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. 2015 Jan 14;6(3):239–243. doi: 10.1021/ml500327q

Discovery of Novel Multiacting Topoisomerase I/II and Histone Deacetylase Inhibitors

Shipeng He †, Guoqiang Dong ‡, Zhibin Wang ‡, Wei Chen ‡, Yahui Huang ‡, Zhengang Li ‡, Yan Jiang ‡, Na Liu ‡, Jianzhong Yao ‡, Zhenyuan Miao ‡, Wannian Zhang ‡, Chunquan Sheng †,‡,*
PMCID: PMC4360171  PMID: 25815139

Abstract

graphic file with name ml-2014-00327q_0010.jpg

Designing multitarget drugs remains a significant challenge in current antitumor drug discovery. Because of the synergistic effect between topoisomerase and HDAC inhibitors, the present study reported the first-in-class triple inhibitors of topoisomerase I/II and HDAC. On the basis of 3-amino-10-hydroxylevodiamine and SAHA, a series of hybrid molecules was successfully designed and synthesized. In particular, compound 8c was proven to be a potent inhibitor of topoisomerase I/II and HDAC with good antiproliferative and apoptotic activities. This proof-of-concept study also validated the effectiveness of discovering triple topoisomerase I/II and HDAC inhibitors as novel antitumor agents.

Keywords: Evodiamine derivatives, topoisomerase I, topoisomerase II, histone deacetylase, antiproliferative activity

Over the last two decades, drug discovery has been primarily focused on the development of single-target drugs with high potency and selectivity.1 However, not all the diseases are amenable to this one disease–one target approach. Also, these drugs are not as effective as expected for the treatment of complex diseases, such as cancer. Recent evidence has shown that most single-target drugs are plagued by toxic side effects and development of resistance. To overcome these problems, designing a single drug molecule that interacts with multiple targets simultaneously and specifically is gaining considerable interests in drug discovery.2−5

Cancer offers a unique opportunity for the multivalent ligand design because of the complicated target networks and multiple cellular pathways contributing to the disease state. Epigenetic control, such as protein acetylation and deacetylation state, is regulated by histone acetyl transferases (HATs) and histone deacetylases (HDACs). Targeting HDACs represents one of the most popular approaches for tumor growth inhibition.6,7 HDACs regulate the acetylation of a diverse range of histone and nonhistone proteins, controlling the transcription and regulation of genes as well as cell proliferation, migration, death, and angiogenesis, and have been recognized as important molecular targets for cancer treatment.8,9 Two HDAC inhibitors (HDACi), SAHA (vorinostat) (Figure 1) and FK228 (romidepsin), have been approved by FDA for the treatment of the cutaneous T-cell lymphoma (CTCL).10,11 In many reports, HDACi can synergistically enhance the inhibitory effect of other antitumor agents, such as tubulin,12 Hsp90,13 EGFR,14 and topoisomerase15−17 inhibitors, to suppress proliferation and induce apoptosis in tumor cells. The synergistic effects of HDAC inhibitors with other antitumor agents can be used as a useful strategy to design multifunctional inhibitors to simultaneously interact with multiple targets with high potency and low toxicity. Among these targets, topoisomerase (Top1 and/or Top2) is a good starting point for multivalent ligand design.8,18 It was reported that the resistance to Top2 inhibitors is often concomitant with a rise in the level of Top1 expression and vice versa.19 In this regard, a single molecule able to inhibit Top1/Top2/HDAC could be helpful to prevent mechanism-based drug resistance and show more powerful antitumor activity. However, the discovery of a single molecule targeting three proteins remains a significant challenge, and no HDAC1/Top1/Top2 triple inhibitors have been reported up to date.

Figure 1.

Figure 1

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Chemical structure of SAHA, evodiamine, and dual Top1/Top2 inhibitor 1.

