insight on Vietnamese bio-waste materials as activated carbon precursors for multiple applications in environmental protection
  108. Antimicrobial activities of the extracts and secondary metabolites from Clausena genus – A review
  109. Bioremediation of organic/heavy metal contaminants by mixed cultures of microorganisms: A review
  110. Sonodynamic therapy for breast cancer: A literature review
  111. Recent progress of amino acid transporters as a novel antitumor target
  112. Aconitum coreanum Rapaics: Botany, traditional uses, phytochemistry, pharmacology, and toxicology
  113. Corrigendum
  114. Corrigendum to “Petrology and geochemistry of multiphase post-granitic dikes: A case study from the Gabal Serbal area, Southwestern Sinai, Egypt”
  115. Corrigendum to “Design of a Robust sliding mode controller for bioreactor cultures in overflow metabolism via an interdisciplinary approach”
  116. Corrigendum to “Statistical analysis on the radiological assessment and geochemical studies of granite rocks in the north of Um Taghir area, Eastern Desert, Egypt”
  117. Corrigendum to “Aroma components of tobacco powder from different producing areas based on gas chromatography ion mobility spectrometry”
  118. Corrigendum to “Mechanical properties, elastic moduli, transmission factors, and gamma-ray-shielding performances of Bi2O3–P2O5–B2O3–V2O5 quaternary glass system”
  119. Erratum
  120. Erratum to “Copper(ii) complexes supported by modified azo-based ligands: Nucleic acid binding and molecular docking studies”
  121. Special Issue on Applied Biochemistry and Biotechnology (ABB 2021)
  122. Study of solidification and stabilization of heavy metals by passivators in heavy metal-contaminated soil
  123. Human health risk assessment and distribution of VOCs in a chemical site, Weinan, China
  124. Preparation and characterization of Sparassis latifolia β-glucan microcapsules
  125. Special Issue on the Conference of Energy, Fuels, Environment 2020
  126. Improving the thermal performance of existing buildings in light of the requirements of the EU directive 2010/31/EU in Poland
  127. Special Issue on Ethnobotanical, Phytochemical and Biological Investigation of Medicinal Plants
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  129. Studies on the chemical composition of plants used in traditional medicine in Congo
  130. Special Issue on Applied Chemistry in Agriculture and Food Science
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  132. Special Issue on Pharmacology and Metabolomics of Ethnobotanical and Herbal Medicine
  133. Phytochemical profiling, antibacterial and antioxidant properties of Crocus sativus flower: A comparison between tepals and stigmas
  134. Antioxidant and antimicrobial properties of polyphenolics from Withania adpressa (Coss.) Batt. against selected drug-resistant bacterial strains
  135. Integrating network pharmacology and molecular docking to explore the potential mechanism of Xinguan No. 3 in the treatment of COVID-19
  136. Chemical composition and in vitro and in vivo biological assortment of fixed oil extracted from Ficus benghalensis L.
  137. A review of the pharmacological activities and protective effects of Inonotus obliquus triterpenoids in kidney diseases
  138. Ethnopharmacological study of medicinal plants in Kastamonu province (Türkiye)
  139. Protective effects of asperuloside against cyclophosphamide-induced urotoxicity and hematotoxicity in rats
  140. Special Issue on Essential Oil, Extraction, Phytochemistry, Advances, and Application
  141. Identification of volatile compounds and antioxidant, antibacterial, and antifungal properties against drug-resistant microbes of essential oils from the leaves of Mentha rotundifolia var. apodysa Briq. (Lamiaceae)
  142. Phenolic contents, anticancer, antioxidant, and antimicrobial capacities of MeOH extract from the aerial parts of Trema orientalis plant
  143. Chemical composition and antimicrobial activity of essential oils from Mentha pulegium and Rosmarinus officinalis against multidrug-resistant microbes and their acute toxicity study
  144. Special Issue on Marine Environmental Sciences and Significance of the Multidisciplinary Approaches
  145. An insightful overview of the distribution pattern of polycyclic aromatic hydrocarbon in the marine sediments of the Red Sea
  146. Antifungal–antiproliferative norcycloartane-type triterpenes from the Red Sea green alga Tydemania expeditionis
  147. Solvent effect, dipole moment, and DFT studies of multi donor–acceptor type pyridine derivative
  148. An extensive assessment on the distribution pattern of organic contaminants in the aerosols samples in the Middle East
  149. Special Issue on 4th IC3PE
  150. Energetics of carboxylic acid–pyridine heterosynthon revisited: A computational study of intermolecular hydrogen bond domination on phenylacetic acid–nicotinamide cocrystals
  151. A review: Silver–zinc oxide nanoparticles – organoclay-reinforced chitosan bionanocomposites for food packaging
  152. Green synthesis of magnetic activated carbon from peanut shells functionalized with TiO2 photocatalyst for Batik liquid waste treatment
  153. Coagulation activity of liquid extraction of Leucaena leucocephala and Sesbania grandiflora on the removal of turbidity
  154. Hydrocracking optimization of palm oil over NiMoO4/activated carbon catalyst to produce biogasoline and kerosine
  155. Special Issue on Pharmacology and metabolomics of ethnobotanical and herbal medicine
  156. Cynarin inhibits PDGF-BB-induced proliferation and activation in hepatic stellate cells through PPARγ
  157. Special Issue on The 1st Malaysia International Conference on Nanotechnology & Catalysis (MICNC2021)
  158. Surfactant evaluation for enhanced oil recovery: Phase behavior and interfacial tension
  159. Topical Issue on phytochemicals, biological and toxicological analysis of aromatic medicinal plants
  160. Phytochemical analysis of leaves and stems of Physalis alkekengi L. (Solanaceae)
  161. Phytochemical and pharmacological profiling of Trewia nudiflora Linn. leaf extract deciphers therapeutic potentials against thrombosis, arthritis, helminths, and insects
  162. Pergularia tomentosa coupled with selenium nanoparticles salvaged lead acetate-induced redox imbalance, inflammation, apoptosis, and disruption of neurotransmission in rats’ brain
  163. Protective effect of Allium atroviolaceum-synthesized SeNPs on aluminum-induced brain damage in mice
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  165. Plant-derived bisbenzylisoquinoline alkaloid tetrandrine prevents human podocyte injury by regulating the miR-150-5p/NPHS1 axis
  166. Network pharmacology combined with molecular docking to explore the anti-osteoporosis mechanisms of β-ecdysone derived from medicinal plants
  167. Chinese medicinal plant Polygonum cuspidatum ameliorates silicosis via suppressing the Wnt/β-catenin pathway
  168. Special Issue on Advanced Nanomaterials for Energy, Environmental and Biological Applications - Part I
  169. Investigation of improved optical and conductivity properties of poly(methyl methacrylate)–MXenes (PMMA–MXenes) nanocomposite thin films for optoelectronic applications
  170. Special Issue on Applied Biochemistry and Biotechnology (ABB 2022)
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