Design, Synthesis and Biological Evaluation of Biphenyl-1,2,3-Triazole Hybrid...

[Full title: Design, Synthesis and Biological Evaluation of Biphenyl-1,2,3-Triazole Hybrid Analogues as PD-1/PD-L1 Inhibitors]

INTRODUCTION

Cancer immunotherapy has engendered a lot of excitement in medicinal chemistry to develop new anticancer agents. In 1959, Thomas proposed a new theory that the immune system has a sensitive and specific recognition function for tumors or abnormal cells in the body. This theory was redefined as an immune surveillance theory by Burnet in 1967¹. Immune checkpoint blockade (ICB) anticancer therapies have seen noteworthy achievements in the past couple of years². A notable immune checkpoint receptor is PD-1 and its ligand, PD-L1. Over-activation of the PD-1/PD-L1 pathway plays a crucial role in the occurrence and progressive development of malignant tumors³. The T cells, B cells and natural killer (NK) cells, are mostly expressed with the PD-1 protein, which is expressed on their surfaces. Essentially, its structural components are made up of three segments: The extracellular, transmembrane and intracellular regions, a major part of the extracellular region is made up of immunoglobulin variable regions (IgV) and the intracellular domain is composed of two sequences, Immunoreceptor Tyrosine- based Inhibition Motifs (ITIMs) and Immune receptor Tyrosine Conversion Sequences (ITSMs)^4,5. The PD-1 protein has two ligands, PD-L1 and PD-L2. The PD-L1 protein has a wider expression range than that of PD-L2 protein and the PD-L2 protein expression quantity on the mature dendritic cell surface is lower, which leads to the overall lower affinity of PD-L2 and PD-1, even though the affinity of PD-L1 for PD-1 is 3-4 times lower than that of PD-L2. Therefore, other than the PD-L2 protein, excessive activation of the PD-1/PD-L1 immune checkpoint is the main condition for the occurrence of tumor immune escape. On the surface of most antigen-presenting cells and tumor cells, PD-L1 appears as a type I transmembrane glycoprotein of 33 kDa and its expression is regulated by the expression of certain pro-inflammatory factors such as interferon and tumor necrosis factor α^6,7.

Ishida et al.⁸ first noticed the PD-1 protein gene, which was found to be inextricable from the programmed death of immune-related cells. With the discovery of PD-1 ligands in the years 2000^7,9 and 2001^10,11, it has found that PD-1 plays an essential role in immune regulation and is an immune regulatory receptor that is vital to autoimmunity inflammation and tumor immunity^8,12.

Under normal circumstances, when PD-1 protein is stimulated after receiving inflammatory signals, it is stimulated to confine the function of lymphocytes in peripheral tissue to avoid continuous amplification of the immune response, thereby avoiding an immune attack on normal tissue cells. However, when this physiological function is inserted into the tumor microenvironment, it leads to the opposite immunosuppression. The up-regulation of this pathway is of great significance in a variety of malignant tumors. There is a need to inhibit the combination of PD-1/PD-L1 in the tumor microenvironment, restore the function of the immune system and mobilize cytotoxic T cells (TLC) to kill tumor cells to avoid unlimited proliferation of tumor cells. Due to this, the PD-1/PD-L1 checkpoint is an extremely valuable antitumor target¹³.

The PD-1 monoclonal antibody first entered clinical trials in 2007. The development of antibody drugs accelerated in the years that followed; by 2014, the rate of antibody development had peaked and the FDA had approved a number of monoclonal antibody drugs. Until now, there has been some good news for antibody drugs in the field of cancer immunotherapy. Four anti-PD-1 monoclonal antibodies and three anti-PD-L1 monoclonal antibodies have been approved by the FDA for the PD-1/PD-L1 pathway so far^14-17. On the other hand, antibody drugs have some related shortcomings, such as the cost of production, long half-life, low penetration and immunogenicity. Compared with the unnegligible disadvantages of monoclonal antibodies, small molecular drugs have more advantages. For example, small molecular drugs are cheaper to use because of their lower cost; their ingredients are stable, so they are easy to transport and preserve; and they can be administered orally to improve patient compliance. Membrane permeability is higher, so it is beneficial to penetrate tumor tissue. As a result, advances in small molecule inhibitors that target immune checkpoints have captured attention, particularly for PD-1/PD-L1^3,18-20. Finding effective PD-1/PD-L1 small molecule inhibitors has been a primary challenge for academic and industrial medicinal chemistry. Recently, Bristol Myers Squibb (BMS) researchers have reported small biphenyl molecule inhibitors, which can bind to PD-L1, disrupting the combination of proteins by inducing the formation of a dimer of PD-L1, thereby weakening or disrupting the interaction of PD-L1/PD-1^21,22. Almost simultaneously, Aurigene researchers reported that oxadiazole and thiadiazole derivatives disrupt the interaction of the PD-1/PD-L1 checkpoint²³.

