Applications of Pyrrole and Pyridine-based Heterocycles in Cancer Diagnosis and Treatment.

BACKGROUND: The escalation of cancer worldwide is one of the major causes of economy burden and loss of human resources. According to the American Cancer Society, there will be 1,958,310 new cancer cases and 609,820 projected cancer deaths in 2023 in the United States. It is projected that by 2040, the burden of global cancer is expected to rise to 29.5 million per year, causing a death toll of 16.4 million. The hemostasis regulation by cellular protein synthesis and their targeted degradation is required for normal cell growth. The imbalance in hemostasis causes unbridled growth in cells and results in cancer. The DNA of cells needs to be targeted by chemotherapeutic agents for cancer treatment, but at the same time, their efficacy and toxicity also need to be considered for successful treatment. OBJECTIVE: The objective of this study is to review the published work on pyrrole and pyridine, which have been prominent in the diagnosis and possess anticancer activity, to obtain some novel lead molecules of improved cancer therapeutic. METHODS: A literature search was carried out using different search engines, like Sci-finder, Elsevier, ScienceDirect, RSC etc., for small molecules based on pyrrole and pyridine helpful in diagnosis and inducing apoptosis in cancer cells. The research findings on the application of these compounds from 2018-2023 were reviewed on a variety of cell lines, such as breast cancer, liver cancer, epithelial cancer, etc. Results: In this review, the published small molecules, pyrrole and pyridine and their derivatives, which have roles in the diagnosis and treatment of cancers, were discussed to provide some insight into the structural features responsible for diagnosis and treatment. The analogues with the chromeno-furo-pyridine skeleton showed the highest anticancer activity against breast cancer. The compound 5-amino-N-(1-(pyridin-4- yl)ethylidene)-1H-pyrazole-4-carbohydrazides was highly potent against HEPG2 cancer cell. Redaporfin is used for the treatment of cholangiocarcinoma, biliary tract cancer, cisplatin-resistant head and neck squamous cell carcinoma, and pigmentation melanoma, and it is in clinical trials for phase II. These structural features present a high potential for designing novel anticancer agents for diagnosis and drug development. CONCLUSION: Therefore, the N- and C-substituted pyrrole and pyridine-based novel privileged small Nheterocyclic scaffolds are potential molecules used in the diagnosis and treatment of cancer. This review discusses the reports on the synthesis of such molecules during 2018-2023. The review mainly discusses various diagnostic techniques for cancer, which employ pyrrole and pyridine heterocyclic scaffolds. Furthermore, the anticancer activity of N- and C-substituted pyrrole and pyridine-based scaffolds has been described, which works against different cancer cell lines, such as MCF-7, A549, A2780, HepG2, MDA-MB-231, K562, HT- 29, Caco-2 cells, Hela, Huh-7, WSU-DLCL2, HCT-116, HBL-100, H23, HCC827, SKOV3, etc. This review will help the researchers to obtain a critical insight into the structural aspects of pyrrole and pyridine-based scaffolds useful in cancer diagnosis as well as treatment and design pathways to develop novel drugs in the future.

Synthesis, molecular modelling, and antibacterial evaluation of new sulfonamide-dyes based pyrrole compounds.

