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Free Samples. Order Library eBook. Order Printed Copy. Download Flyer. Table of Contents List of Contributors. Table of Contents Contributors - Pp. Editorial - Pp. Photochemical Activation of Functional Groups - Pp. Bochet View Abstract Download Free. Pressure Activation in Organic Synthesis - Pp. Ultrasound in Synthetic Organic Chemistry - Pp. Activation of Organic Reactions by Microwaves - Pp. Activation of Organic Reactions by Perchlorates - Pp. Rama Rao, Y. Spot diameter 2. Functionalization with 4-pentynoic acid enables further surface patterning by thiol-yne photoclick chemistry.

Hydrophobic borders are generated by PFDT, followed by the formation of hydrophilic spots using 2-mercaptoethanol. Therefore, in the next step we produced High Surface Tension Liquids HSTL slides—glass slides coated with a porous polymer layer patterned with hydrophilic spots separated by hydrophobic barriers, leading to the effect of discontinuous dewetting of aqueous solutions 21 , The combination of highly hydrophilic spots possessing very strong affinity to aqueous solutions and hydrophobic, extremely water-repellent regions enabled the formation of arrays of droplets of high surface tension aqueous solutions such as liposomes or cell suspension using discontinuous dewetting Supplementary Fig.

We then used the LSTL slides to develop and optimize the parallel, combinatorial synthesis of cationic lipid-like molecules lipidoids to be used in the following cell screening experiment. For this purpose, we chose a one-pot three-component reaction based on thiolactone opening by an amine, followed by a disulfide exchange reaction Fig. We used two methods to apply solutions in droplet-array format to the slides: a printing method, where we applied droplets to each spot via a non-contact liquid dispenser system, and the rolling droplet method, where we applied solutions via discontinuous dewetting.

Organic Chemistry Synthesis Reactions - Examples and Practice Problems - Retrosynthesis

On-chip synthesis and characterization of a lipidoid library. The application is done by rolling a droplet of solution to form rows of separate droplets. In the next step, slide A and slide B are sandwiched SW with each other to bring individual droplets into contact to merge the droplets, thereby initiating the reaction.

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MALDI-TOF mass spectrometry measurement examples of spectra shown in the insets, positive mode enables rapid and convenient characterization of the entire library of synthesized compounds. Source data are provided as a Source Data file. We used the released 2-thiopyridone to monitor the reaction kinetics and estimate the yield via UV-Vis spectroscopy. The open format of the chemBIOS system is compatible with further on-chip steps such as investigating, treating or converting the chemical compound library, to achieve high-throughput parallel on-chip purification.

In a proof-of-principle experiment, we showed how crude products could be purified by on-chip two-phase liquid extraction Fig. Therefore, we dissolved Nile red and methylene blue in 1-octanol which resulted in a dark blue solution. Next, we applied this solution on several spots on an LSTL slide D and sandwiched that slide with an HSTL slide E containing water droplets, resulting in the formation of an octanol-water interface for each droplet Fig.

Methylene blue is highly water-soluble, and was therefore extracted from the organic phase into the aqueous phase, while water-insoluble Nile red remained in the organic phase. We analyzed the mixture before purification, as well as the organic and aqueous phases after purification by UV-Vis spectroscopy Fig. Both analytical methods yielded similar results. Using UV-Vis spectroscopy, the concentration of methylene blue measured The concentration of Nile red was measured 6. On-chip parallel liquid-liquid extraction.

An interface between the two non-miscible solvents was formed, and the water-soluble methylene blue was extracted into the aqueous phase. After the extraction, the intensity of the absorbance maximum of methylene blue in the organic phase decreased while the intensity of Nile red remained constant. In the aqueous phase, no Nile red could be detected. This step was performed to transfer lipidoids into aqueous cell-compatible droplets simultaneously, forming either liposomes or lipoplexes required for cell transfection experiments.

The buffer also contained 0.

Having been transferred into an aqueous environment, the amphiphilic lipidoids spontaneously formed liposomes, subsequently complexing plasmid DNA to form lipoplexes Fig. We characterized both liposome and lipoplex solutions by pipetting them directly from the HSTL slide C into a cuvette to analyze via dynamic light scattering DLS and zeta potential analysis. The lipoplex solutions revealed significantly larger particles than the corresponding liposome solutions Fig. Furthermore, lipoplex solutions demonstrated a lower zeta potential than the corresponding liposomes, indicating the formation of complexes between the positively charged lipidoids and negatively charged DNA Fig.

On-chip parallel formation of a library of liposomes or lipoplexes.

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The Organic Chemistry of Drug Synthesis, Volumes 1 to 4

Liposomes were produced in the same way without adding plasmid DNA. Liposomes display smaller particles and higher zeta potential than corresponding lipoplexes. Next, we investigated the lipoplex library in an on-chip cell-based screening using reverse transfection of HEKT cells Fig. On-chip reversed cell transfection screening of the produced lipoplex library. ScreenFect A was used as a positive control, while dilution buffer without pDNA and untreated cells served as negative controls.

The process of developing biologically active compounds and potential drug candidates is difficult due to several factors. The transfer of commercially available drug libraries into a suitable screening format poses huge handling and logistics challenges. The parallel addition of reagents and solutions, and the transfer to another platform requires many multi-pipetting steps and thus large amounts of consumables as well as the loss of material due to large dead volumes.

