Click Chemistry Research Articles

Crown-Ether-Based Artificial K+ Selective Ionic Filter.

In this study, we have successfully synthesized bis (cholesterol-dibenzo-18-crown-6-ether)-pillar[5]arene compound 1 through a click reaction, which could spontaneously insert into lipid bilayers to form ion channel due to the membrane anchor cholesterol group and show significant transport activity of K+ superior to Na+, with a permeability ratio of K+/Na+ equal to 4.58. Compound 1 two crown ether modules act as selective filters similar to natural K+ channel, which are determined to 1:2 binding stoichiometry to K+ by Job's plot and NMR titration. This structurally unambiguously unimolecule artificial channel provides ideas for constructing highly K+/Na+ selective molecular filters.

Controlled Synthesis of Bioderived Poly(limonene carbonate)-Oligolysine Hybrid Macromolecules.

A straightforward and stepwise functionalization of poly(limonene carbonate) (PLC) was achieved through the use of thiol-ene click chemistry introducing primary amine groups. These amines are initiating points for N-carboxy anhydride (NCA) ring-opening polymerization (ROP) reactions, allowing us to modify the PLC backbone with oligolysine fragments, thereby creating a polymer brush type macromolecule. These newly prepared biohybrid structures show a clear hydrophilic behavior as evident from their physical behavior and contact angle measurements.

Cytocompatible Hydrogels with Tunable Mechanical Strength and Adjustable Swelling Properties through Photo-Cross-Linking of Poly(vinylphosphonates).

Herein, the synthesis, characterization, and application of a novel synthetic hydrogel based on the photoinitiated cross-linking of poly(vinylphosphonates) is presented. First, statistical copolymers with adjustable ratios of the monomers diallyl vinylphosphonate (DAlVP) and diethyl vinylphosphonate (DEVP), as well as different molecular weights, were obtained via rare earth metal-mediated group-transfer polymerization (REM-GTP) while maintaining narrow polydispersities. The copolymers were cross-linked by applying photoinitiated thiol-ene click chemistry (λ = 365 nm). The network formation was monitored via oscillatory rheology coupled with UV-irradiation, revealing the high spatiotemporal control of the reaction. Moreover, the equilibrium storage moduli of poly(vinylphosphonate)-based hydrogels increased with a growing number of DAlVP units and upon application of a different cross-linker, which was additionally confirmed by nanoindentation experiments. In contrast, the water uptake of hydrogels decreased with higher DAlVP amounts in the corresponding hydrogels due to lower chain mobility and an overall increase in the hydrophobicity of the samples. Upon successful functionalization of P(DEVP-stat-DAlVP) copolymers with sodium 3-mercaptopropane-1-sulfonate, as indicated via 1H DOSY NMR, the respective cross-linked materials displayed a remarkable increase in the water uptake; thus, presenting highly hydrophilic gels with an apparent interplay between water uptake, cross-linking density, and functionalization degree. Finally, the purified hydrogels showed cytocompatibility and enabled cell adhesion of human umbilical artery smooth muscle cells (HUASMCs) after direct seeding. The materials further allowed the adhesion and growth of an endothelial layer, triggered no pro-inflammatory response as evidenced by cytokine release of M0 macrophages, and exhibited antibacterial properties toward S. aureus and E. coli.

Sustainable strategy for lignin etherification and its promotion of anti-UV aging PLA biocomposite

Achieving efficient modification of both phenolic (Phe)-OH and aliphatic (Aliph)-OH groups in lignin simultaneously via sustainable method, remained a significant challenge. In this study, a series of highly hydroxyl-substituted alkali lignin phenyl propylene ketone ethers (ALK) were obtained under 50 °C without any by-products via the mild and sustainable hydroxyl-yne click reaction method. Notably, phenolic (Phe)-OH content of lignin decreased from 4.12 mmol g−1 to 0.07 mmol g−1 with a conversion rate of 98 %, while the aliphatic (Aliph)-OH content of lignin decreased from 2.57 mmol g−1 to 0.10 mmol g−1 with a conversion rate of 96 %. Owing to the efficient etherification, ALK showed excellent organic solvent (such as trichloromethane, DCM, THF, and acetone) solubility, which thereby improving the interfacial compatibility between ALK and PLA matrix. 3 wt% ALK obviously enhanced the mechanical properties of ALK/PLA biocomposite films, with the yield strength, breaking strength, and Young’s modulus improving by 114.2 %, 30.7 % and 250.2 %, respectively. Additionally, due to the newly introduced vinyl ether bonds (−C–O–CC–) in ALK by hydroxyl-yne click reaction, only 1 % ALK could endow ALK/PLA biocomposite with excellent UV shielding (100 %), high transmittance (84.3 %) and Anti-UV aging property. The yield strength and Young’s modulus represented an increase of 209 % and 86 %, respectively, even after 3 h of UV-irradiation. This study presents an environmentally friendly lignin functionalization method that unleashes the inherent Anti-UV aging properties of lignin, opening new avenues for the development of high-performance lignin-based composites.