The 1,2,3-triazole is one of the most prominent nitrogen-containing heterocycles. As 1,2,3-triazoles can form several noncovalent interactions via hydrogen bonds, hydrophobic interactions, van der Waals forces and dipole-dipole bonds with many biological macromolecules and possess diverse biological activities. The 1,2,3-triazole containing cefatrizine and carboxyamido-triazole are used as anticancer agents²⁴. In recent years, so many anticancer agents have been developed based on a hybrid approach of 1,2,3-triazole with pharmacophores. These hybrid molecules also exhibited better activity against drug resistance and drug-sensitive cancers with their discrete mechanisms of action^25,26.

Fig. 1: Designed strategy for synthesized analogues

The 1,2,3-triazoles generally hybridize with active pharmacophores or act as linkers to show better anticancer activity. Based on this hybrid approach, a biphenyl-triazole hybrid analogues was designed (Fig. 1).

On the basis of previous studies, especially those from BMS²¹ and the laboratory of Chemical Biology and Molecular Drug Design²⁷ related to active molecules impeding PD-1/PD-L1 combinations, some biphenyl-triazole conjugates were designed by modifying an aromatic linker linking biphenyl to 1,2,3-triazole and synthesized them. This study evaluated their anticancer activity via an immunological strategy, that is, blocking the PD-1/PD-L1 combination or a non-immune strategy.

MATERIALS AND METHODS

Study area: The study was conducted at the Zhejiang University of Technology, China, from January, 2023 to April, 2023.

Research design: All solvents and chemicals were analytically pure, purchased from the supplier and did not require further purification. The progress of the reaction system was monitored by thin-layer tomography, in which thin plates were observed under a UV lamp at a wavelength of 254 nm. A melting point instrument (XT-5A) was used to measure the melting point of compounds. With the Shimadzu LC-20A, the purity of the compounds was obtained. The ¹H NMR and ¹³C NMR spectra were measured using a Bruker NMR spectrometer (AVANCE-III 500 MHZ). Chemical shifts are expressed in parts per million (δ) relative to TMS (δ = 0.0) as internal standards and coupling constants (J) in Hertz. The mass spectra of the compounds were measured by an Agilent 6210 TOF LC/MS (USA). While (2-methylbiphenyl-3-yl) methanol, propargyl bromide, aromatic azides and substituted amine purchased from bidepharm; sodium hydride, copper sulfate pentahydrate, sodium ascorbate, thionyl chloride, tetrahydrofuran, dichloromethane and acetonitrile purchased from Energy Chemical. The HTRF kit (Cisbio, Cat. No. 64PD1PEG), Cell Counting Kit-8 (Adamas).

Experimental section
Chemistry: The synthesis of biphenyl-1,2,3-triazole conjugates 3a-r, 4a-b, 5a-b and 6a-h is described in Scheme 1 and 2. (2-methylbiphenyl-3-yl)methanol (Scheme 1) was treated with propargyl bromide solution in the presence of sodium hydride to obtain 2-methyl-3-((prop-2-ynyloxy)methyl) biphenyl (Scheme 2). The title conjugates were synthesized by click chemistry. The 2-methyl-3-((prop-2-ynyloxy)methyl) biphenyl (Scheme 2) was treated with various aromatic azides, copper sulfate pentahydrate and sodium ascorbate in THF:H₂O to obtain 3a-r, 4a-b.