The handling of very large drug libraries is often impossible for a single individual to accomplish within a reasonable time. Additional labor costs make the development of bioactive compounds prohibitively expensive. Furthermore, commercially available drug libraries are extremely costly, and the number of available compounds remains limited. Synthesizing new compounds is very time- and resource-consuming, since traditional solution-based organic synthesis is not designed for miniaturized and parallelized applications. In addition, the temporal and spatial separation of synthesis, characterization, and biological screening significantly slows down entire biological discovery and drug development pipelines.

There is currently no system that could efficiently hyphenate these parts. To solve these challenges, we developed a chemBIOS platform that unifies the miniaturized combinatorial solution-based organic synthesis in the microarray format and biological high-throughput screenings. The platform uses LSTL slides with omniphobic-omniphilic patterns to form arrays of organic solvents, where each droplet functions as a separate microreactor for solution-based organic synthesis. Furthermore, sandwiching the array with another droplet array enables the rapid and parallel addition, transfer, and copying of the whole library.

For example, we carried out a three-component lipidoid combinatorial synthesis to create a library of 25 small molecules in triplicates Fig. By sandwiching two droplet arrays, we simultaneously mixed all educts in 75 droplets and thus initiated the synthesis of an entire library in a single step Fig. Although this platform can be readily utilized for many types of solution-based reactions using various organic or aqueous solvents, there are still some challenges in adapting other chemical techniques. Reactions at elevated temperatures and highly exothermic reactions as well as adding solid reagents or purging gaseous educts might be difficult to realize using the chemBIOS platform in its current state.

Chemical reactions requiring a protective atmosphere or controlled pressure are feasible, but would require a closed chamber with controlled pressure and atmosphere. On-chip parallel high-throughput purification is another key challenge that we will be focusing on in future studies.

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The advantages of the chemBIOS platform are that its configuration is open and flat, making all microcompartments accessible and potentially compatible with parallel high-throughput purification methods, e. Due to the low sensitivity, most organic synthesis characterization methods are often incompatible with the micro-, nano- or even picomolar scale reactions required for high-throughput miniaturized synthetic applications. The open system of the chemBIOS platform enabled us to copy the entire droplet-based library in a single step by stamping it onto a MALDI plate, followed by mass spectrometric analysis Fig.

We also demonstrated the feasibility of transferring the chemical compounds from the LSTL to a HSTL slide in a parallel manner that enables rapid and convenient hyphenation between the two realms—chemical and biological. We used HSTL slides to create highly hydrophilic-hydrophobic microarrays that could be used to form the arrays of aqueous droplets needed for biochemical and cellular screenings. We demonstrate the single-step transfer of the entire lipidoid library from the platform for organic solvents LSTL slide to the platform for aqueous solvents HSTL slide by simply sandwiching both types of slides.

The single-step formation of liposomes and lipoplexes during this transfer step was proved by dynamic light scattering and zeta potential analysis—observing higher zeta potentials for liposomes than for lipoplexes Fig. The lipoplexes we produced were successfully screened with cells by printing cellular suspension into the individual spots containing lipoplexes to perform a reversed cell transfection experiment Fig.

The screening of lipidoids to determine their cell transfection efficiency using plasmid DNAs is an example of a biological assay that is combinable with synthesized libraries. Overall, this demonstrates the possibility to hyphenate combinatorial organic chemistry with biological screenings using the chemBIOS platform. Unifying chemistry and biology both temporally and spatially on the same platform accelerates the entire process of developing bioactive compounds important for various applications.

Current Organic Synthesis, Volume 15 - Number 2

Using the chemBIOS platform, in situ synthesized small molecule libraries can be screened immediately for their biological activity, thereby saving time, effort, chemicals, cells, and other consumables. This allowed us to repeat the whole process from the synthesis to the biological screening multiple times; our final analysis of transfection efficiency by fluorescence microscopy yielded reproducible transfection results for all the library compounds Fig.

The platform is compatible with further miniaturization, despite possible future challenges associated with further reductions in droplet size, such as faster solvent evaporation, difficult alignment during the sandwiching process, compatibility with and sensitivity of analytical methods.


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In summary, by unifying on-chip in situ miniaturized and parallelized solutions-based combinatorial synthesis of bioactive compounds, the feasibility of rapid and parallel characterization by copying the library microarray onto a separate slide for analysis e. MALDI-MS , and on-chip biological and cellular screenings, the chemBIOS platform hyphenates all aspects of early-stage drug discovery, which will be useful for various other biological or biotechnological screening applications.


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The surface was patterned by first generating the hydrophobic borders. Round hydrophilic spots with a diameter of 2. An activated glass slide was modified by inserting into modification mixture 0.

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Round omniphilic spots with a diameter of 2. On-chip synthetic procedure was performed in a standard chemistry fume hood. Solvent was evaporated in a desiccator under vacuum. We evaporated the solvent under high vacuum and dissolved the raw product in deuterated chloroform VWR for analysis. The on-chip synthesis of a lipidoid library via the printing method was performed by printing 1. Next, 1. On-chip purification was performed in a standard chemistry fume hood: Three microliter per spot of a mixture of Nile red 2.

In all, 4. For positive control we used ScreenFect dilution buffer containing 0. In a PCR tube we mixed In a separate PCR tube, we mixed 1.