Nanoplatelets modified with RVG for targeted delivery of miR-375 and temozolomide to enhance gliomas therapy

Gliomas are one of the most frequent primary brain tumors and pose a serious threat to people’s lives and health. Platelets, a crucial component of blood, have been applied as drug delivery carriers for disease diagnosis and treatment. In this study, we designed engineered nanoplatelets for targeted delivery of therapeutic miR-375 and temozolomide (TMZ, a first-line glioma treatment agent) to enhance glioma therapy. Nanoplatelets were prepared through mild ultrasound, TMZ and miR-375 were co-loaded through ultrasound and electrostatic interactions, respectively, to combine chemotherapy with gene therapy against glioma. To improve the blood brain barrier (BBB) crossing efficiency and glioma targeting ability, the nanoplatelets were modified with central nervous system-specific rabies viral glycoprotein peptide (RVG) through thiol-maleimide click reaction. The RVG modified nanoplatelets co-loaded TMZ and miR-375 (NR/TMZ/miR-375) not only inherited the good stability and remarkable biocompatibility of platelets, but also promoted the cellular uptake and penetration of glioma tissues, and effectively induced cell apoptosis to enhance the therapeutic effect of drugs. In vivo studies showed that NR/TMZ/miR-375 significantly increased the circulation time of TMZ, and exhibited superior combined antitumor effects. In summary, this multifunctional ‘natural’ nanodrug delivery system provides a potent, scalable, and safety approach for platelet-based combined cancer chemotherapy and gene therapy.

Efficient Multidriven Strand Displacement Reaction for Biosensing.

A key challenge for achieving high-efficient DNA strand displacement reaction (SDR) with existing technologies is the inferior kinetic performance due to the alternately cumbersome conjunction and dissociation of dsDNA. In this work, a novel multidriven SDR collaborated by toehold initiator, strand towing, and click chemistry is engineered. The invasion strand (O) endows the hybridization with a basal strand (M) in dsDNA for releasing a displacement strand (P), which can be significantly boosted by the towing of a helper strand and impetus from the click reaction. Accordingly, the hybridization rate and dissociation extent of P can be largely improved and showed a desiring displacement rate close to 6-fold compared with the traditional method, providing a newly high-efficient SDR strategy for potential application in biosensing, clinical diagnostics, and DNA nanotechnology. In view of this, a practical biosensing platform by combining the multidriven SDR (MSDR) with waste-free DNA multi-cycle amplification is constructed for the rapid and ultrasensitive electrochemical detection of cancer-related miRNA-21. The substantial output DNA as an invasion strand (O) from target-triggered waste-free DNA multicycle can high-efficiently release a signal probe (Fc)-labeled displacement strand (P) on an electrode by using the proposed MSDR, obtaining a low detection limit below 106.8 aM.

Synthesis, Biophysical and Biological Evaluation of Splice-Switching Oligonucleotides with Multiple LNA-Phosphothiotriester Backbones.

Polyanionic antisense oligonucleotides hold great promise as RNA targeting drugs but issues with bioavailability hinder their development. Uncharged phosphorus-based backbones are promising alternatives but robust methods to produce them are limited. We report the synthesis and properties of oligonucleotides containing charge-neutral LNA alkyl phosphothiotriester backbones combined with 2'-O-methyl phosphorothioate nucleotides for therapeutic applications. The nature of the triester alkyl group dictates the success of solid-phase synthesis; tertiary alkyl groups are lost during the P(III) oxidation step, whereas primary alkyl groups are partially cleaved during deprotection. In contrast, oligonucleotides containing secondary phosphothiotriester linkages are stable, and large numbers of triesters can be incorporated. The modified oligonucleotides have excellent duplex stability with complementary RNA and exhibit strong nuclease resistance. To expand synthetic flexibility, oligonucleotides containing multiple internal alkynyl phosphothiotriesters can be conjugated to lipids, carbohydrates, or small molecules through CuAAC click chemistry. Oligonucleotides containing LNA-THP phosphothiotriesters exhibit high levels of pre-mRNA splice switching in eukaryotic cells.

