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. 2020 Jul 15;11(8):1611–1619. doi: 10.1021/acsmedchemlett.0c00278

Synthesis, Biological Evaluation, and Molecular Docking of Arylpyridines as Antiproliferative Agent Targeting Tubulin

JiaPeng He †, Mao Zhang †, Lv Tang †, Jie liu †, JiaHong Zhong †, Wenya Wang †, Jiang-Ping Xu †,‡, Hai-Tao Wang †, Xiao-Fang Li §, Zhong-Zhen Zhou †,*
PMCID: PMC7430968  PMID: 32832031

Abstract

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Mimicking different pharmacophoric units into one scaffold is a promising structural modification tool to design new drugs with enhanced biological properties. To continue our research on the tubulin inhibitors, the synthesis and biological evaluation of arylpyridine derivatives (9–29) are described herein. Among these compounds, 6-arylpyridines (13–23) bearing benzo[d]imidazole side chains at the 2-position of pyridine ring displayed selective antiproliferative activities against HT-29 cells. More interestingly, 2-trimethoxyphenylpyridines 25, 27, and 29 bearing benzo[d]imidazole and benzo[d]oxazole side chains displayed more broad-spectrum antitumor activities against all tested cancer cell lines. 29 bearing a 6-methoxybenzo[d]oxazole group exhibited comparable activities against A549 and U251 cells to combretastatin A-4 (CA-4) and lower cytotoxicities than CA-4 and 5-Fu. Further investigations revealed 29 displays strong tubulin polymerization inhibitory activity (IC50 = 2.1 μM) and effectively binds at the colchicine binding site and arrests the cell cycle of A549 in the G2/M phase by disrupting the microtubules network.

Keywords: Arylpyridines, antiproliferative activities, tubulin polymerization inhibitor, cell cycle arrest, molecular docking

It is widely known that malignant tumors always compromise human health.1 However, recovery rates of cancer patients have improved in recent years with the emergence of new antitumor drugs. It is commonly known that microtubules, an effective target for cancer chemotherapy, play important roles in various cellular functions and participate in the formation of mitotic bipolar spindles.2,3 By altering microtubule dynamics at the mitotic stage, microtubule-targeting agents (MTAs), also called antimitotic drugs, directly interrupt spindle microtubules and arrest cells in the G2/M phase. Microtubules contain six unique binding sites (taxanes, vinca alkaloids, epothilone, laulimalide, pironetin, and colchicine domains).4,5 And the epothilone binding site is an undistinct site, which has been proposed in the taxane pocket of β-tubulin.6 Currently, several MTAs are approved for the treatment of tumors, and these include paclitaxel,7,8 vinca alkaloids,9 eribulin (vinca binding site inhibitors),10 and ixabepilone (taxanes binding site inhibitor).11

However, none of the approved tubulin inhibitors target the colchicine domain for treating the tumor. Despite all this, extensive efforts have been made to promote the discovery of colchicine site inhibitors.12,13 The cis-stilbene combretastatin A-4 (CA-4, Figure 1) is one of the most antitubulin active compounds by strongly binding to the colchicine site in β-tubulin.14 The cis-configuration of the double bond connecting two ring moieties present in the structures is very important for the high cytotoxic and antitubulin activities of combretastatin derivatives. To avoid the cis–trans isomerization, many efforts have focused on the replacement of the double bond with a ring or other functionalities to increase the biological efficiency and minimize possible metabolism.14,15 Interestingly, numerous novel microtubule-destabilizing agents with six-membered heterocyclic bridging groups displayed potential activities. Among them, sulfonamide tubulin polymerization inhibitor (ABT-751, Figure 1)16 with a pyridine bridging group is reported to cause a significant reduction in rat tumor blood flow and was well tolerated in the clinical trial.17,18 Pyridine-bridged analogs (3) with a 3-atom distance between two phenyl rings exhibited comparable antitumor activity to CA-4 and blocked angiogenesis invivo.19

Figure 1.

Figure 1

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Examples of some reported tubulin polymerization inhibitors and the proposed design of novel arylpyridine conjugates (9–29) containing benzo[d]imidazole, benzo[d]thiazole, and benzo[d]oxazole side chains.

