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
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.
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 (ppm) values but the aldehydic protons of 2a-Z-CHO and 2a-E-CHO resonated at 9.93 (ppm) and 9.60 (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).
References (53)
- et al.
Construction of efficient blue AIE emitters with triphenylamine and TPE moieties for non-doped OLEDs
J Mater Chem C
(2014) - et al.
New angular-shaped and isomerically pure anthradithiophene with lateral aliphatic side chains for conjugated polymers: synthesis, characterization, and implications for solution-prossessed organic field-effect transistors and photovoltaics
Chem Mater
(2012) - et al.
Azobenzene Photomechanics: Prospects and potential applications
Polym Bull
(2012) - et al.
Fluorescence behavior of bis(cyanostyryl)pyrrole derivatives depending on substituent position of cyano groups in solution and in solid state
J Org Chem
(2019) - et al.
Cu(OAc)2.H2O-catalyzed N-arylation of nitrogen-containing heterocycles
Tetrahedron
(2011) - et al.
Luminescent metal organic frameworks for chemical sensing and explosive detection
Chem Soc Rev
(2014) - et al.
Recent progress in the development of fluorescent, luminescent and colorimetric probes for detection of reactive oxygen and nitrogen species
Chem Soc Rev
(2016) - et al.
Metal-organic frameworks for luminescence thermometry
Chem. Commun.
(2015) - et al.
Efficient and tunable white-light emission of metal–organic frameworks by iridium-complex encapsulation
Nat Commun
(2013) - et al.
A luminescent microporous metal–organic framework for the fast and reversible detection of high explosives
Angew Chem Int Ed
(2009)
Vapor phase detection of nitroaromatic andnitroaliphatic explosives by fluorescence active metal organic frameworks
Cryst Eng Comm
Achieving exceptionally high luminescence quantum efficiency by immobilizing an AIE molecular chromophore into a metal-organic framework
Chem. Commun.
Metal-organic frameworks: functional luminescent and photonic materials for sensing applications
Chem Soc Rev
Aggregation-induced emission of 1-methyl-1,2,3,4,5-pentaphenylsilole
Chem. Commun.
Efficient blue emission from siloles
J Mater Chem
Aggregation-induced emission: together we Shine, united we soar
Chem Rev
Aggregation-induced emission
Chem Soc Rev
Click synthesis, aggregation-induced emission, E/Z isomerization, self-organization, and multiple chromisms of pure stereoisomers of a tetraphenylethene-cored luminogen
J Am Chem Soc
Synthesis, light emission, nano aggregation, and restricted intramolecular rotation of 1,1-substituted 2,3,4,5-tetraphenylsiloles
Chem Mater
Understanding the pressure-induced emission enhancement for triple fluorescent compound with excited-state intramolecular proton transfer
J Phys Chem
Switching of non-helical overcrowded tetrabenzohepta- fulvalene derivatives
Chem Sci
Structural changes accompanying intramolecular electron transfer: focus on twisted intramolecular charge-transfer states and structures
Chem Rev
Modulation of fluorescent protein chromophores to detect protein aggregation with turn-on fluorescence
J Am Chem Soc
Study of aggregation induced emission of cyano-substituted oligo (p-phenylenevinylene) by femtosecond time resolved fluorescence
Spectrochim Acta Part A: Mol Biomol Spectrosc
Aggregation‐induced emission: the whole is more brilliant than the parts
Adv. Mater.
Efficient non-doped near infrared organic light-emitting devices based on fluorophores with aggregation-induced emission enhancement
Chem Mater
Tuning the electronic nature of aggregation-induced emission luminogens with enhanced hole-transporting property
Chem Mater
An efficient AIE-active blue-emitting molecule by incorporating multifunctional groups into tetraphenylsilane
Chem Eur J
An AIE-active hemicyanine fluorogen with stimuli-responsive red/blue emission: extending the pH sensing range by “switch + knob” effect
Chem Sci
Cited by (8)
Computational insights into E/Z isomerism of fluoxastrobin, an antifungal agent: A DFT/TD-DFT study
2023, Journal of Molecular StructureAn efficient multicomponent synthesis, characterization, SAR, In-silico ADME prediction and molecular docking studies of 2-Amino-7-(substituted-phenyl)-3-cyano-4-phenyl-4,5,6,7-tetrahydropyrano[2,3-b] pyrrole-5-carboxylic acid derivatives and their in-vitro antimicrobial activity
2023, Journal of Molecular StructureCitation Excerpt :In addition, pyrrole structural motif appears in a large number of natural products [36] (Fig. 1 and 2). Among many privileged classes of five-membered aza-heterocycles, pyrrolidine derivatives are highly valuable compounds with a wide range of activities such as anti-microbials [37,38], antagonists [39], cholinesterase inhibitors [40], anti-inflammatory agents [41,42], anti-diabetic agents [43], Mcl-1 inhibitors [44], anti-mycobacterial [45–48], anti-tumor agents [49,50], anti-convulsant agents [51,52] and anti-cancer agents [53]. These compounds are also known for prominent sphingosine-1-phosphate (S1P) receptor agonists [54,55], Malic enzyme Inhibitors [56], ketoamide-based cathepsin K inhibitors [57] and human melanocortin-4 receptor agonists [58] (Fig. 3).
Vilsmeier Haack Reaction: An Exemplary Tool for Synthesis of different Heterocycles
2024, Letters in Organic Chemistry