In this study, we synthesized new series of 5-oxo-2-phenyl-4-(arylsulfamoyl)sulphenyl) hydrazono)-4,5-dihydro-1H-pyrrole-3-carboxylate hybrids 4a-f with the goal of overcoming sulfonamide resistance and identifying novel therapeutic candidates by chemical changes. The chemical structures of the synthesized hybrids were established over the spectroscopic tools. The frontier molecular orbitals configuration and energetic possessions of the synthesized compounds were discovered utilizing DFT/B3LYP/6-311++ G** procedure. The 3D plots of both HOMO and LUMO showed comparable configuration of both HOMO and LUMO led to close values of their energies. Amongst the prepared analogues, the sulfonamide hybrids 4a-f, hybrid 4a presented potent inhibitory towards S. typhimurium with (IZD = 15 mm, MIC = 19.24 µg/mL) and significant inhibition with (IZD = 19 mm, MIC = 11.31 µg/mL) against E.coli in contrast to sulfonamide (Sulfamethoxazole) reference Whereas, hybrid 4d demonstrated potent inhibition with (IZD = 16 mm, MIC = 19.24 µg/mL) against S. typhimurium with enhanced inhibition against E. Coli, Additionally, the generated sulfonamide analogues'' molecular docking was estimated over (PDB: 3TZF and 6CLV) proteins. Analogue 4e had the highest documented binding score as soon as linked to the other analogues. The docking consequences were fitting and addressed with the antibacterial valuation.

Synthesis, molecular docking study and biological evaluation of new pyrrole scaffolds as potential antitubercular agents for dual targeting of enoyl ACP reductase and dihydrofolate reductase.

In this study, new series of N'-(2-(substitutedphenoxy)acetyl)-4-(1H-pyrrol-1-yl)benzohydrazides (3a-j) 4-(2,5-dimethyl-1H-pyrrol-1-yl)-N'-(2-(substitutedphenoxy)acetyl)benzohydrazides (5a-j) were synthesized, characterized and assessed as inhibitors of enoyl ACP reductase and DHFR. Most of the compounds exhibited dual inhibition against the enzymes enoyl ACP reductase and DHFR. Several synthesized substances also demonstrated significant antibacterial and antitubercular properties. A molecular docking analysis was conducted in order to determine the potential mechanism of action of the synthesized compounds. The results indicated that there were binding interactions seen with the active sites of dihydrofolate reductase and enoyl ACP reductase. Additionally, important structural details were identified that play a critical role in sustaining the dual inhibitory activity. These findings were useful for the development of future dual inhibitors. Therefore, this study provided strong evidence that several synthesized molecules could exert their antitubercular properties at the cellular level through multi-target inhibition. By shedding light on the mechanisms through which these compounds exert their inhibitory effects, this research opens up promising avenues for the future development of dual inhibitors with enhanced antibacterial and antitubercular properties. The study's findings underscore the importance of multi-target approaches in drug design, providing a strong foundation for the design and optimization of novel compounds that can effectively target bacterial infections at the cellular level.

Insight into soft chemometric computational learning for modelling oily-wastewater separation efficiency and permeate flux of polypyrrole-decorated ceramic-polymeric membranes.

Reliable modeling of oily wastewater emphasizes the paramount importance of sustainable and health-conscious wastewater management practices, which directly aligns with the Sustainable Development Goals (SDG) while also meeting the guidelines of the World Health Organization (WHO). This research explores the efficiency of utilizing polypyrrole-coated ceramic-polymeric membranes to model oily wastewater separation efficiency (SE) and permeate flux (PF) based on established experimental procedures. In this area, computational simulation still needs to be explored. The study developed predictive regression models, including robust linear regression (RLR), stepwise linear regression (SWR) and linear regression (LR) for the ceramic-polymeric porous membrane, aiming to interpret its complex performance across diverse conditions and, thus, develop its utility in oily wastewater treatment applications. Subsequently, a novel, simple average ensemble paradigm was explored to reduce errors and improve prediction skills. Prior to the development of the model, stability and reliability analysis of the data was conducted based on Philip Perron tests with the Bartlett kernel estimation method. The accuracy of the SE exhibited a high consistency, averaging 99.92% with minimal variability (standard deviation of 0.026%), potentially simplifying its prediction compared to PF. The modes were validated and evaluated using metrics like MAE, RMSE, Speed, and MSE, in addition to 2D graphical and cumulative distribution function graphs. The LR model emerged as the best with the lowest RMSE =0.21951, indicating superior prediction accuracy, followed closely by RLR with an RMSE = 0.22359. SWLR, while having the highest RMSE = 0.34573, marked its dominance in prediction speed with 110 observations per second. Notably, the RLR model justified a reduction in error by approximately 35.29% compared to SWLR. Moreover, the training efficiency of the LR model exceeded, demanding a mere 2.9252 s, marking a reduction of about 32.54% compared to SWLR. The improved simple ensemble learning proved merit over the three models regarding error accuracy. This study emphasizes the essential role of soft-computing learning in optimizing the design and performance of ceramic-polymeric membranes.