Our recent research was mainly focused on potential heterocyclic anticancer agents based on different kinds of heterocyclic scaffolds.20−22 Our reported compounds 4 and 5 with purine bridging group displayed promising antitumor activities and lower cytotoxicity in normal cells but weak tubulin polymerization inhibition activity.20 Nevertheless, the potent biological profile encouraged us to continue our search for high-potency antitumor drugs. Herein, different skeleton modifications on the CA-4 scaffold were described, especially the replacement of the olefinic bond with a pyridine ring and the incorporation of five-membered heterocyclic rings (such as benzo[d]imidazoles, benzo[d]thiazoles, and benzo[d]oxazoles). Many tubulin polymerization inhibitors with these five-membered heterocyclic rings displayed strong activities,23−27 such as compounds 6,277,26 and 8.25 Consequently, arylpyridines (9–29, Figure 1) with benzo[d]imidazole, benzo[d]thiazole, and benzo[d]oxazole side chains were designed and synthesized in the current study. The antiproliferative activities, arresting the cell cycle abilities, and tubulin polymerization inhibitory activities of these obtained derivatives were subsequently evaluated. To better understand structure–activity relationships, molecular docking was also performed.

The synthetic routes of the arylpyridines (9–29) are illustrated in Scheme 1. Overall, the arylpyridylaldehyde (35–39) intermediates were prepared by the Suzuki reaction of bromopicolinaldehydes (33–34) with the substituted phenylboronic acid (30–32). Arylpyridines bearing benzo[d]thiazole side chains (9–10) and benzo[d]oxazole side chains (11–12 and 26–29) were prepared by one-pot aerobic oxidative condensation of arylpyridylaldehydes (35–39) with substituted 2-aminophenols and 2-aminobenzenethiol, respectively, using 1-butyl-3-methylimidazolium bromide as the catalyst. 6-Arylpyridines (13–25) possessing the benzo[d]imidazole side chains were synthesized by the heterocyclic condensation of arylpyridylaldehydes with substituted o-phenylenediamines.

Scheme 1. Synthetic Routes for Arylpyridines 9–29.

Scheme 1

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Antiproliferative activities (GI50) of arylpyridines (9–29) were evaluated against three human cancer cell lines [HT-29 (Human colon carcinoma), A549 (Human nonsmall cell lung cancer cells), and U251 (glioma)], using fluorouracil (5-Fu) and CA-4 as the reference cytotoxic compounds. The growth inhibitory concentration values (GI50) against tumor cells indicate 50% growth inhibition of cell growth compared to untreated controls after 48 h of incubation (Table 1).

Table 1. Antiproliferative Activity of Arylpyridine Derivatives 9–29.

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a

GI50 is the dose for 50% cells growth inhibition after 48 h of incubation. The GI50 values (means ± SDs) were averaged over at least two independent experiments.

b

Tubulin polymerization assay conditions in vitro: tested compounds (10 μM) and tubulin (4 mg/mL), 40 min, 37 °C; DMSO (0.1% v/v) was used as blank (100%: no inhibition).

c

CC50 values represent the 50% cytotoxic concentration after 48 h. All data were averaged over three separate experiments.

d

Not tested.

As shown in Table 1, 6-arylpyridines bearing benzo[d]thiazole side chains (9–10) and benzo[d]oxazole side chains (11–12) at the 2-position of the pyridine ring displayed noninhibitory activities toward tested cancer cell lines. However, 2-arylpyridines bearing benzo[d]oxazole side chains (27 and 29) at the 3-position of the pyridine ring showed satisfactory activities toward all tested cancer cell lines and higher activities than 5-Fu. Intriguingly, the activities of compound 29 against the A549 and U251 cell lines reached submicromole values (GI50 = 0.89 and 0.17 μM, respectively), which were comparable to that of the positive control CA-4. Besides, the toxicity evaluation in mouse normal hippocampal neuron (HT22) cells demonstrated that 27 and 29 exhibited lower cytotoxicities than the positive control CA-4.

