Elsevier

Dyes and Pigments

Volume 184, January 2021, 108733
Dyes and Pigments

Stereoselective synthesis of E, E / E, Z isomers based on 1-(4- iodophenyl)-2,5-divinyl-1H-pyrrole core skeleton: A configuration-controlled fluorescence characteristics and highly selective anti-cancer activity

https://doi.org/10.1016/j.dyepig.2020.108733Get rights and content

Highlights

  • This work is a first example to stereoselective synthesis of 1-(4-iodo phenyl)-2,5-divinyl-1H-pyrrole E, E / E, Z isomers.

  • The E, E isomers proved to be excellent luminescent compounds, while E, Z isomer of 2a displayed better anticancer activity.

  • A strategy was developed to utilize the impact of configuration on fluorescence characteristics and anti-cancer activity.

Abstract

The E and Z isomeric intermediates based on ethyl/methyl-2-cyano-3-(5-formyl-1-(4-iodo-phenyl)-1H-pyrrol-2-yl)acrylate have been synthesized and these intermediates (E or Z) were further stereo-selectively converted into their respective E, E or E, Z isomers of diethyl/dimethyl-3,3'-(1-(4-iodophenyl)-1H-pyrrole-2,5-diyl)bis (2-cyanoacrylate) at the first time. The E, E isomers of both 2a and 3a, in solid state displayed higher quantum efficiency with longer fluorescent lifetime as compared to E, Z isomers. Notably, the E, E isomers proved to be better AIEs while, E, Z isomer of 2a has eminent anticancer activity against human nasopharyngeal carcinoma. A simple and straight forward strategy has been firstly developed to utilize the impact of configuration on fluorescence and anti-cancer activity.

Graphical abstract

Noval E, E/E, Z isomers based on 1-(4-iodo phenyl)-2,5-divinyl-1H-pyrrole core skeleton, have been stereoslectively synthesized and easily separated. The comparative study shown that upon aggregation the E, E isomers shown remarkable AIE characteristics and exhibited higher quantum efficiency in solid state. Notable, the 2a-E, Z is highly active against cancer as compared to E, E isomers. A simple and straightforward strategy has been developed to utilize the impact of configuration on fluorescence characteristics and anti-cancer activity.

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Introduction

Over the past few years, organic luminescent material got considerable attention due to their tunable emitting color and utility in sensors, bioimaging and lighting devices [[1], [2], [3], [4], [5], [6], [7], [8]]. Majority of aromatic organic luminophore exhibited good emission in solution phase but the π-π stacking interactions in aggregation or solid phase make them non-emissive and the phenomenon is known aggregation-caused quenching (ACQ). Contrary to this, some of chromophores which are non-emissive in dilute solutions, exhibited excellent emission in aggregated, solid or crystalline phase under the phenomenon of aggregation induced-emission (AIE) and crystallization induced-emission (CIE) [9,10].

Generally, the molecules which have strained structures exhibited the phenomenon of aggregation induced emission (AIE) [11]. According to that concept, a number of mechanism have been put forward to understand the phenomenon of AIE, such as E/Z isomerization (EZI) [12], restricted intramolecular rotation (RIR) [13,14], restricted intramolecular vibration (RIV) [15] and intramolecular charge transfer [16], etc. Although the restricted intramolecular rotation (RIR) and vibration (RIV) are considered to be the root cause of AIE [17].

TPEs is particular example among the luminogens which exhibit the phenomenon of AIE and CIE due to which reasons, these having variety of applications in optoelectronic [[18], [19], [20], [21]], biosensors [22,23], bioimaging [24] and fluorescent chemo sensors [25]. During past years, synthesis of configurational isomers has got tremendous attention of researchers due to vital role in medical [26,27] and chemical fields [[28], [29], [30], [31], [32], [33], [34], [35], [36], [37]]. Although E and Z isomers comprising same molecular formula but exhibiting quite distinguishable characteristics due to variable geometrical position [[38], [39], [40]]. In this aspect, the distinct behavior in two isomeric forms E-DPYDPE and Z-DPYDE of Dipyrroleyldiphenylethene have been studied where E-isomer exhibited AIE while Z-isomer shown CIE as shown in Fig. 1a [41]. Recently, Wanli Tian et al. explored the remarkably distinguished characteristics of TPE based E and Z isomers with respect to PL emission, fluorescence life time, piezofluoro-chromisim and thermal stability [42]. Furthermore, the inner (i-DCSP) and outer (o-DCSP) isomers (Fig. 1b) depending on the position of cyno group of the distyrylpyrole derivatives were explored with respect to the fluorescence properties. The inner isomer exhibited higher quantum efficiency as compared to outer one in solution phase and pattern was reversed in crystalline and nano-particles form [43]. Zheng et al. explored the stereoselective bioactivity of isomers (2R,4S)-difenoconazole [44].