A liquid metal/polypyrrole electrospun TPU composite conductive network for highly sensitive strain sensing in human motion monitoring.

Developing soft wearable sensors with high sensitivity, low cost, and a wide monitoring range is crucial for monitoring human health. Despite advances in strain sensor technology, achieving high sensitivity and a wide operating range in a single device remains a major challenge in its design and preparation. Herein, a liquid metal (LM) is innovatively ultrasonically anchored to the gaps and surfaces of thermoplastic polyurethane (TPU) electrospun fibers, and then a conductive pathway is constructed through polypyrrole (PPy) self-polymerization to prepare a composite film. The strain sensor developed by ultrasonic anchoring and original polymerization technology shows a high strain coefficient (GF = 4.36 at 12.5% strain) and a low detection limit (less than 1% strain). Importantly, this sensor can monitor joint motion and subtle skin deformations in real time. In addition, the integration of strain sensors and N95 masks enables real-time monitoring of human respiration.

Akt Inhibitor Advancements: From Capivasertib Approval to Covalent-Allosteric Promises.

Akt kinase is vital in cell growth, survival, metabolism, and migration. Dysregulation of Akt signaling is implicated in cancer and metabolic disorders. In the context of cancer, overactive Akt promotes cell survival and proliferation. This has spurred extensive research into developing Akt inhibitors as potential therapeutic agents to disrupt aberrant Akt signaling. Akt inhibitors are classified into three main types: ATP-competitive, allosteric, and covalent-allosteric inhibitors (CAAIs). ATP-competitive inhibitors compete with ATP for binding to Akt, allosteric inhibitors interact with the Pleckstrin homology (PH) domain, and covalent-allosteric inhibitors form covalent bonds, making them more potent and selective. Notably, capivasertib (AZD5363), a potent ATP-competitive Akt inhibitor, received FDA approval in November 2023 for use in combination with the estrogen receptor degrader fulvestrant to treat breast cancer. Challenges remain, including improving selectivity, identifying biomarkers to tailor treatments, and enhancing therapeutic efficacy while minimizing adverse effects. Particularly covalent-allosteric inhibitors hold promise for future more effective and personalized treatments.

Enhancing Glioblastoma Immunotherapy with Integrated Chimeric Antigen Receptor T Cells through the Re-Education of Tumor-Associated Microglia and Macrophages.

Glioblastoma (GBM) is an aggressive brain cancer that is highly resistant to treatment including chimeric antigen receptor (CAR)-T cells. Tumor-associated microglia and macrophages (TAMs) are major contributors to the immunosuppressive GBM microenvironment, which promotes tumor progression and treatment resistance. Hence, the modulation of TAMs is a promising strategy for improving the immunotherapeutic efficacy of CAR-T cells against GBM. Molecularly targeting drug pexidartinib (PLX) has been reported to re-educate TAMs toward the antitumorigenic M1-like phenotype. Here, we developed a cell-drug integrated technology to reversibly conjugate PLX-containing liposomes (PLX-Lip) to CAR-T cells and establish tumor-responsive integrated CAR-T cells (PLX-Lip/AZO-T cells) as a combination therapy for GBM. We used a mouse model of GBM to show that PLX-Lip was stably maintained on the surface of PLX-Lip/AZO-T cells in circulation and these cells could transmigrate across the blood-brain barrier and deposit PLX-Lip at the tumor site. The uptake of PLX-Lip by TAMs effectively re-educated them into the M1-like phenotype, which in turn boosted the antitumor function of CAR-T cells. GBM tumor growth was completely eradicated in 60% of the mice after receiving PLX-Lip/AZO-T cells and extended their overall survival time beyond 50 days; in comparison, the median survival time of mice in other treatment groups did not exceed 35 days. Overall, we demonstrated the successful fusion of CAR-T cells and small-molecule drugs with the cell-drug integrated technology. These integrated CAR-T cells provided a superior combination strategy for GBM treatment and presented a reference for the construction of integrated cell-based drugs.