For arylpyridines (13–25) bearing benzo[d]imidazole side chains, most of them exhibited very weak antiproliferative activities against A549 and U251 cell lines but higher antiproliferative activities against HT-29 cells than 5-Fu (GI50 = 12.6 μM). Among these compounds, compounds 13, 15, 20, and 22 displayed more potential activities (0.96 < GI50 < 1.4 μM) against HT-29 cells, and lower cytotoxicity in normal HT22 cells than CA-4 and 5-Fu. Compound 25 bearing 5-methyl benzo[d]imidazole side chains at 3-position of pyridine ring showed good activities against HT29 (GI50 = 2.9 μM), A549 (GI50 = 2.8 μM), and U251 (GI50 = 1.7 μM) cell lines, but higher cytotoxicities in normal HT22 cells than the positive control CA-4 and 5-Fu.

Further structure–activity relationship results indicated that the number of methoxy groups on the benzene ring and suitable position of side chains (benzo[d]imidazole, benzo[d]thiazole, and benzo[d]oxazole) in pyridine ring are essential for their selectivity and antiproliferative activities. First, dimethoxyphenylpyridines bearing benzo[d]imidazole side chains showed selective antiproliferative activities against HT-29 cells, such as compounds 13, 14, 16, 17, 19, 20, and 22.

Second, trimethoxyphenylpyridines bearing substituted benzo[d]imidazole displayed more broad-spectrum antitumor activities. For example, trimethoxyphenylpyridines 15 and 24 bearing nonsubstituted benzo[d]imidazole selectively inhibited HT-29 cells. However, trimethoxyphenylpyridines 18, 21, and 25 bearing substituted benzo[d]imidazole displayed good antitumor activity toward A549 cells or U251 cells. Trimethoxyphenylpyridines 25 bearing 5-methyl benzo[d]imidazole side chains at the 3-position of the pyridine ring displayed broad-spectrum antitumor activities toward tested tumor cells.

Third, 2-trimethoxyphenylpyridines (such as 27 and 29) displayed higher activities than 2-dimethoxyphenylpyridines (such as 26 and 28). As reported in the literature, the trimethoxyphenyl (TMP) moiety of combretastain A-4 analogues (tubulin colchicine binding site inhibitors) is an important pharmacophore for interaction with tubulin.15,28 The replacement of the trimethoxyphenyl group with the 3,4-dimethoxyphenyl group can lead to a decrease in activity.19,24 The possible reason is that replacing the trimethoxyphenyl group with a 3,4-dimethoxyphenyl group will cause the hydrogen bond with tubulin to weaken. Furthermore, benzo[d]oxazole side chains at the 3-position of the pyridine ring are favorable for antiproliferative activities. 2-Trimethoxyphenylpyridines 27 and 29 bearing 3-benzo[d]oxazole side chains displayed satisfactory activities against all tested tumor cells, which were higher than that of 5-Fu. Finally, introducing the methoxy group into benzo[d]oxazole is conducive to the improvement of the activity. The activity of compound 29 (0.89 < GI50 < 2.1 μM) bearing a 6-methoxybenzo[d]oxazole group was higher than that of 27 (4.6 < GI50 < 7.9 μM) bearing a benzo[d]oxazole group.

To validate the relationship between the antiproliferative activities, in vitro microtubule dynamics of arylpyridine derivatives were investigated using microtubule-destabilizing agent CA-4 as control. Tubulin polymerization assay results indicated the tubulin polymerization inhibition ability of these compounds was increased by introducing side chains into the 3-position of the pyridine ring. All arylpyridine derivatives 9–23 with side chains at the 2-position of the pyridine ring showed very weak activities (74% to 96% polymerization grade compared with the DMSO control). Arylpyridine derivatives 24–29 with side chains at the 3-position of pyridine ring displayed strong to weak polymerization inhibitory activities at a concentration of 10 μm. Among these compounds, 25 and 27 with good activities against all tested tumor cells produced good antitubulin polymerization activities. As shown in Table 1 and Figure 2A, 29 bearing a 6-methoxybenzo[d]oxazole group at the 3-position of the pyridine ring showed the best polymerization inhibitory activity (IC50 = 2.1 μM), which was close to that of CA-4 (IC50 = 1.6 μM). These results demonstrated that their antiproliferative activities may be caused by their antitubulin polymerization activities.

Figure 2.

Figure 2

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(A) Effect of arylpyridines 25, 29, and CA-4 on in vitro tubulin polymerization. DMSO (0.1% v/v) was used as vehicle control. (B) Effect of 25 on the cellular microtubule networks of A549 cells. (C) Effect of 29 on the cellular microtubule networks of A549 cells. Microtubules and DNA are stained in red and blue, respectively. Untreated cells (DMSO, 0.1% v/v) were used as a negative control, and cells treated with CA-4 (0.6 μM) were used as a positive control.