Evodiamine (Figure 1) is a quinazolinocarboline alkaloid isolated from the fruits of traditional Chinese herb Evodiae fructus (Chinese name: Wu-Chu-Yu) with diverse biological activities.20 In our previous study, a number of evodiamine derivatives were designed and synthesized.21,22 Among them, 3-amino-10-hydroxylevodiamine (1) showed excellent antitumor activity against a variety of cancer cell-lines with good in vivo potency in xenograft nude mice. Moreover, compound 1 was proven to be a dual Top1/Top2 inhibitor by in silico target identification in combination with biological assays. Inspired by these results, compound 1 and SAHA can be used as good templates to design triple HDAC/Top1/Top2 inhibitors.

As depicted in Figure 2, a series of novel evodiamine–SAHA hybrids were rationally designed and synthesized as triple-targeting antitumor agents. First, using a molecular hybridization strategy, compound 1 and SAHA were merged into a new hybrid molecule (7). From structure–activity relationship studies on evodiamine derivatives,21−23 substitution at the 3-amino group was tolerable. Thus, SAHA was attached at this position. Meanwhile, because of the presence of large hydrophobic patches at the HDAC surface rim, conjugating SAHA with hydrophobic antitumor agent 1 may generate potent HDAC inhibitors.24 Second, 1,2,4-oxadiazoles and 1,3,4-oxadiazoles were introduced as a proper spacer between the evodiamine scaffold and the zinc binding group of SAHA (compounds 8a–c and 9a–c). Oxadiazole was chosen as the spacer because it is a drug-like privileged structure in many therapeutic drugs and always used as a flat, aromatic linker to place substituents in the appropriate orientation for ligand binding.25 Moreover, introduction of 1,3,4-oxadiazole ring was proven to be an effective strategy to modulate lipophilicity and pharmacokinetic profiles.25 Third, our previous study indicated that the C-10 hydroxyl group of evodiamine was important in maintaining antitumor potency. In order to validate the importance of this hydroxyl group in the newly designed hybrid molecules, a series of 10-methoxyl derivatives (10a–d) were also designed and synthesized.

Figure 2.

Figure 2

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Design of triple-acting Top1/Top2/HDAC inhibitors.

The synthetic routes of the target compounds are shown in Schemes 1–4. The commercially available compound 2 was reacted with monomethyl suberate to give intermediate 4,26 which was further oxidized by pyridinium chlorochromate (PCC) to afford aldehyde 5. Treatment of compounds 5 and 1 via reductive amination reaction yielded the key intermediate 6, which was reacted with freshly prepared hydroxylamine methanol solution to give the target compound 7 (Scheme 1).

Scheme 1. Chemical Synthesis of Compound 7.

Scheme 1

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Reagents and conditions: (a) HBTU (O-benzotriazole-N,N,N,N-tetramethyl-uronium-hexafluorophosphate), Et3N, MeCN, rt, 2 h, 76%; (b) PCC, rt, 2 h, 95%; (c) NaBH3CN, THF, rt, 3 h, 46%; (d) KOH, CH3OH, 40 °C, 45 min, 89%.

Scheme 4. Chemical Synthesis of Compounds 10a–d.

Scheme 4

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Reagents and conditions: (a) HBTU, Et3N, DMF, rt, 2 h, 63–75%; (b) KOH, CH3OH, 45 °C, 45 min, 83–90%.

Similar strategy was applied for the synthesis of 1,2,4-oxadiazole-based conjugates (8a–c) (Scheme 2). Acetalization of the 4-formylbenzonitrile 11 afforded the propanediol-protected compound 12, which was treated by hydroxylamine hydrochloride in the presence of NaHCO3 and methanol to give compound 13 in good yield. Condensation of compound 13 with one of three carboxylic acid monomethyl esters under microwave conditions afforded compounds 14a–c. Deprotection of 1,3-propanediol group of 14a–c yielded the requisite aldehydes 15a–c using freshly prepared Fe(HSO4)3 solution. Then, the synthesis of target compounds 8a–c was similar to that of compound 7. Synthesis of compounds 9a–c was summarized in Scheme 3. Protection of aldehyde 17 with 1,3-propanediol gave the intermediate 18, which was reacted with hydrazine hydrate to yield compound 19. Acylation of 19 provided the amides 20a–c, which were cyclized to give key intermediates 21a–c. Then, compounds 9a–c were synthesized using conditions similar to that of compounds 8a–c. As depicted in Scheme 4, compounds 10a–d were prepared from 3-amino-10-methoxylevodiamine (24) by a two-step synthesis via the condensation and ammonolysis reaction.