Tofacitinib and peficitinib inhibitors of Janus kinase for autoimmune disease treatment: a quantum biochemistry approach.

Autoimmune inflammatory diseases, such as rheumatoid arthritis (RA) and ulcerative colitis, are associated with an uncontrolled production of cytokines leading to the pronounced inflammatory response of these disorders. Their therapy is currently focused on the inhibition of cytokine receptors, such as the Janus kinase (JAK) protein family. Tofacitinib and peficitinib are JAK inhibitors that have been recently approved to treat rheumatoid arthritis. In this study, an in-depth analysis was carried out through quantum biochemistry to understand the interactions involved in the complexes formed by JAK1 and tofacitinib or peficitinib. Computational analyses provided new insights into the binding mechanisms between tofacitinib or peficitinib and JAK1. The essential amino acid residues that support the complex are also identified and reported. Additionally, we report new interactions, such as van der Waals; hydrogen bonds; and alkyl, pi-alkyl, and pi-sulfur forces, that stabilize the complexes. The computational results revealed that peficitinib presents a similar affinity to JAK1 compared to tofacitinib based on their interaction energies.

Dynamic simulation and experimental studies of molecularly imprinted label-free sensor for determination of milk quality marker.

Bovine serum albumin (BSA) has emerged as a biomarker for mammary gland health and cow quality, being recognized as a significant allergenic protein. In this study, a novel flexible molecular imprinted electrochemical sensor by surface electropolymerization using pyrrole (Py) as functional monomer, which can be better applied to the detection of milk quality marker BSA. Based on computational results, with regard to all polypyrrole (PPy) conformations and amino-acid positions within the protein, the BSA molecule remained firmly embedded into PPy polymers with no biological changes. The molecular imprinted electrochemical sensor displayed a broad linear detection range from 1.0 × 10-4 to 50 ng·mL-1 (R2 = 0.995) with a low detection limit (LOD) of 4.5 × 10-2 pg·mL-1. Additionally, the sensor was highly selective, reproducible, stable and recoverable, suggesting that it might be utilized for the evaluation of milk quality.

Design, Synthesis, Biological Evaluation and in Silico Studies of Curcumin Pyrrole Conjugates.

Curcumin conjugated heterocyclic compounds are potent candidates with drug likeness against various bacterial pathogens. A set of curcumin-based pyrrole conjugates (CPs) were synthesized and characterized by FT-IR, 1H and 13C NMR and HR-MS techniques. The results of free radical scavenging activity of the synthesized CPs, evaluated by FRAP and CUPRAC assays, showed the potency of these compounds as effective antioxidants. CP3 exhibits the highest antioxidant activity amongst the CPs. The bactericidal efficacy of CPs was screened against ESKAP bacterial pathogens, and CPs were found to possess better antibacterial property than curcumin, specifically against staphylococcus aureus bacteria. In addition, serum albumin (BSA and HSA) binding interaction of these CPs were determined by UV-visible and fluorescence spectrophotometric techniques. In-silico molecular docking study was performed to determine the binding patterns of molecular targets against Staphylococcus aureus tyrosyl tRNA synthetase, and serum albumin proteins. The structure-activity relationship showed that the presence of multiple phenolic hydroxyl groups, and electron withdrawing groups on the structure of CP molecule, enhances its antioxidant and antibacterial activity, respectively.

