Design, synthesis and biological evaluation of novel indanone containing spiroisoxazoline derivatives with selective COX-2 inhibition as anticancer agents

doi:10.1016/j.bmc.2020.115960

Bioorganic & Medicinal Chemistry

Volume 32, 15 February 2021, 115960

https://doi.org/10.1016/j.bmc.2020.115960 Get rights and content

Highlights

•
Novel indanonic spiroisoxazoline derivatives were designed and synthesized.
•
Structure-activity relationships regarding COX-2 inhibition potency and cell toxicity of studied spiroisoxazoline derivatives were discussed.
•
The binding of the most potent anti-COX-2 derivative 9f into the active site of enzyme was studied by molecular docking.
•
Mechanism of induced apoptosis by compound 9f in MCF-7 cells was investigated.

Abstract

Objective

A new family of 3′-(Mono, di or tri-substituted phenyl)-4′-(4-(methylsulfonyl) phenyl) spiroisoxazoline derivatives containing indanone spirobridge was designed, synthesized, and evaluated for their selective COX-2 inhibitory potency and cytotoxicity on different cell lines.

Methods

A synthetic reaction based on 1,3-dipolar cycloaddition mechanism was applied for the regiospecific formation of various spiroisoxazolines. The activity of the newly synthesized compounds was determined using in vitro cyclooxygenase inhibition assay. The toxicity of the compounds was evaluated by MTT assay. In addition, induction of apoptosis, and expression levels of Bax, Bcl-2 and caspase-3 mRNA in MCF-7 cells were evaluated following exposure to compound 9f. The docking calculations and molecular dynamics simulation were performed to study the most probable modes of interactions of compound 9f upon binding to COX-2 enzyme.

Results

The docking results showed that the synthesized compounds were able to form hydrogen bonds with COX-2 involving methyl sulfonyl, spiroisoxazoline, meta-methoxy and fluoro functional groups. Spiroisoxazoline derivatives containing methoxy group at the C-3′ phenyl ring meta position (9f and 9g) showed superior selectivity with higher potency of inhibiting COX-2 enzyme. Furthermore, compound 9f, which possesses 3,4-dimethoxyphenyl on C-3′ carbon atom of isoxazoline ring, exhibited the highest COX-2 inhibitory activity, and also displayed the most potent cytotoxicity on MCF-7 cells with an IC₅₀ value of 0.03 ± 0.01 µM, comparable with that of doxorubicin (IC₅₀ of 0.062 ± 0.012 µM). The results indicated that compound 9f could promote apoptosis. Also, compared to the control group, the mRNA expression of Bax and caspase-3 significantly increased, while that of Bcl-2 significantly decreased upon exposure to compound 9f which may propose the activation of mitochondrial-associated pathway as the mechanism of observed apoptosis.

Conclusion

In vitro biological evaluations accompanied with in silico studies revealed that indanone tricyclic spiroisoxazoline derivatives are good candidates for the development of new anti-inflammatory and anticancer (colorectal and breast) agents.

Graphical abstract

Introduction

Selective COX-2 inhibitors, such a celecoxib, in addition to pain and inflammation treatment, showed great promise as inhibitors of tumor growth ¹ and angiogenesis 2, 3. COX-2/PGE2 pathway has been reported to play a key role in the hallmarks of cancer and adaptation to the tumor microenvironment ⁴. Moreover, COX-2 is chronically overexpressed in many premalignant, malignant, and metastatic human cancers 5, 6, 7, 8, 9, 10 such as colorectal and breast cancers ¹¹ and is an important index for the genesis of breast ¹² and colorectal cancers 13, 14. These observations have led the researchers to study specific COX-2 inhibitors as chemopreventive and potential chemotherapeutic agents. Numerous studies have shown that COX-2 inhibitors are able to inhibit tumor growth and metastasis in animal cancer models ¹⁵. New preclinical and early clinical findings suggest selective COX-2 inhibitors as potential chemoprotective agents against colon, breast, lung, esophageal and oral tumors 10, 16. For example, it has been demonstrated that aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) reduce risk of colon cancer and promote tumor regression in both humans and animal colon cancer models 17, 18.

