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. 2018 Dec 18;10(4):571–576. doi: 10.1021/acsmedchemlett.8b00596

Investigating the Anticancer Activity of Isatin/Dihydropyrazole Hybrids

Rita Meleddu †, Vilma Petrikaite ‡,§, Simona Distinto †,*, Antonella Arridu †, Rossella Angius ∥, Lorenzo Serusi †, Laura Škarnulytė ‡, Ugnė Endriulaitytė ‡, Miglė Paškevičiu̅tė ‡, Filippo Cottiglia †, Marco Gaspari ⊥, Domenico Taverna ⊥, Serenella Deplano †, Benedetta Fois †, Elias Maccioni †
PMCID: PMC6466827  PMID: 30996798

Abstract

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A series of isatin–dihydropyrazole hybrids have been synthesized in order to assess their potential as anticancer agents. In particular, 12 compounds were evaluated for their antiproliferative activity toward A549, IGR39, U87, MDA-MB-231, MCF-7, BT474, BxPC-3, SKOV-3, and H1299 cell lines, and human foreskin fibroblasts. Four compounds exhibited interesting antiproliferative activity and were further examined to determine their EC50 values toward a panel of selected tumor cell lines. The best compounds were then investigated for their induced mechanism of cell death. Preliminary structure–activity relationship indicates that the presence of a substituent such as a chlorine atom or a methyl moiety in position 5 of the isatin nucleus is beneficial for the antitumor activity. EMAC4001 proved the most promising compound within the studied series with EC50 values ranging from 0.01 to 0.38 μM.

Keywords: Anticancer agents, isatin-dihydropyrazole hybrids, apoptosis inducers

Several anticancer chemotherapeutic agents act by causing cell death either by directly inhibiting the synthesis of DNA or by interfering with its function. Unfortunately, they are generally not specific for tumor cells and are therefore associated with high toxicity. Not surprisingly, nowadays, the focus of the scientific community is oriented toward the development of new target-directed, more specific cytotoxic agents. Such agents must be able to inhibit or modulate identified molecular targets that are involved in the control of cancer cells, such as signal transduction, apoptosis, transcription regulation, matrix invasion, and angiogenesis. Our research group is currently involved in several projects regarding the design and synthesis of anticancer agents directed toward several targets such as human carbonic anhydrases (hCA),1−5 DNA G-quadruplex, and hCA/COX2 dual inhibitors.6−9 However, it is commonly recognized that cancer is a complex multifactorial disease and, therefore, cannot be treated with a single drug therapy. Accordingly, new agents, combining diverse pharmacophores in a single hybrid molecule, might represent a goal for the treatment of cancer and indeed a big effort has been put into the identification of anticancer multitarget hybrid agents.10−18 In this respect, isatin is commonly recognized as a privileged scaffold in drug design.2,19−24 Moreover, it is a highly represented structural motif in kinase inhibitor anticancer drugs (Figure 1).25−28 The structure–activity relationships of the isatin based multikinase inhibitor nintedanib, as well as its drug development to phase III clinical trial, has been recently reported.28 More in detail the relevant role of the isatin nitrogen and of the carbonyl group in positions 1 and 2, as H-bond donor and acceptor network, was outlined. However, with respect to the structurally similar, multikinase inhibitor sunitinib, the isatin nucleus was, in this case, decorated by a methoxycarbonyl group in position 6, instead of a fluorine atom in position 5. On this basis, we have synthesized a new series of dihydropyrazole isatin dihydrothiazole hybrids EMAC4000, 4001, 4003, 4005, 4007, 4008, 4011, 4012, 4014, 4015, 4018, and 4019 to evaluate their activity toward diverse cancer cell lines. Analogous compounds have been previously reported, and the most relevant structural features that are essential or beneficial for the activity have been outlined.23

Figure 1.