Aptamer-drug conjugates-loaded bacteria for pancreatic cancer synergistic therapy

Pancreatic cancer is one of the most malignant tumors with the highest mortality rates, and it currently lacks effective drugs. Aptamer-drug conjugates (ApDC), as a form of nucleic acid drug, show great potential in cancer therapy. However, the instability of nucleic acid-based drugs in vivo and the avascularity of pancreatic cancer with dense stroma have limited their application. Fortunately, VNP20009, a genetically modified strain of Salmonella typhimurium, which has a preference for anaerobic environments, but is toxic and lacks specificity, can potentially serve as a delivery vehicle for ApDC. Here, we propose a synergistic therapy approach that combines the penetrative capability of bacteria with the targeting and toxic effects of ApDC by conjugating ApDC to VNP20009 through straightforward, one-step click chemistry. With this strategy, bacteria specifically target pancreatic cancer through anaerobic chemotaxis and subsequently adhere to tumor cells driven by the aptamer’s specific binding. Results indicate that this method prolongs the serum stability of ApDC up to 48 h and resulted in increased drug concentration at tumor sites compared to the free drugs group. Moreover, the aptamer’s targeted binding to cancer cells tripled bacterial colonization at the tumor site, leading to increased death of tumor cells and T cell infiltration. Notably, by integrating chemotherapy and immunotherapy, the effectiveness of the treatment is significantly enhanced, showing consistent results across various animal models. Overall, this strategy takes advantage of bacteria and ApDC and thus presents an effective synergistic strategy for pancreatic cancer treatment.

Gradient Functionalization of Poly(lactic acid)-Based Materials with Polylysine for Spatially Controlled Cell Adhesion.

The development of biomaterials with gradient surface modification capable of spatially controlled cell adhesion and migration is of great importance for tissue engineering and regeneration. In this study, we proposed a method for the covalent modification of PLA-based materials with a cationic polypeptide (polylysine, PLys) via a thiol-ene click reaction carried out under a light gradient. With this aim, PLA-based films were fabricated and modified with 2-aminoethyl methacrylate (AEMA) as a double bond source. The latter was introduced by reacting pre-formed and activated surface carboxyl groups with the amino group of AEMA. The success of the modification was confirmed by 1H NMR, Raman and X-ray photoelectron spectroscopy data. A further photoinduced thiol-ene click reaction in the presence of a photosensitive initiator as a radical source was further optimized using cysteine. For grafting of PLys via the thiol-ene click reaction, PLys with a terminal thiol group was synthesized by ring-opening polymerization using Cys(Acm) as an amine initiator. Deprotection of the polypeptide resulted in the formation of free thiol groups of Cys-PLys. Successful gradient grafting of Cys-PLys was evidenced by covalent staining with the fluorescent dye Cy3-NHS. In addition, PLys gradient-dependent adhesion and migration of HEK 293 cells on PLys-PLA-based surfaces was confirmed.

Enhanced-electrochemiluminescence biosensor for detecting miRNA-21 based on a CuO-mediated click reaction and catalytic hairpin self-assembly