Nonsmall cell lung cancer (NSCLC), the main subtype of lung cancer, is the leading cause of cancer deaths worldwide. And drugs for NSCLC have been a hot and difficult problem. Thus, A549 cells were used in immunofluorescence staining assay to examine the effects of the most potent compounds 25 and 29 on the cellular microtubule networks (Figure 2B). After treatment with 25, 29, and CA4 for 18 h, the microtubule morphology (red) was visualized. As shown in Figure 2B, the microtubule network was a normal arrangement and organization in untreated A549 cells. In contrast, the interphase microtubule network around the cell nucleus was disrupted dramatically by 25, 29, and CA4, resulting in disassembly and fragmentation. These results confirm that 25 and 29 were like CA-4 inducing tubulin depolymerization and disturbing microtubule networks.

Tubulin depolymerization and disruption of microtubule networks can induce the G2/M arrest. Thus, the arrest effects of compound 25 and 29 on the cell cycle of A549 cells were measured at different concentrations via flow cytometry after 48 h of treatment and following propidium iodide (PI) staining of the cells (Figure 3). As illustrated in Figure 3, compounds 25, 29, and CA-4 showed the same behavior, arresting the cell cycle of A549 cells at the G2/M phase. At the same concentration, the percentage of cells in the G2/M phase arrested by compound 29 was higher than the percentage of cells in the G2/M phase arrested by compound 25. As the concentration of 29 increased from 0 to 2 μM, the percentage of cells in the G2/M phase was increased from 17.03% to 88.18%. Thus, compound 29 caused a significant G2/M arrest in the A549 cells in a concentration-dependent manner. The cell cycle arrest effects of 29 correlated well with its strong antitubulin and antiproliferative activities.

Figure 3.

Figure 3

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Analysis of the effects of 25 and 29 on the cell cycle distribution in the A549 cells using the flow cytometry analysis. DMSO (0.1% v/v) and CA-4 (0.6 μM) were utilized as a blank control and a positive control, respectively. DNA content was determined by DNA intercalating dye and propidium iodide staining.

In general, CA4-like derivatives with trimethoxyphenyl groups and cis-conformation inhibit colchicine binding to tubulin.15 To investigate the potential binding site of 29 in tubulin (PDB: 5LYJ)28 at the colchicine site, molecular docking simulations were performed in Maestro 11.1. After the native ligand (CA-4) was redocked into the active site cavity, the Glide RMSD (resulting root-mean-square deviation) value was given as 0.666 Å, which confirmed the reliability of our docking method. As shown in Figure 4, 29 adopted a similar conformation in the colchicine site to that of CA-4. The trimethoxyphenyl moiety of 29 formed one hydrogen bond with the β/Cys241 residue, and hydrophobic interactions with β/Cys241, β/Leu242, β/Ala250, β/Lys352, and β/Ala354. The intermolecular hydrogen bonding distance between 29 and the β/Cys241 residue is 2.50 Å, which is shorter than that of CA-4 with the β/Cys241 residue. Moreover, the pyridine bridging group occupied the position of the double bond bridging group of CA-4, forming π–cation interaction with β/Lys352 and hydrophobic interactions with β/Asn258, β/Leu248, and α/Thr179. The 6-methoxybenzo[d]oxazole scaffold occupied the position of the 3-hydroxy-4-methoxyphenyl moiety of CA-4. Compared with CA-4, the 6-methoxybenzo[d]oxazole group cannot form hydrogen bonds with surrounding amino acid residues, but it formed more hydrophobic interactions with the α/Val181, α/Val180, β/Asn258, β/Met259, β/Val315, β/Ala317, β/Ile347, β/Asn350, and β/Lys352 residues. To further confirm whether compound 29 could bind to the colchicine site on tubulin, the colchicine competitive binding assay of compound 29 was performed using CA-4 and paclitaxel as a positive control and a negative control, respectively. As shown in Figure 5, the fluorescence (F) of the colchicine–tubulin complex was reduced by compound 29 in a dose-dependent manner. Combined with the results of the molecular modeling study, these indicated that the binding site of 29 is located at the colchicine binding site of tubulin.