Scheme 2. Chemical Synthesis of Compounds 8a–c.

Scheme 2

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Reagents and conditions: (a) propane-1,3-diol, toluene, reflux, 6 h, 95%; (b) NH2OH·HCl, NaHCO3, CH3OH, reflux, 2 h, 76%; (c) HO2C(CH2)nCO2CH3 (n = 3, 4, 6), HBTU, DIPEA, DMF, microwave, 191 °C, 2 min; (d) Fe(HSO4)3, acetone/H2O = 1:1, reflux, 1 h, 85–86%, over two steps; (e) 1, NaBH3CN, CH3OH, rt, 3 h, 45%; (f) KOH, CH3OH, 45 °C, 45 min, 90–92%.

Scheme 3. Chemical Synthesis of Compounds 9a–c.

Scheme 3

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Reagents and conditions: (a) propane-1,3-diol,toluene, reflux, 6 h, 93%; (b) N2H4·H2O, rt, 24 h, 73%; (c) HO2C(CH2)nCO2CH3 (n = 3, 4, 6), HBTU, Et3N, DMF, rt, 2 h, 72%; (d) p-toluenesulfonyl chloride, Et3N, THF, reflux, 8 h, 78%; (e) Fe(HSO4)3, acetone/H2O = 1:1, reflux, 1 h, 59–69%; (f) 1, NaBH3CN, CH3OH, rt, 3 h; (g) KOH, CH3OH, 45 °C, 45 min, 84–91%, over two steps.

Initially, we tested the inhibitory activity of the target compounds against human recombinant HDAC1 enzyme using the assay as previously described by Bradner et al.27 Generally, most compounds showed good to excellent HDAC1 inhibitory activity (Table 1). For example, compound 7 was highly active against HDAC1 (IC50 = 30 nM). Interestingly, all the 1,2,4-oxadiazole derivatives (8a–c) potently inhibited HDAC1 with IC50 values in the nanomolar range. Moreover, it was observed that the HDAC1 inhibitory activity was enhanced with the increasing of the carbon chain length (8c > 8b > 8a, 9c > 9b > 9a, and 10d > 10b > 10a) with the exception of compound 10c. Compounds 9c and 10d exhibited good anti-HDAC1 activity with the IC50 values of 89 and 64 nM, respectively. In particular, compound 8c, the best HDAC1 inhibitor (IC50 = 24 nM), showed comparable activity to SAHA (IC50 = 23 nM). To obtain evidence for the HDAC isoform selectivity, the inhibitory activity of compound 8c was examined against selected recombinant HDAC2, HDAC3, HDAC6, and HDAC8 (Table 2). Compound 8c displayed nanomolar activity against HDAC2 (IC50 = 275 nM), HDAC3 (IC50 = 71 nM), and HDAC6 (IC50 = 13 nM). In contrast, its activity against HDAC8 (IC50 = 2.5 μM) was significantly decreased. As compared with SAHA, compound 8c was more potent against HDAC6 and HDAC8.