The [4-(((2-methylbiphenyl-3-yl)methoxy)methyl]-1H-1,2,3-triazol-1-yl)phenyl)methanols (4a-b) were treated with thionyl chloride in dichloromethane at 0°C to RT to yield 5a-b. Various aliphatic amines were reacted with 5a-b in the presence of K₂CO₃ and acetonitrile at RT to produce 6a-h. Mass spectroscopy, ¹H NMR and ¹³C NMR analysis were used to verify the characterization of the synthesized compounds.

In general, ¹H NMR of all title compounds displayed a singlet peak of a triazole proton in the range of 8.14-7.72 ppm. Methoxy protons are responsible for two of the observed singlet peaks in the range of 4.89-4.72 ppm. Methyl protons are responsible for the singlet peak in the range of 2.26-2.23 ppm.

Scheme 1(a-b): Reagents and conditions (a) Propargyl bromide solution, NaH, THF, 0°C-RT, 8 hrs and (b) Substituted azides, CuSO₄⋅5H₂O, Na ascorbate, THF:H₂O (1:1), RT and 8 hrs

Scheme 2(a-d): Reagents and conditions (a) Propargyl bromide solution, NaH, THF, 0°C-RT, 8 hrs (b) Substituted azides, CuSO₄⋅5H₂O, Na Ascorbate, THF:H₂O (1:1), RT, 8 hrs, (c) SOCl₂, CH₂Cl₂, 0°C-RT, 2 hrs and (d) Amine, K₂CO₃, ACN, RT and 8 hrs

Biology
Homogeneous Time-Resolved Fluorescence (HTRF) method: The effectiveness of inhibitors against PD-1/PD-L1 binding was evaluated using HTRF (Cisbio, Cat. No. 64PD1PEG) by detecting fluorescence emission at a specific wavelength. The corresponding signal values were obtained by reading the 384-well plates at 665 and 620 nm wavelengths and the blocking efficacy of the compounds was determined by calculating the 665/620 nm signal value ratio, which was inversely proportional to the efficacy of the compounds²⁸. The IC₅₀ (half maximal inhibitory concentration) for all the compounds was calculated according to the PD-1/PD-L1 binding kit manufacturer’s guidelines using GraphPad Prism 8.0 software.

Wound-healing assay: Firstly, an early-generation A549 cell line was selected, resuscitated and passed through until the cells grew robustly and entered the rapid growth phase. Subsequently, A549 cells were plated in 12-well plates. The inoculation density is 10⁵ cells per well. Once the cells reached 80-90% confluency, the supernatant was removed and the cells in the well were digested, then gently washed with PBS buffer. Invert the 12-well plate and draw a line across the bottom of the plate with a marker (the line crosses the center of the circle). The plate was turned over again and vertical lines were drawn inside the hole using a 10 μL pipette tip at a straight angle from the horizontal line. The floating cell mass was again washed with PBS. A complete medium containing a certain concentration of compounds was added. In the control group, an equal volume of DMSO was added without the drug. The plate was continued cultured in a constant temperature incubator (Thermo Fisher Scientific, United States). The cells were observed under a microscope at 0, 24 and 48 hrs after administration and the cell migration at the same position at different times was analyzed by taking pictures with the horizontal line drawn in the bottom as a reference.

CCK-8 assay: To assess the ability of the compounds to inhibit tumor cell proliferation, the tumor cells were seeded into 96-well plates at appropriate concentrations and allowed to adhere. Subsequently, the cells were treated with specific concentrations of the compounds for 36 hrs. The viability of the cells was then evaluated using the CCK-8 assay and the absorbance of the 96-well plate was measured at a wavelength of 450 nm.

Statistical analysis: The SPSS 11.0 software was used for statistical analysis. The data are presented as Mean±Standard Deviation and percentage. The *p<0.05, **p<0.01, ***p<0.001 are considered significant. The t-test and Analysis of Variance (ANOVA) were applied to determine statistically significant variations among the experimental groups.