Synthesis of anti-cancer drugs is a crucial field of chemistry. During past years, a number of studies have been conducted to prepare AIE dots for anticancer activity and tumor cell imaging [[45], [46], [47], [48], [49]]. One of well-known and frequently used chemotherapeutic complex, cisplatin (cis-dichlorodiamineplatinum (II)) showed excellent anticancer activity while it's trans isomer didn't work [50].

Later, cisplatin complex was used to synthesize an AIES photosensitizer-based prodrug to check the drug activity and to inhibit the cisplatin resistant cancer cells under the combine effect of photodynamic therapy and chemotherapy [51]. Organotin derivatives are also vastly explored as anti-proliferative agents comprising of carboxylate ligand and cyno group. The photophysical properties of –CN group have been extensively studied due to its high electron withdrawing capacity which also made it capable to deep tissue penetration. It can also provide the acidic medium that is favorable for deprotonation which in turn enhance the binding affinity with metals. The carboxylate moiety might assist the organotin derivatives to penetrate across the cell membrane and alkyl chains prone to be lipophilic which can increase the solubility [52].

It is evident from above discussion that the change in configuration affects the photophysical and biochemical properties of luminophore. Considering the disparate behaviors of isomers as well as the vital role of –CN and carboxylate substituent in the synthesis of anti-cancer drugs, we have synthesized E, E and E, Z isomers of Diethyl- 3,3'-(1-(4-iodophenyl)-1H-pyrrole-2,5-diyl)bis(2-cyanoacrylate), Dimethyl-3,3'-(1-(4-iodo -phenyl)-1H-pyrrole-2,5-diyl)bis(2-cyanoacrylate) and explore the effect of configurations on the luminescent properties and anti-cancer activities. We successfully synthesized and separated the pure isomers, which exhibited distinguishable photoluminescent behaviors and anti-cancer activities. The chemical structures of isomers are shown in Fig. 1c.

Section snippets

Synthesis

Synthesis of isomers is clearly descripted in Scheme 1. Compound 1 is synthesized through the method reported in literature in 70–75% yield [53]. Compound 2a-Z and 3a-Z was prepared by the Knoevenagel condensation reaction of 1 with ethyl cyanoacetate and methyl cyanoacetate respectively. The compound 2a-Z and 3a-Z were used as starting material to prepare the intermediates 2a-Z-CHO, 2a-E-CHO and 3a-Z-CHO, 3a-E-CHO using POCl3 and DMF under Vilsmeier-Haack reaction. After series of operation we

1H NMR

The 1H NMR spectra were recorded in CDCl3 on 600 MHz spectrometer. The spectra of compounds 2a-Z, 3a-Z, 2a-Z-CHO, 2a-E-CHO, 3a-Z-CHO, 3a-E-CHO, 2a-E, Z, 2a-E, E, 3a-E, Z and 3a-E, E are given in supporting information. In the spectral profile of 2a-Z-CHO and 2a-E-CHO intermediates, the protons of CH3-and CH2- in COOEt group resonated at almost same δ (ppm) values but the aldehydic protons of 2a-Z-CHO and 2a-E-CHO resonated at 9.93 δ (ppm) and 9.60 δ (ppm) respectively. The olefinic protons of

MTT assay

Cells were seeded in 96-well plate (Falcon). Different concentrations of compounds were added to the medium and incubated for 3 days. Cell viability was determined by MTT assay. Briefly, MTT was dissolved and sterilized in PBS at 5 mg/mL and 10 μL was added into each cavity. The plates were incubated in an incubator (37 °C, 5% CO2) for 4 h, and then the entire medium was removed. DMSO (100 μL) was into each cavity to dissolve the dark blue crystal, and the plate was shaken gently for 5 min.

Conclusion

We successfully synthesized the E, E/E, Z isomers of Diethyl- and dimethyl-3,3'-(1-(4-iodophenyl)-1H-pyrrole-2,5-diyl)bis (2-cyanoacrylate). We explored the photochemical characteristics and anti-cancer activity of E, Z and E, E isomers comparatively. The E, E isomers of both 2a and 3a in THF exhibited bathochromic shift about 49 nm in absorption and 30 nm in emission spectra from their respective E, Z isomers. In solid state, the 2a-E, E and 3a-E, E exhibited red shift of 24 nm, 77 nm

CRediT authorship contribution statement

Majeed Irfan: Investigation, Resources, Methodology, Data curation, Writing - original draft, Formal analysis. Rong Deng: Resources. Idrees Sumra: Resources. Xiao-Feng Zhu: Resources. Tingting Liu: Project administration, Funding acquisition, Supervision. Zhuo Zeng: Project administration, Funding acquisition, Supervision.

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.

Acknowledgement

The authors gratefully acknowledge the support of Scienceand Technology Planning Project of Guangdong Province (2017A010103017), National Natural Science Foundation of China (51703069, 21272080), Special Innovation Projects of Common Universities in Guangdong Province (20178S0182).

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