Figure 1

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Structurally related multikinase inhibitor sunitinib (VEGFR, PDGFR, KIT, RET), nintedanib (VEGFR, EGFR, PDGFR), and EMAC4000, 4001, 4003, 4005, 4007, 4008, 4011, 4012, 4014, 4015, 4018, and 4019 derivatives.

Prompted by these observations, we aimed to further investigate the effect of both the introduction of diverse substituents on the isatin nucleus and of the replacement of the naphthalen-2-yl group with a thiazol-2-yl ring on the biological activity. EMAC compounds were synthesized slightly modifying previously reported methods (Scheme 1).2,29

Scheme 1. Synthetic Pathway to Compounds EMAC4000, 4001, 4003, 4005, 4007, 4008, 4011, 4012, 4014, 4015, 4018, and 4019.

Scheme 1

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Reagents and conditions: (i) 2-acetylnaphtalene or 2-acetylthiophene, ethanol, NaOH 10% water solution, 0 °C; (ii) thiosemicarbazide, ethanol, KOH 5%, reflux; (iii) ethyl bromoacetate, R-isatin, dry sodium acetate, acetic acid, reflux.

Briefly, an ethanol solution of 2-acetylnaphthalene (for the synthesis of EMAC4000, 4001, 4003, 4005, 4007, 4008) or 2-acetylthiophene (for the synthesis of EMAC4011, 4012, 4014, 4015, 4018, 4019) was reacted at 0 °C with an equimolar amount of 4-methoxybenzaldehyde in the presence of 1.2 equiv of sodium hydroxide 10% water solution. The obtained solids were crystallized from ethanol. The obtained diarylpropenones were reacted with thiosemicarbazide in refluxing ethanol by adding a freshly prepared KOH 5% ethanol solution. The formation of the dihydrothiazole ring and the condensation of the substituted isatin was accomplished in a single three component step. The 3,5-diaryldihydropyrazole, ethyl bromoacetate, and the appropriate isatin derivative were refluxed in acetic acid in the presence anhydrous sodium acetate to give the desired products EMAC4000, 4001, 4003, 4005, 4007, 4008, 4011, 4012, 4014, 4015, 4018, and 4019.

All compounds were characterized by means of analytical and spectroscopic methods (SI, Tables S1 and S2, and Figures S2–S36) and then evaluated for their ability to inhibit tumor cell growth. First, the activity of the new derivatives was evaluated for antiproliferative activity in the MTT assay at a fixed concentration of 10 μM toward a panel of nine human cancer cell lines, namely A549 (lung carcinoma), IGR39 (melanoma), U87 (glioblastoma), MDA-MB-231 (triple-negative breast cancer), MCF-7 (breast adenocarcinoma), BT474 (invasive ductal carcinoma), H1299 (non-small-cell lung carcinoma), SKOV-3 (ovarian cancer), and BxPC-3 (pancreatic adenocarcinoma) cell lines, and human foreskin fibroblasts. When tested toward cancer cell lines, some of the compounds exhibited antiproliferative activity (Table 1). In particular, compounds bearing a 2-naphthyl substituent in position 3 of the dihydropyrazole ring were generally more active than their corresponding 2-thiophenyl analogues. Although with some differences, compounds EMAC4001, EMAC4007, and EMAC4008 were found to be the most active toward the entire cell panel.

Table 1. Antiproliferative Activity of Compounds EMAC4000, 4001, 4003, 4005, 4007, 4008, 4011, 4012, 4014, 4015, 4018, and 4019 at 10 μM concentration.

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Interestingly, EMAC4012 and EMAC4019 were the most active within the 2-thiophenyl series when tested on IGR39 and U87 and IGR39, respectively, with antiproliferative activity comparable to that of the 2-naphthyl analogues. Nevertheless, it should be noted that these derivatives are the analogues of the two most potent compounds of the 2-naphthyl series EMAC4001 and EMAC4008, indicating that the presence of the 5-chloro or of its isostere 5-CH3 substituent is optimal for the antiproliferative activity within this class of compounds. Prompted by these encouraging results, we measured the EC50 values of the most active compounds of the 2-naphthyl series, EMAC4001, EMAC4007, and EMAC4008, and of the best performing derivative within the 2-thiophenyl series, EMAC4012, on a panel of selected cancer cell lines (Table 2).