RESULTS AND DISCUSSION

Biological activity
Newly synthesized compounds (3a-r, 4a-b, 5a-b and 6a-h) were evaluated by the CCK-8 assay for antitumor activity: Firstly, the inhibitory effect of 30 newly synthesized compounds were investigated (3a-r, 4a-b, 5a-b and 6a-h) on the proliferation of tumor cells. The CCK-8 assay was used, paclitaxel and BMS202 were used as positive control groups and an equal volume of DMSO was used as a negative control group. Three cell lines were selected with high expression of the human PD-L1 protein, including the human non-small cell lung cancer cell lines A549 and HCC827, as well as the human breast cancer cell line MDA-MB-231^29,30. As shown in Fig. 2(a-c), among all compounds, three compounds (6d, 6e and 6h) and two compounds (6d and 6h) at 10 μM exhibited strong anti-proliferation activities against two types of A549 and HCC827 cells and MDA-MB-231 cells, respectively. It is worth mentioning that BMS202, which is a potent inhibitor of PD-1/PD-L1 interaction, exhibited weak inhibitory effects on cancer cells when T cells were absent. Further, the anti-proliferative ability of 6d, 6e and 6h was evaluated against the three types of the above cancer cells at compound concentrations: 0.2, 0.4, 0.8, 1.6, 3.2 and 6.4 μM (Fig. 2d-f). The results indicated that compounds 6d, 6e and 6h had the strongest inhibitory activity on A549 cells compared to HCC827 and MDA-MB-231 cells, with compound 6d demonstrating the lowest IC₅₀ value of 0.315±0.13 μM (Table 1). These findings suggest that compound 6d has the potential to be developed into a non-immune pathway drug against non-small cell lung cancer.

Compounds affected the migration ability of A549 lung cancer cells: According to the above CCK-8 experimental results, the compounds tested at the 10 μM screening concentration, 6d, 6e and 6h, inhibited the proliferation of the A459 cell line most effectively and the values of IC₅₀ are 0.315±0.13, 0.821±0.07 and 0.576±0.15 μM, respectively. Since the migration of cancer cells is an important indicator of the progression of malignant tumors, wound healing assays were conducted to investigate the potential inhibitory effects of compounds 6d, 6e and 6h on the migration of A549 cells at various concentrations and treatment durations. The observed phenomenon was shown in Fig. 3. The A549 cells were significantly less able to migrate when the compounds were incubated with them compared with the vehicle control group and the inhibitory effect was concentration-dependent. At the same time, under the premise of the same compound concentration, the longer the compound treatment time, the stronger the inhibitory effect on the cells. In the control group without compounds, the distance between cells was the closest. When compounds were incubated with the cells, A549 cells exhibited a significant decline in migration ability and the increased concentrations and prolonged action times of compounds resulted in a stronger migration inhibition effect. At 0.2 and 0.4 μM concentrations, a strong inhibition of cell migration was observed in the 6d treatment group. The findings of the wound healing assays were in line with those of the CCK-8 assay. Taken together, the results demonstrate that compounds 6d, 6e and 6h are potent inhibitors of both the proliferation and migration of A549 cells.

Blocking efficacy of compounds in inhibiting PD-1/PD-L1 was evaluated using a HTRF assay: Compounds with a biphenyl structure, particularly 6d, 6e and 6h, displayed notable anti-tumor activity without the involvement of immune cells such as T cells. Further investigated their ability to inhibit the interaction between PD-1 and PD-L1. Studies have shown that these compounds containing the biphenyl structure have a high potential to block the PD-1/PD-L1 interaction by inducing the formation of double PD-L1 proteins^28,31. To assess the efficacy of the newly synthesized compounds (3a-r, 4a-b, 5a-b and 6a-h) in order to inhibit the interaction between PD-1 and PD-L1, we conducted HTRF (Homogeneous Time-Resolved Fluorescence) analysis. The compounds contain a biphenyl structure (as depicted in Scheme 1 and 2) that was designed based on previously reported compounds from BMS (Fig. S1a).