N-Cinnamoylpyrrole-derived alkaloids from the genus Piper as promising agents for ischemic stroke by targeting eEF1A1.

BACKGROUND: Ischemic stroke (IS) is a serious cerebrovascular disease characterized by significantly elevated mortality and disability rates, and the treatments available for this disease are limited. Neuroinflammation and oxidative stress are deemed the major causes of cerebral ischemic injury. N-Cinnamoylpyrrole alkaloids form a small group of natural products from the genus Piper and have not been extensively analyzed pharmacologically. Thus, identifying the effect and mechanism of N-cinnamoylpyrrole-derived alkaloids on IS is worthwhile. PURPOSE: The present research aimed to explore the antineuroinflammatory and antioxidative stress effects of N-cinnamoylpyrrole-derived alkaloids isolated from the genus Piper and to explain the effects and mechanism on IS. METHODS: N-cinnamoylpyrrole-derived alkaloids were isolated from Piper boehmeriaefolium var. tonkinense and Piper sarmentosum and identified by various chromatographic methods. Lipopolysaccharide (LPS)-induced BV-2 microglia and a mouse model intracerebroventricularly injected with LPS were used to evaluate the antineuroinflammatory and antioxidative stress effects. Oxygen‒glucose deprivation/reperfusion (OGD/R) and transient middle cerebral artery occlusion (tMCAO) models were used to evaluate the effect of PB-1 on IS. To elucidate the fundamental mechanism, the functional target of PB-1 was identified by affinity-based protein profiling (ABPP) strategy and verified by cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS), and circular dichroism (CD) analyses. The effect of PB-1 on the NF-κB and NRF2 signaling pathways was subsequently evaluated via western blotting and immunofluorescence staining. RESULTS: The results showed that N-cinnamoylpyrrole-derived alkaloids significantly affected neuroinflammation and oxidative stress. The representative compound, PB-1 not only inhibited neuroinflammation and oxidative stress induced by LPS or OGD/R insult, but also alleviated cerebral ischemic injury induced by tMCAO. Further molecular mechanism research found that PB-1 promoted antineuroinflammatory and antioxidative stress activities via the NF-κB and NRF2 signaling pathways by targeting eEF1A1. CONCLUSION: Our research initially unveiled that the therapeutic impact of PB-1 on cerebral ischemic injury might rely on its ability to target eEF1A1, leading to antineuroinflammatory and antioxidative stress effects. The novel discovery highlights eEF1A1 as a potential target for IS treatment and shows that PB-1, as a lead compound that targets eEF1A1, may be a promising therapeutic agent for IS.

Reagentless Glucose Biosensor Based on Combination of Platinum Nanostructures and Polypyrrole Layer.

Two types of low-cost reagentless electrochemical glucose biosensors based on graphite rod (GR) electrodes were developed. The electrodes modified with electrochemically synthesized platinum nanostructures (PtNS), 1,10-phenanthroline-5,6-dione (PD), glucose oxidase (GOx) without and with a polypyrrole (Ppy) layer-(i) GR/PtNS/PD/GOx and (ii) GR/PtNS/PD/GOx/Ppy, respectively, were prepared and tested. Glucose biosensors based on GR/PtNS/PD/GOx and GR/PtNS/PD/GOx/Ppy electrodes were characterized by the sensitivity of 10.1 and 5.31 µA/(mM cm2), linear range (LR) up to 16.5 and 39.0 mM, limit of detection (LOD) of 0.198 and 0.561 mM, good reproducibility, and storage stability. The developed glucose biosensors based on GR/PtNS/PD/GOx/Ppy electrodes showed exceptional resistance to interfering compounds and proved to be highly efficient for the determination of glucose levels in blood serum.

A biomimetic approach to lycogarubin C, lynamicin D and related analogues.