Table 2. EC50 Values of EMAC4001, EMAC4007, EMAC4008, and EMAC4012 toward a Panel of Selected Tumor Cells.

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All compounds exhibited EC50 values in the low micromolar to high nanomolar range. EMAC4001 was the most potent within all the tested compounds with EC50 values ranging from 0.01 μM against H1299 to 0.38 μM against U87 cells (Table 2). The substitution of the 2-naphthyl moiety with the 2-thiophenyl group in the position 3 of the dihydropyrazole ring in EMAC4012 led to an evident decrease of the potency and to EC50 values of 2.97 μM and 5.76 μM toward IGR39 and U87 cell lines, respectively. Interestingly, when tested on A549, IGR39, and U87, EMAC4008 exhibited the highest activity compared with compounds EMAC4001, EMAC4007, and EMAC4012, with EC50 values of 0.18 μM, 0.14 μM, and 0.23 μM, respectively. On the basis of these results, it can be observed that the 5-Cl-isatin is generally the most efficient, but at least in some cases, its isosteric replacement with the 5-CH3-isatin is well tolerated or even more advantageous. Furthermore, to better characterize the biological behavior of these derivatives, we investigated the mechanism of cellular death when the cells are treated with half of the EC50 concentration of compounds EMAC4001 and EMAC4008. Results are presented in Figure 2, and the percentage of apoptotic and necrotic cells is reported in Figure 3.

Figure 2.

Figure 2

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Visualization of apoptotic (bright blue) and necrotic (red) cells after treatment with 1/2 EC50 of EMAC4001 and EMAC4008.

Figure 3.

Figure 3

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(a) Percentage of necrotic cells after treatment with 1/2 EC50 of EMAC4001 and EMAC4008. (b) Percentage of apoptotic cells after treatment with 1/2 EC50 of EMAC4001 and EMAC4008.

Results were more than encouraging. In all three considered cell lines, the percentage of apoptotic cells ranges between 13.5% and 27%. Conversely, when the number of necrotic cells is considered, EMAC4001 or EMAC4008 induced necrosis of less than 1% of the cell population. Results show that tested compounds induce cell death mostly through apoptosis. Overall these results indicate that a specific mechanism, such as the inhibition of a signaling pathway, might be the target of EMAC derivatives.

Although further studies are needed to clarify and identify the exact mechanism of action of such derivatives, our data indicate that the hybridization of 5-chloroisatin with 3,5-diaryldihydropyrazoles by the interposition of a dihydrothiazole spacer is a promising approach to the identification of anticancer agents. With this information in our hand, we are encouraged to further investigate these scaffolds in order to optimize their activity and pharmacokinetic properties.

Acknowledgments

The authors acknowledge the “Ufficio Valorizzazione dei Risultati della Ricerca” of Sardegna Ricerche Technological Park, Pula (CA), Italy. The authors also thank the COST action CA15135 (Multitarget Paradigm for Innovative Ligand Identification in the Drug Discovery Process MuTaLig) for support.

Glossary

Abbreviations

hCA

human carbonic anhydrase

COX2

cyclooxygenase2

VEGFR

vascular endothelial growth factor

PDGFR

platelet-derived growth factor receptor

KIT

Mast/stem cell growth factor receptor

RET

proto-oncogene tyrosine-protein kinase receptor

MTT

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.8b00596.

  • Experimental procedures and compound characterization (PDF)

Author Contributions

∇ R.M. and V.P. contributed equally. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.

Supplementary Material

ml8b00596_si_001.pdf (2.4MB, pdf)

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Supplementary Materials

ml8b00596_si_001.pdf (2.4MB, pdf)

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