Synthesis and biological evaluation of novel bavachinin analogs as anticancer agents

doi:10.1016/j.ejmech.2018.01.006

European Journal of Medicinal Chemistry

Volume 145, 10 February 2018, Pages 511-523

https://doi.org/10.1016/j.ejmech.2018.01.006 Get rights and content

Highlights

•
Synthesis of 28 Bavachinin derivatives.
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Several derivatives were active against human cancer cell lines.
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The molecules inhibits the colony formation and restrict the migration of HCT-116 cells.
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The molecule induced the morphological changes and mediated the apoptotic cell death of HCT-116 cells.

Abstract

A library of 28 analogs of bavachinin including aliphatic and aromatic ethers, epoxide, chalcone, oxime, semicarbazide, oxime ether and triazole derivatives have been synthesized and evaluated for cytotoxicity against four different human cancer cell lines. Bio-evaluation studies exhibited better cytotoxic profile for many analogs compare to bavachinin. Best results were observed for a 1,2,3-triazole analog (17i) with IC₅₀ values 7.72, 16.08, 7.13 and 11.67 μM against lung (A549), prostate (PC-3), colon (HCT-116) and breast (MCF-7) cancer cell lines respectively. This analog showed three and four fold improvement in cytotoxicity against HCT-116 and A549 cell lines than parent molecule (1). Structure activity relationship (SAR) study for all synthesized analogs was carried out. Further, mechanistic study of the lead molecule (17i) revealed that it inhibits colony formation and in vitro migration of human colon cancer cells (HCT-116). Also, it induced the morphological changes and mediated the apoptotic cell death of HCT-116 cells with perturbance in mitochondrial membrane potential (MMP) and PARP cleavage.

Graphical abstract

Design and synthesis of bavachinin analogues as potent cytotoxic agents.

Introduction

Flavanoids are one of largest classes of polyphenolic compounds that occur naturally in plants which possess broad spectrum of biological activities and are considered as suitable therapeutic agents against cancer. They generally possess a phenylbenzopyrone structure (C6-C3-C6) consisting of two aromatic rings, A and B connected by a central pyran ring C. The saturation level and opening of central pyran ring categorize various classes of flavonoids namely flavones, flavonols, isoflavones, flavanols, flavanones and flavanonols [1,2]. Unlike other flavonoids, flavanones like bavachinin 1, hesperetin 2 and naringenin 3 (Fig. 1) have been potential sources to search for new leads in the area of cancer therapy [3,4].

The seeds of Psoralea corylifolia are major source of bavachinin [5] and exhibit diverse pharmacological activities including anticancer [3], PPAR agonist [6], anti-inflammatory [7], anti-alzheimer [8] and immunomodulatory [9]. Cytotoxic effects of bavachinin have also been studied on various cancer cell lines [3,10] and possess 20 S proteasome inhibitory activity that inhibits the signaling action of NFκB leading to cell death via apoptosis [11]. Beside this bavachinin also inhibited in vitro migration of human KB cells and during in vivo studies in nude mice with KB xenografts, it significantly reduced tumor volume and CD31 expression [12]. Bavachinin 1 nucleus is capable of undergoing suitable chemical transformation studies at various key positions available on molecule (Fig. 1). Several bavachinin derivatives have synthesized and reported for their different biological activities. Chen et al. prepared bavachinin derivatives 4 and 5 via biotransformation to study their T cell differentiation effects [13]. Dai et al. reported anticancer activity of bavachinin and its enzymatically synthesized glucoside 6 [14] while Du et al. reported PPAR-γ agonist activity of several bavachinin analogs among which compounds 7 and 8 were found as most potent derivatives [15] (Fig. 2). However, further investigation is desired to develop the potent anticancer agents based on bavachinin.

Therefore, the natural product bavachinin was isolated in bulk quantity from the seeds of Psoralea corylifolia for synthesis of its analogs being our interest in isolation and structural modification of natural products for drug discovery of potent analogs in the area of anticancer [[16], [17], [18], [19]]. Further the synthesized analogs were screened for cytotoxicity against four different human cancer cell lines (A549, PC3, HCT-116 and MCF-7). The most active compound was taken further to study its cytotoxic mode of action.

Section snippets

Chemistry

Bavachinin 1 was isolated in gram quantities from the seeds of P. corylifolia and was used for structural modification studies. The configuration at C-2 an asymmetric center in the molecule was observed (S) based on NOESY (Fig. S1) which was also confirmed by comparing the observed specific rotation value [α]_D = −20 (c = 1.0, CHCl₃) with literature [5,20]. Different analogs of bavachinin 1 were synthesized with modifications at ring A, B, C and prenyl chain of the molecule (Fig. 3) as shown in

Conclusion

In conclusion, a novel library of 28 analogs of bavachinin was synthesized and evaluated for cytotoxicity against a panel of four different human cancer cell lines namely lung (A549), prostate (PC-3), colon (HCT-116) and breast (MCF-7) along with the parent molecule. Cytotoxicity results revealed that many compounds exhibit significant cytotoxic effects against different cancer cell lines. More significantly, compounds 13, 14 and 17i were found to be promising derivatives with IC₅₀ < 20 μM

Chemistry

All the reagents and solvents used for isolation, purification and synthesis were purchased from Sigma-Aldrich/E. Merck. All chemical reactions were monitored by TLC on silica gel 60 F₂₅₄ plates (E. Merck) using 2% ceric ammonium sulphate solution as spraying reagent for detection of spots. All synthesized derivatives were purified by column chromatography using silica gel 60–120 mesh as stationary phase. NMR spectra were recorded on Bruker DPX 400 and DPX 500 instruments using CD₃OD,

Acknowledgement

Council of Scientific and Industrial Research (CSIR), New Delhi is well acknowledged for funding support 12th FYP project (BSC-0108). Authors (NG, AQ and AR) are greatly thankful to CSIR-New Delhi for providing the senior research fellowships. The authors are also thankful to the staff of instrumentation division of our institute for recording the spectroscopic (NMR and HRMS) data. IIIM cummunication no. IIIM/2168/2017

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Research paperSynthesis and biological evaluation of novel bavachinin analogs as anticancer agents

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Chemistry

Conclusion

Chemistry

Acknowledgement

Eur. J. Med. Chem.

J. Food Compos. Anal.

FEBS Lett.

Phytomedicine

Eur. J. Pharmacol.

Int. Immunopharm.

Eur. J. Med. Chem.

Steroids

Bioorg. Med. Chem. Lett

Tetrahedron Lett.

Eur. J. Med. Chem.

J. Biosci. Bioeng.

Eur. J. Med. Chem.

Eur. J. Med. Chem.

Med. Res. Rev.

Eur. J. Nutr.

Research paper
Synthesis and biological evaluation of novel bavachinin analogs as anticancer agents