MicroRNAs (miRNAs) are closely associated with cancer and have been considered cancer biomarkers. Herein, we propose an electrochemiluminescence (ECL) biosensor for detecting miRNA-21 based on target-induced catalytic hairpin self-assembly (CHA) and CuO-mediated azide–alkyne cycloaddition. Two hairpin DNAs were employed: one was immobilized on magnetic beads (HP2) and another was labeled with CuO (HP1–CuO). HP1 and HP2 formed a duplex through CHA induced by miRNA-21, resulting in the immobilization of CuO on magnetic beads and in the recycling of miRNA-21. After magnetic separation, CuO was treated with hydrochloric acid to release Cu2+, which concentration is quantitatively proportional to the target concentration. Subsequently, Cu2+ was reduced to Cu+, which catalyzed the click reaction between Fc–C CH and SH-DNA-N3+ immobilized on a Au/g-C3N4 modified electrode. Thus, the ECL of Au/g-C3N4 was quenched by Fc, and miRNA-21 was indirectly detected through a change in ECL intensity. Benefiting from the amplification effect of CuO nanoparticle loading, CHA-based target recycling, and the catalytic effect of click reaction, the proposed ECL biosensor showed high sensitivity. Experimental results indicate that the ECL biosensor proposed for detecting miRNA-21 exhibits a wide linear range from 1 fM to 1 nM and a low detection limit of 0.26 fM (3σ/S). Furthermore, the ECL sensor was capable of measuring miRNA-21 in real serum with high selectivity, indicating its notable applicable potential in biomedicine and clinical diagnosis.

Reshaping the tumor microenvironment by degrading glycoimmune checkpoints Siglec-7 and -9.

Cancer treatment has been rapidly transformed by the development of immune checkpoint inhibitors targeting CTLA-4 and PD-1/PD-L1. However, many patients fail to respond, especially those with an immunosuppressive tumor microenvironment (TME), suggesting the existence of additional immune checkpoints that act through orthogonal mechanisms. Sialic acid-binding immunoglobulin-like lectin (Siglec)-7 and -9 are newly designated glycoimmune checkpoints that are abundantly expressed by tumor-infiltrating myeloid cells. We discovered that T cells express only basal levels of Siglec transcripts; instead, they acquire Siglec-7 and -9 from interacting myeloid cells in the TME via trogocytosis, which impairs their activation and effector function. Mechanistically, Siglec-7 and -9 suppress T cell activity by dephosphorylating T cell receptor (TCR)-related signaling cascades. Using sulfur fluoride exchange (SuFEx) click chemistry, we developed a ligand that binds to Siglec-7 and -9 with high-affinity and exclusive specificity. Using this ligand, we constructed a Siglec-7/9 degrader that targets membrane Siglec-7 and -9 to the lysosome for degradation. Administration of this degrader induced efficient Siglec degradation in both T cells and myeloid cells in the TME. We found that Siglec-7/9 degradation has a negligible effect on macrophage phagocytosis, but significantly enhances T cell anti-tumor immunity. The degrader, particularly when combined with anti-CTLA-4, enhanced macrophage antigen presentation, reshaped the TME, and resulted in long-lasting T cell memory and excellent tumor control in multiple murine tumor models. These findings underscore the need to consider exogenous checkpoints acquired by T cells in the TME when selecting specific checkpoint blockade therapy to enhance T cell immunity.

ESOMA-DM1, a Maytansinoid-Based Theranostic Small-Molecule Drug Conjugate for Neuroendocrine Tumors.

Background: The main challenges of conventional chemotherapy lie in its lack of selectivity and specificity, leading to significant side effects. Using a small-molecule drug conjugate (SMDC) ensures specific delivery of a cytotoxic drug to the tumor site by coupling it to a targeting vector. This promising strategy can be applied to neuroendocrine tumors (NETs) by choosing a targeting vector that binds specifically to somatostatin receptor subtype 2 (SSTR2). Additionally, incorporation of a bifunctional chelate into the molecule enables complexation of both diagnostic and therapeutic radionuclides. Thus, it facilitates monitoring of the distribution of the SMDC in the body and allows for the implementation of combination therapy. In our study, we designed eSOMA-DM1, a SMDC combining the SSTR2-targeted octreotate peptide and the cytotoxic agent DM1 via a chelate-bridged linker (N3-Py-DOTAGA). This approach warrants conjugation of the targeting vector and the drug at opposite sites to avoid undesired steric hindrance effects. Methods: Synthesis of the DM1 moiety (4) involved a three-step synthetic route, followed by the conjugation to the cyclic peptide, N3-Py-DOTAGA-d-Phe-cyclo[Cys-Tyr-d-Trp-Lys-Thr-Cys]-Thr-OH, through a copper-free click reaction, resulting in eSOMA-DM1. Subsequent labeling with [111In]InCl3 gave a high radiochemical yield and purity. In vitro assessments of eSOMA-DM1 binding, uptake, and internalization were conducted in SSTR2-transfected U2OS cells. Ex vivo biodistribution and fluorescence imaging were performed in H69-tumor bearing mice. Results: eSOMA-DM1 exhibited an IC50 value for SSTR2 similar to the gold standard DOTA-TATE. The uptake of [111In]In-eSOMA-DM1 in U2OS.SSTR2 cells was 1.2-fold lower than that of [111In]In-DOTA-TATE. Tumor uptake in H69-xenografted mice was higher for [111In]In-eSOMA-DM1 at all-time points compared to [111In]In-DOTA-TATE. Prolonged blood circulation led to increased accumulation of [111In]In-eSOMA-DM1 in highly vascularized tissues, such as the lungs, skin, and heart. Excretion through the kidneys, liver, and spleen was also observed. Conclusion: eSOMA-DM1 is a SMDC developed for NET showing promising characteristics in vitro. However, the in vivo results obtained with [111In]In-eSOMA-DM1 suggest the need for adjustments to optimize its distribution.