Figure 4.

Figure 4

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(A) Proposed binding models of 29 (shown in green ball and stick model) with tubulin (PDB: 5LYJ). (B) The native CA-4 ligand is illustrated in a blue ball and stick model. The glide docking scores of 29 and CA-4 are 8.349 and 8.864, respectively. In the 2D representation (C) of the ligand–protein interactions, all residues within 3 Å of the ligand (29) are shown. The intermolecular hydrogen bond is colored in magenta dash line. The π–cation interaction is colored in a red dash line (B) or a red solid line (C).

Figure 5.

Figure 5

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Based on fluorescence, colchicine competitive binding assays of compound 29 were performed in the 5.0 μM colchicine–tubulin complex at various concentrations, using CA-4 and paclitaxel positive control and negative control, respectively. Percent inhibition was determined by the ratio of F/F0, whereas F0 is the fluorescence of samples without inhibitor, and F is the fluorescence of samples with inhibitor at various concentrations.

In summary, a series of arylpyridines 9–29 containing benzo[d]imidazole, benzo[d]thiazole, and benzo[d]oxazole side chains was successfully designed and synthesized. Among these compounds, four 6-arylpyridines (13, 15, 20, and 22) bearing benzo[d]imidazole side chains at the 2-position of the pyridine ring showed selective antiproliferative activities against the HT-29 colon carcinoma cell line in the range of 0.96 μM to 1.4 μM. 2-Trimethoxyphenylpyridines 25, 27, and 29 bearing benzo[d]imidazole and benzo[d]oxazole side chains at the 3-position of the pyridine ring displayed more broad-spectrum antitumor activities against all tested cancer cell lines (HT29, A549, and U251 cells). 2-Trimethoxyphenylpyridine 25 bearing 5-methyl benzo[d]imidazole side chains at the 3-position of the pyridine ring showed good activities (1.7 < GI50 < 2.9 μM) against all tested cancer cell lines (HT29, A549, and U251 cells), but higher cytotoxicities in normal HT22 cells than the positive control CA-4 and 5-Fu. However, 2-trimethoxyphenylpyridines 27 and 29 bearing the benzo[d]oxazole side chains with satisfactory antiproliferative activities against three different cancer cell lines displayed lower cytotoxicities in normal HT22 cells than the positive control CA-4 and 5-Fu. What’s exciting is that compound 29 displayed comparable antiproliferative activities against A549 (GI50 = 0.82 μM) and U251 (GI50 = 0.17 μM) cell lines to CA-4.

Tubulin polymerization assay results indicated all 6-arylpyridine derivatives 9–23 showed very weak activities, whereas 2-arylpyridine derivatives 24–29 displayed weak to strong polymerization inhibitory activities. Among these compounds, 2-trimethoxyphenylpyridine 25 bearing benzo[d]imidazole side chains showed moderate tubulin polymerization inhibition activity (IC50 = 2.1 μM), whereas 2-trimethoxyphenylpyridines 29 bearing the benzo[d]oxazole side chains displayed strong tubulin polymerization inhibition activity (IC50 = 2.1 μM). Further investigations revealed 29 effectively binds at the colchicine binding site and arrests the cell cycle of A549 in the G2/M phase by disrupting the microtubules network. These results provide further guidance for the discovery of new CA-4 analogs with lower cytotoxicities.

Acknowledgments

This work was financially supported by Foundation for Distinguished Young Teachers in Higher Education of Guangdong Province (Yue Teacher (2014)145), Natural Science Foundation of Guangdong Province (2018A030313046), and National Natural Science Foundation of China (No. 81872735).

Glossary

Abbreviations

CA-4

combretastatin-A4

NSCLC

nonsmall cell lung cancer

HT22

hippocampal neuron (HT22)

HT-29

human colon carcinoma

A549

human nonsmall cell lung cancer cells

U251

glioma

5-Fu

fluorouracil

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.0c00278.

  • Experimental details (synthetic experimental details, pharmacological assays, molecular docking, and (1H and 13C) spectral information) (PDF)

Author Contributions

# J.H., M.Z., and L.T. contributed equally to this work. In addition, all authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.

Supplementary Material

ml0c00278_si_001.pdf (2MB, pdf)

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