Table 1: Inhibitory activity of compounds 6d, 6e and 6h against A549, HCC827 and MDA-MB-231 cells Compound A549 MDA-MB-231 HCC827 6d 0.315±0.13^a 3.34±0.20 4.60±0.11 6e 0.821±0.07 - 51.7±0.43 6h 0.576±0.15 2.03±0.24 4.48±0.19 Paclitaxel 1.35±0.16 5.66±0.18 4.16±0.24 Paclitaxel was used as a positive control here (n = 3) and ^aStandard deviation is given (p<0.05)

Fig. 2(a-f): Effects of compounds on the mortality rate of three tumor cell lines, (a) A549, (b) MDA-MB-231, (c) HCC827 cells were treated with 10 μM of 30 compounds (3a-r, 4a-b, 5a-b and 6a-h), (d) A549, (e) MDA-MB-231 and (f) HCC827 cells were incubated with three compounds (6d, 6e and 6h), two compounds (6d and 6h) and three compounds (6d, 6e and 6h), respectively, at concentrations of 0.2, 0.4, 0.8, 1.6, 3.2 and 6.4 μM for 36 hrs

^{Paclitaxel and BMS202 were used as two positive control drugs and the control group was set at 1% DMSO}

The effect of 30 compounds (3a-r, 4a-b, 5a-b and 6a-h) at a concentration of 32 μM on protein-protein interaction was shown by the HTRF assay in Fig. 4. It was preliminary estimated that the IC₅₀ values of all compounds targeting the PD-1/PD-L1 interaction are greater than or equal to 32 μM, compared to the much smaller one of BMS-202 with very strong inhibition ability, suggesting that at the concentration of 32 μM, the efficacy of compounds to impede the PD-1/PD-L1 immune checkpoint is very weak.

Fig. 3: Impact of compounds 6d, 6e and 6h on the migration ability of A549 lung cancer cells. Based on wound healing assay results using compounds 6d, 6e and 6h to test the migration ability of the A549 cells at concentrations of 0.2 and 0.4 μM, respectively, at 24 and 48 hrs^{Data are expressed as Mean±SD, *p<0.05, **p<0.01 and ***p<0.001}

But it was still worth noting that the 4a-b, 5a-b and 6a-h series of compounds presented slightly stronger inhibitory activity than the 3a-r series of compounds, implying that the formers can still have a chance to develop into compounds targeting the PD-1/PD-L1 checkpoint after structural optimization, in particular the 6a-h series of compounds, with a combination of results from molecular simulation and docking. A large structural difference between small molecules and BMS is caused by unfitted 1,2,3-triazole rings (Scheme 1 and Fig. 1). It means that it is possible to optimize the structure of these newly designed compounds to block the binding of proteins in the immunosuppressive pathway and play an immunomodulatory role to activate the immune system and mobilize immune cells to kill cancer cells.

Fig. 4: HTRF assay was used to identify the blocking efficacy of compounds 3a-r, 4a-b, 5a-b and 6a-h, the initial screening concentration was 32 μM and BMS202 was used as a positive control

CONCLUSION

The 30 biphenyl-1,2,3-triazole conjugates were designed and synthesized and their anti-cancer effects were well evaluated against three types of cells: A549, MDA-MB-231 and HCC827 by the CCK-8 assay. The results indicated that while immune cells were absent, the compounds 6d, 6e and 6h showed strong antiproliferative properties against three types of cancer cells, including T cells and particularly against A549 cells, specific IC₅₀ values were determined. According to the wound healing assay, there was a strong inhibitory effect of compounds 6d, 6e and 6h on A549 cell migration. Meanwhile, increased concentrations and prolonged treatment times increased the compound’s inhibitory effect on tumor cell migration. Results of the present study have reported a recommended use of compounds 6d, 6e and 6h for their potential anti-cancer effects via both immunological and non-immune pathways, specifically by blocking the PD-1/PD-L1 combination.

SIGNIFICANCE STATEMENT

This study evaluated the antineoplastic activity of thirty biphenyl-1,2,3-triazole hybrid analogues. It was found that compounds 6d, 6e and 6h had strong antiproliferative effects against three types of cancer cells, including T cells and especially against A549 cells, even when immune cells were not present (IC₅₀ values were found). Compounds 6d, 6e and 6h strongly inhibited the migration of A549 cells, as shown in the wound healing assay. The compound’s inhibitory effect on tumor cell migration was enhanced with increasing concentrations and prolonged treatment durations.

ACKNOWLEDGMENTS

This work was supported by grants from the National Natural Science Foundation of China (Nos. 21877101, 22177105), the Zhejiang Leading Innovation and Entrepreneurship Team (2018R01015) and the Zhejiang Provincial Key Discipline of Chemical Biology.

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