The selective COX-2 inhibitors in the market never were free of side effects. Rofecoxib was removed from the market as of September 30, 2004 (Fig. 1) due to a higher than acceptable cardiovascular side effects and this may also happen for celecoxib for the same reason too. As a result, attempts are continuously made to develop next generation COX-2 inhibitors with different toxicity profiles, which can be used clinically as antitumor, anti-angiogenesis and chemopreventive agents ². Isoxazolines and spirocyclic isoxazoline derivatives have emerged as promising drug candidates due to their numerous biological activities, including those related to their anticancer effects 19, 20, 21, 22, 23, 24, 25, 26, 27, 28. For instance, the antibreast and antiprostate cancer activities of some spiroisoxazoline derivatives have recently been investigated by Das and co-workers ²⁹. The majority of selective COX-2 inhibitors, on the other hand, are diaryl heterocycles containing vicinal diaryl substitution ³⁰ attached to central mono ³¹, bi ³² and tricyclic ring systems.24, 25, 27 Optimum selective COX-2 inhibitory potency is often provided by SO₂NH₂ or SO₂Me substituent at the para position of one of the phenyl rings, as shown by comprehensive structure–activity relationship (SAR) studies on this class of COX-2 inhibitors ³⁰. Studies have shown that 4-spiro 1,2-diarylcyclopentens are also very potent cyclooxygenase (COX-2) inhibitors (Fig. 1) ³⁴. Thus, hybrid compounds having central spiroisoxazoline bridge are more likely to exert improved anticancer effects due to their antiproliferative and anti-inflammatory (COX-2 inhibitory) mechanisms ^23–24,26. The design, synthesis, selective COX-2 inhibitory effects and cytotoxicity evaluation as well as induction of apoptosis for a group of 3′-(Mono, di or tri-substituted phenyl)-4′-(4-(methylsulfonyl) phenyl) spiroisoxazoline derivatives containing indanone spiroisoxazoline scaffold (Fig. 1) are reported in this work.

Combination of the pharmacophoric elements from COX-2 inhibitors with added extra anticancer and anti-inflammatory properties as a result of bioisosteric replacement of the central cyclic bridge with spiroisoxazoline motif, as shown in Fig. 1, was used as the design strategy. The application of COX-2 inhibitors in the treatment of cancer and modulating multidrug resistance is still at the infancy level although these inhibitors are mainly applied as anti-inflammatory agents ³⁵.

Section snippets

Results and discussions

The synthesis and cytotoxicity evaluation of compounds 9f and 9g have been reported previously.²⁶ In the current study new NMR and biological data (COX-1 and COX-2 inhibition, cell toxicity on MCF10A and HEK293 cells, induction of apoptosis, and apoptosis-related genes regulation) were obtained for these compounds. They are included here to expand the diversity of the studied structures in relation to the aim of the current work, which is the design of COX-2 selective derivatives with cytotoxic

Conclusion

New indanone containing spiroisoxazoline derivatives were designed, synthesized and evaluated for their COX enzymes inhibition and cell toxicity. The interaction modes of the studied compounds with COX enzymes were examined using molecular docking. The findings of the current study support the notion that compounds, which fit better within the active site of COX-2 enzyme (shown in the docking studies) and are more effective inhibitors of COX-2 enzyme, show higher cytotoxicity on cancerous

Materials and method

A Thomas Hoover capillary apparatus (Philadelphia, USA) was used to measure melting points (mp) HPTLC spectra which was used to assess the purity of the compounds, were recorded by winCATS Planar Chromatography Manager. A Perkin-Elmer 1420 ratio spectrophotometer was used to record infrared spectra. ¹H NMR (CDCl₃, 500 MHz) and ¹³C NMR (CDCl₃, 100 MHz) spectra were recorded by a Bruker fourier transform (FT)-NMR spectrometer (Bruker Biosciences, USA). Chemical shifts are reported as δ (ppm)

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

Research Office, Biotechnology Research Center and School of Pharmacy at Tabriz University of Medical Sciences, Research Deputy of Shahid Beheshti University of Medical Sciences and Cellular and Molecular Research Center and School of Medicine of Qom University of Medical Sciences (Project Code:94640 and Specific code of the Research Ethics Committee: IR.MUQ.REC.1394.155) are gratefully acknowledged for providing financial support.

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Design, synthesis and biological evaluation of novel indanone containing spiroisoxazoline derivatives with selective COX-2 inhibition as anticancer agents

Highlights

Abstract

Objective

Methods

Results

Conclusion

Graphical abstract

Introduction

Section snippets

Results and discussions

Conclusion

Materials and method

Declaration of Competing Interest

Acknowledgements

Bioorg Med Chem Lett

Semin Oncol

Gastroenterology

Arabian J Chem

Tetrahedron Lett

Tetrahedron Lett

Bioorg Med Chem

Bioorg Med Chem Lett

Eur J Med Chem

Eur J Surg Oncol

J Surg Res

J Mol Biol

The role of cyclooxygenase-2 in cell proliferation and cell death in human malignancies

Int J Cell Biol

COX-2 Inhibition Potentiates Antiangiogenic Cancer Therapy and Prevents Metastasis in Preclinical Models

Sci Transl Med

The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment

Carcinogenesis

COX-2 inhibitors in cancer treatment and prevention, a recent development

Anticancer Drugs.

Cyclooxygenase-2 expression is abundant in alveolar type II cells in lung cancer-sensitive mouse strains and in premalignant lesions

Carcinogenesis

Cyclooxygenase-2 is overexpressed in human cervical cancer

Clin Cancer Res

Cytoplasmic induction and over-expression of cyclooxygenase-2 in human prostate cancer: implications for prevention and treatment

BJU International.

Over-expression of COX-2 mRNA in colorectal cancer

BMC Gastroenterol.

Potential role of selective COX-2 inhibitors in cancer management

Oncology (Williston Park).

Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer

Cancer Res

Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2

Nat Rev Cancer