Chemically Self-Assembled Monolayer Semiconducting Single-Walled Carbon Nanotube-Based Biosensor Platform for Amyloid-β Detection.

This paper presents a platform for amyloid-β (Aβ) biosensors, employing nearly monolayer semiconducting single-walled carbon nanotubes (sc-SWNTs) via click reaction. A high-purity sc-SWNT ink was obtained by employing a conjugated polymer wrapping method with the addition of silica gel. Aβ detection involved monitoring the electrical resistances of the sc-SWNT layers. Electrical resistances increased rapidly corresponding to the concentration of amyloid-β 1-42 (Aβ1-42) peptides. Furthermore, we introduced Aβ peptides onto the 1-pyrenebutanoic acid succinimidyl ester (PBASE) linker, confirming that only the chemical adsorption of the peptide by the antibody-antigen reaction yielded a significant change in electrical resistance. The optimized sensor exhibited a high sensitivity of 29% for Aβ at a concentration of 10 pM. Notably, the biosensor platform featuring chemically immobilized sc-SWNT networks can be customized by incorporating various bioreceptors beyond Aβ antibodies.

Click Reaction Inspired Enzyme Inhibitors in Diabetes Care: An Update in the Field of Chronic Metabolic Disorder.

Diabetes is a chronic metabolic disorder that impacts all age groups and affects a large population worldwide. Humans receive glucose from almost every food source, and after absorption from the gut, it reaches the liver, which functions as the distribution center for it. The insulin-responsive glucose transporter type 4 (GLUT-4) is a major carrier of glucose to the various cells (majorly expressed in myocytes, adipocytes, and cardiomyocytes) in a well-fed state. In fasting periods, the glucose supply is maintained by glycogenolysis and gluconeogenesis. In diabetes, the distribution of glucose is hampered due to several reasons. Furthermore, to treat this disorder, several drugs have been synthesized, and click chemistry plays an important role. A more recent concept for producing pharmaceuticals with a click chemistry approach makes any reaction more practical and stereospecific, along with a higher yield of products and a smaller number of by-products. This approach comprises a compiled study of the activity of numerous compelling antidiabetic drugs containing 1, 2, 3-triazole derivatives supported by click chemistry. In this review, we discuss the synthetic antidiabetic drugs made via click chemistry and their commendable role in improving diabetes care.

CuI@MIM-SBA-15 hybrid catalyst in the ultrasound-assisted synthesis of 1,4-disubstituted 1,2,3-triazoles in water

Click chemistry reactions transformed organic synthesis by creating enormous compound libraries connecting almost any chemical entity. The copper-catalyzed alkyne-azide cycloaddition (CuAAC) was the most versatile and efficient and transcended diverse scientific fields such as biology and materials science. Thus, the development of new methodologies based on CuAAC keeps growing. A green approach was envisioned by stabilizing the air and water-sensitive CuI over an ordered mesoporous silica/ionic liquid matrix (MIM-SBA-15). The best catalyst performance was in the water as solvent under ultrasound irradiation, which reached quantitative transformation in a short time. Then, the scope was extended to 24 compounds primarily synthesized with high yields (75–99 %); the methodology tolerated different alkynes and azides with aromatic and alkyl groups. This methodology was also successfully tested in high yields in the multicomponent synthesis of 1,4-disubstituted 1,2,3-triazoles from organic bromides, alkynes, and KN3. The hybrid catalyst recovery and reuse were evaluated along ten reaction cycles; there was no significant loss in activity up to cycle number six (94 % yield).