An efficient and biomimetic synthetic approach to 3,4-diindolylpyrrole-2,5-dicarboxylate derivatives, including lycogarubin C, lynamicin D and related analogues, was discovered. The crucial transformation included the one-pot formation of two C-N bonds and one C-C bond to construct characteristic pyrrole rings.

Stimuli-responsive thin film composites of conducting polymers and cellulose nanocrystals for tissue engineering.

Thin composite films comprising two primary representatives of conducting polymers, poly(3, 4-ethylenedioxythiophene) (PEDOT) and polypyrrole (PPy), with eco-friendly cellulose nanocrystals (CNC) were prepared through electrochemical polymerization. The combination of CNC and PEDOT (or PPy) results in the formation of films with highly different surface topography and thickness. Intriguingly, different surface conductivity of PEDOT and PPy was revealed by atomic force microscopy albeit that the electrochemical properties were rather similar. The biological properties of the composites in contact with prospective human induced pluripotent stem cells (hiPSC) and cardiomyocytes derived from hiPSC demonstrated good cytocompatibility of both composites and their potential in engineering of electro-sensitive tissues. The as-prepared conducting, eco-friendly and cytocompatible composites are thus promising candidates for biomedical applications where stimuli-responsivity is a crucial cell-instructive property.

Design, synthesis, and anticancer evaluation of alkynylated pyrrole derivatives.

A series of alkynylated pyrrole derivatives were meticulously designed, drawing inspiration from the structure of 3-alkynylpyrrole-2,4-dicarboxylates, which were synthesized via a cyclization process involving methylene isocyanides and propiolaldehydes under mild conditions. These derivatives were subsequently subjected to evaluation for their anticancer properties against a panel of cell lines, including U251, A549, 769-P, HepG2, and HCT-116. According to the detailed analysis of structure-activity relationship, compound 12l emerged as the most promising molecule, with IC50 values of 2.29 ± 0.18 and 3.49 ± 0.30 µM toward U251 and A549 cells, respectively. Subsequent mechanistic investigations revealed that compound 12l exerts its effects by arresting the cell cycle in the G0/G1 phase and inducing apoptosis specifically in A549 cells. These innovative alkynylated pyrrole derivatives hold the potential to serve as a valuable template for the discovery of novel anticancer molecules.

Preparation of a novel polypyrrole/dolomite composite adsorbent for efficient removal of Cr(VI) from aqueous solution.

A novel adsorbent, deposited PPy on the DMI (PPy/DMI) composite, was successfully synthesized for Cr(VI) removal from aqueous solution. PPy/DMI composite was characterized by BET, SEM, TEM, XRD, and XPS. The SEM and TEM analyses revealed that DMI can greatly reduce the aggregation of PPy and significantly enhance its adsorption performance. The Cr(VI) removal was highly pH dependent. The high selectivity of PPy/DMI composite for Cr(VI) removal was found even in the presence of co-existing ions. The adsorption kinetic process followed the pseudo-second-order equation, demonstrating that the Cr(VI) adsorption behavior onto PPy/DMI is chemisorption. Furthermore, the intra-particle diffusion model implied that the adsorption was controlled by both liquid membrane diffusion and internal diffusion. The adsorption isotherm data fitted well with the Langmuir model with the maximum adsorption capacity (406.50 mg/g at 323 K) which was considerably higher than that of other PPy-based adsorbents. The Cr(VI) adsorption onto PPy/DMI composite was endothermic. The main mechanisms of Cr(VI) removal are involved in adsorption through electrostatic attractions, ion exchange, and in situ reduction. The results suggested that PPy/DMI composite could be a promising candidate for efficient Cr(VI) removal from aqueous solution.

Synthesis and evaluation of cellulose/polypyrrole composites as polymer electrolytes for lithium-ion battery application.