Table 1. In VitroHDAC1 Inhibition and Antitumor Activity of Target Compounds.

compd HDAC1 IC50 (nM) MDA-MB-231 IC50 (μM) HCT116 IC50 (μM) HLF IC50 (μM)
1 NTa 0.49 ± 0.02 0.43 ± 0.03 0.47 ± 0.03
SAHA 23 ± 2.1 7.4 ± 0.65 3.7 ± 0.30 3.0 ± 0.33
7 30 ± 4.5 14 ± 1.0 2.1 ± 0.26 13 ± 1.5
8a 321 ± 21 16 ± 1.9 3.5 ± 0.39 6.7 ± 0.48
8b 190 ± 13 5.9 ± 0.43 3.7 ± 0.28 8.2 ± 0.75
8c 24 ± 3.2 2.3 ± 0.14 0.41 ± 0.03 1.3 ± 0.10
9a >10000 >168 11 ± 2.4 >168
9b 93 ± 5.7 30 ± 3.4 4.9 ± 0.32 26 ± 3.0
9c 89 ± 7.9 5.7 ± 0.61 9.7 ± 1.2 6.1 ± 0.55
10a 527 ± 45 191 ± 20 31 ± 3.1 97 ± 10
10b 275 ± 23 36 ± 3.1 22 ± 2.1 62 ± 5.6
10c >10000 58 ± 4.5 35 ± 4.1 68 ± 6.7
10d 64 ± 5.5 54 ± 5.7 20 ± 2.3 30 ± 3.8
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a

NT = not tested.

Table 2. Inhibitory Activity of HDAC6 and HDAC8.

compd HDAC2 IC50 (nM) HDAC3 IC50 (nM) HDAC6 IC50 (nM) HDAC8 IC50 (μM)
8c 275 ± 52 71 ± 6.4 13 ± 1.7 2.5 ± 0.29
SAHA 174 ± 70 56 ± 4.6 23 ± 2.1 8.8 ± 0.70
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Previously, compound 1 and other evodiamine derivatives were identified as dual Top1/Top2 inhibitors.22 Top1- and Top2α-mediated pBR322 DNA relaxation assays with purified Top1 and Top2α were used to evaluate the inhibitory activity of the target compounds. Camptothecin (CPT, Top1 inhibitor) and etoposide (Eto, Top2 inhibitor) were employed as positive controls. As shown in Figure 3A, all the tested compounds were found to be active against Top1-mediated DNA relaxation. Most of them exhibited comparable or superior Top1 inhibitory activity to CPT. The 1,2,4-oxadiazole derivatives (8a–c) showed higher Top1 inhibitory activity than CPT. The best inhibition was observed for compound 8c containing the six methylene alkyl chain. In contrast, the 10-methoxyl derivatives (10a–c) showed weak inhibitory activity, and compound 10c was almost inactive. Similarly, all the tested compounds were active against Top2 (Figure 3B). As compared to Eto, compounds 7, 8b–c, 10a, and 10c showed stronger Top2 inhibitory activity. Among them, compound 7 was the most active one. Interestingly, the activity of 1,2,4-oxadiazole derivatives was dependent on the length of the methylene chain. Reducing the alkyl chain to three carbon atoms (8a) resulted in decrease of Top2 inhibitory activity.

Figure 3.

Figure 3

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Top1 and Top2 inhibitory activity of target compounds. (A) Inhibition of Top1 relaxation activity at 50 μM. Lane 1, supercoiled plasmid DNA; Lane 2, DNA + Top1; Lane 3, DNA + Top1 + CPT (50 μM); Lanes 4–14, DNA + Top1 + compounds (1, 7, 8a–c, 9a–c, and 10a–c at 50 μM). (B) Inhibition of Top2 relaxation activity at 50 μM. Lane 1, supercoiled plasmid DNA; Lane 2, DNA + Top2; Lane 3, DNA + Top2 + Eto (50 μM); Lanes 4–14, DNA + Top2 + compounds (1, 7, 8a–c, 9a–c, and 10a–c at 50 μM). The assay was repeated 3 times.