Fabrication of polyurethane/polythiourethane core–shell microspheres via thiol-isocyanate click chemistry and their application in toughening epoxy resin

Fabrication of polyurethane/polythiourethane core–shell microspheres via thiol-isocyanate click chemistry and their application in toughening epoxy resin

Construction of a chemiluminescent biosensor based on enzymatic extension and click chemistry for sensitive measurement of MGMT activity in human breast tissues

O6-methylguanine methyltransferase (MGMT) is responsible for dealkylation of naturally occurring O6-methylguanines, and it is closely related with DNA replication, transcription, and cancers. Herein, we develop a chemiluminescent biosensor based on enzymatic extension and click chemistry for sensitive measurement of MGMT activity. When MGMT is present, the MGMT-catalyzed demethylation reaction initiates the cleavage of biotinylated dumbbell probes by PvuII restrictive enzyme, releasing two DNA fragments with 3′-OH end. The resultant DNA fragments can trigger terminal transferase (TdT)- and click chemistry-assisted isothermal amplification to obtain abundant G-rich sequences. The G-rich sequences can be captured by magnetic beads to produce a high chemiluminescence signal. This biosensor can greatly amplify the chemiluminescence signal, facilitating label-free and template-free measurement of MGMT. Especially, the introduction of dumbbell probe and PvuII enzyme can efficiently eliminate the false positive and improve the assay specificity. This biosensor possesses high sensitivity with a detection limit of 1.4 × 10−9 ng/μL, and it may accurately quantify the intracellular MGMT. Importantly, this biosensor can be used to screen the MGMT inhibitors and distinguish the MGMT level in breast tumor tissues and normal tissues, with great potential in drug discovery and cancer diagnosis.

Multifunctional Polymer Synthesis via Sequential Postpolymerization Modification Using a Single Aldehyde Repeat Unit: Allylation and Orthogonal Esterification and Thiol-ene Reaction.

Herein, we present a highly efficient method for synthesizing multifunctional polymers. This method involves the sequential postpolymerization modification (PPM) of a highly reactive aldehyde polymer. We introduce an allylic alcohol functionality into the polymer backbone via Barbier-type allylation, a process facilitated by easy-to-handle indium(0) powder. This step enables the formation of orthogonal pendants, secondary alcohol, and terminal alkene, which can be further functionalized through esterification and thiol-ene click reactions. All of these processes are carried out under mild conditions, ensuring high efficiency and a wide range of functional groups. Our study underscores PPM's operational simplicity and versatility in developing advanced polymer materials and expanding the scope of multifunctional polymer design.

Selenium(II)-Nitrogen Exchange (SeNEx) Chemistry: A Good Chemistry Suitable for Nanomole-Scale Parallel Synthesis, DNA-encoded Library Synthesis and Bioconjugation.

The continuous development of click reactions with new connecting linkage is crucial for advancing the frontiers of click chemistry. Selenium-nitrogen exchange (SeNEx) chemistry, a versatile chemistry in click chemistry, represents an all-encompassing term for nucleophilic substitution events that replace nitrogen at an electrophilic selenium(II) center, enabling the flexible and efficient assembly of linkages around a Se(II) core. Several SeNEx chemistries have been developed inspired by the biochemical reaction between Ebselen and cysteine residue, and demonstrated significant potential in on-plate nanomole-scale parallel synthesis, selenium-containing DNA-encoded library (SeDEL) synthesis, as well as peptide and protein bioconjugation. This concept aims to present the origins, advancements, and applications of selenium(II)-nitrogen exchange (SeNEx) chemistry while also outlining the potential directions for future research in this field.

Synthesis of Substituted 1-Benzyl-2H-1,2,3-Triazoles by a Click Reaction Using Calcium Carbide as an Acetylene Source

AbstractAn effective strategy for constructing substituted 1-benzyl-1H-1,2,3-triazoles was developed through click reactions of benzylic halides with sodium azide and calcium carbide as sources of nitrogen and acetylene, respectively. The advantages of this method are an easily handled inexpensive source of acetylene, a wide range of substrates, satisfactory yields, and simple workup procedures, which could promote the use of calcium carbide as a sustainable acetylene source in modern industrial chemistry.