Natural polymers as battery components have a number of advantages, including availability, biodegradability, unleakage, stable form, superior process, electrochemical stability, and low cost. In other sides, conductive polymers can improve the electrochemical properties of the battery, such as charge/discharge rates, cycling stability, and overall energy storage capacity. Therefore, the combination of these two materials can provide acceptable features. In this study, polymer electrolytes based on cellulose have been synthesized by solution casting method to prepare a thin polymer film. Then, polypyrrole (PPy) was blended with cellulose in different weight ratios. To prevent electrical conductivity of blends, PPy was used <10 wt%. The electrochemical properties of prepared electrolytes have been investigated by different methods. The results showed that ionic conductivity was increased by addition of PPy to cellulose due to the creation of pores and also due to the high dielectric constant of conductive polymers. All synthesized electrolytes had suitable ionic conductivity (in the range of 10-3 S cm-1), significant charge capacity, stable cyclic performance, excellent electrochemical stability (above 4.8 V), and high cation transfer number (between 0.38 and 0.66 for pure cellulose and the sample containing 10 wt% PPy).

Selective determination of an ovarian cancer biomarker at low concentrations with surface imprinted nanotube based chemosensor.

In this study, an electrochemical chemosensor that utilizes a conductive polymer-based molecularly imprinted polymer (MIP) surface for rapid and reliable determination of CA125 was devised. A novel method has been applied to fabricate CA125 imprinted polypyrrole nanotubes (MI-PPy NT) via vapor deposition polymerization (VDP) as a recognition element for highly selective and sensitive determination of CA125. The chemosensor was prepared by immobilizing MI-PPy NT onto screen-printed gold electrodes (Au-SPE) and the performance of the sensor was evaluated by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) in terms of selectivity, sensitivity, linear dynamic concentration range (LDR) and limit of detection (LOD). The MI-PPy NT@Au-SPE sensor exhibited high sensitivity (68.57 µA per decade) to the CA125 concentration ranging from 0.1 U mL-1 to 100 U mL-1 at an LOD of 0.4 U mL-1 with a correlation coefficient of 0.9922. The developed chemosensors with their novel design combined with a facile fabrication method, prove to be promising as future state-of-the-art biosensors.

Access to 2,4-Disubstituted Pyrrole-Based Polymer with Long-Wavelength and Stimuli-Responsive Properties via Copper-Catalyzed [3+2] Polycycloaddition.

Pyrrole-based polymers (PBPs), a type of fascinating functional polymers, play a crucial role in materials science. However, efficient synthetic strategies of PBPs with diverse structures are mainly focused on conjugated polypyrroles and still remain challenging. Herein, an atom and step economy protocol is described to access various 2,4-disubstituted PBPs by in situ formation of pyrrole core structure via copper-catalyzed [3+2] polycycloaddition of dialkynones and diisocyanoacetates. A series of PBPs is prepared with high molecular weight (Mw up to 18 200 Da) and moderate to good yield (up to 87%), which possesses a fluorescent emission located in the green to yellow light region. Blending the PBPs with polyvinyl alcohol, the stretchable composite films exhibit a significant strengthening of the mechanical properties (tensile stress up to 59 MPa, elongation at break >400%) and an unprecedented stress-responsive luminescence enhancement that over fourfold fluorescent emission intensity is maintained upon stretching up to 100%. On the basis of computational studies, the unique photophysical and mechanical properties are attributed to the substitution of carbonyl chromophores on the pyrrole unit.

Synthesis and biological evaluation of 1H-pyrrolo[3,2-g]isoquinolines.

A structure-activity relationship study performed on 1H-pyrrolo[3,2-g]isoquinoline scaffold identified new haspin inhibitors with nanomolar potencies and selectivity indices (SI) over 6 (inhibitory potency evaluated against 8 protein kinases). Compound 22 was the most active of the series (haspin IC50 = 76 nM). Cellular evaluation of 22 confirmed its activity for endogenous haspin in U-2 OS cells and its anti-proliferative activity against various cell lines. In addition, the binding mode of analog 22 in complex with haspin was determined by X-ray crystallography.