On the basis of the above results, the hybrid compounds derived from 1 and SAHA were proven to be triple-targeting inhibitors of HDAC/Top1/Top2. Particularly, compound 8c generally exhibited the highest activity. Furthermore, we investigated the antiproliferative activities of the target compounds against MDA-MB-231 (breast cancer), HCT116 (colon cancer), and HLF (liver cancer) cell lines using parent compounds 1 and SAHA as reference drugs. The antitumor activity was determined using the standard MTT assay.21 As shown in Table 1, most of the target compounds showed moderate to good antiproliferative activity against all the three cell lines. Moreover, these compounds showed better activity against HCT116 than the other two cell lines. Increasing the length of the methylene chain of 1,2,4-oxadiazole derivatives led to the improvement of antiproliferative activities, which was closely correlated to their anti-HDAC activities. This trend was also observed in 1,3,4-oxadiazole and 10-methoxyl derivatives, respectively. In particular, compound 8c showed the most potent antitumor activity with IC50 values in the range of 0.41 to 2.29 μM. For the HCT116 cell line, compound 8c was significantly more active than the reference drug SAHA and comparable to lead compound 1. Thus, it was subjected to an apoptotic assay for further evaluation. Apoptosis was evaluated by annexin V test.22 As shown in Figure 4, compound 8c exhibited strong pro-apoptotic activity in the HCT116 cell line. After treating with 5 μM compound for 24 and 48 h, the percentage of apoptotic cells for compound 8c was 39.32% and 79.1% (Q2 + Q4), respectively. It displayed a much higher apoptosis level than compound 1 and SAHA (11.09% and 16.39% for 1 and 25.54% and 46.81% for SAHA, respectively). This result demonstrated that combination topoisomerase and HDAC inhibitor in one single molecule led to synergy at the cellular level. On the basis of the above results, compound 8c was subjected for further evaluation of cellular HDAC inhibition. The effect of the compound 8c on the acetylation level of histone 3 is shown in Figure 5. Exposure to compound 8c for 24 and 48 h induced a hyperacetylation of histone 3 in the HCT116 cell line.

Figure 4.

Figure 4

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Cell apoptosis induced by compound 1, 8c, and SAHA. HCT116 cells were treated with DMSO and 5 μM compounds for 24 and 48 h, respectively. Apoptosis was examined by flow cytometer (n = 3).

Figure 5.

Figure 5

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Western blot probing for acetylated histones H3 in the HCT116 cell line after 24 h treatment with compounds. Lanes: (1) control, (2) SAHA, 2.5 μM, (3) SAHA, 5.0 μM, (4) 8c, 2.5 μM, and (5) 8c, 5 μM.

In summary, a series of novel evodiamine/SAHA hybrids were rationally designed and synthesized on the basis of synergistic effect observed between topoisomerase and HDAC inhibitors. They were identified as the first-in-class triple inhibitors of Top1/Top2/HDAC. Notably, compound 8c was proven to be a potent inhibitor of Top1/Top2/HDAC, which also showed good antiproliferative activities and remarkable apoptotic effect. Taken together, the present study provided a proof-of-concept study for discovering inhibitors simultaneously targeting Top1/Top2/HDAC. Further evaluation and optimization of the evodiamine/SAHA hybrids are in progress.

Glossary

Abbreviations

Top1

topoisomerase I

Top2

topoisomerase II

HDAC

histone deacetylase

HDACi

HDAC inhibitors

PCC

pyridinium chlorochromate

HBTU

O-benzotriazole-N,N,N,N-tetramethyl-uronium-hexafluorophosphate

CPT

camptothecin

Eto

etoposide

Supporting Information Available

Chemical synthesis and structural characterization of the target compounds; protocols of biological assays. This material is available free of charge via the Internet at http://pubs.acs.org.

Author Contributions

§ S.H. and G.D. contributed equally to this work.

This work was supported by National Natural Science Foundation of China (Grants 81222044, 81373278), Key Project of Science and Technology of Shanghai (Grant 11431920402 and 14YF1405400), and the 863 Hi-Tech Program of China (Grant 2014AA020525) for financial support.

The authors declare no competing financial interest.

Supplementary Material

ml500327q_si_001.pdf (2.1MB, pdf)

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Supplementary Materials

ml500327q_si_001.pdf (2.1MB, pdf)

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