High-throughput Parallel Synthesis Research Articles

Performance and robustness of small molecule retention time prediction with molecular graph neural networks in industrial drug discovery campaigns

This study explores how machine-learning can be used to predict chromatographic retention times (RT) for the analysis of small molecules, with the objective of identifying a machine-learning framework with the robustness required to support a chemical synthesis production platform. We used internally generated data from high-throughput parallel synthesis in context of pharmaceutical drug discovery projects. We tested machine-learning models from the following frameworks: XGBoost, ChemProp, and DeepChem, using a dataset of 7552 small molecules. Our findings show that two specific models, AttentiveFP and ChemProp, performed better than XGBoost and a regular neural network in predicting RT accurately. We also assessed how well these models performed over time and found that molecular graph neural networks consistently gave accurate predictions for new chemical series. In addition, when we applied ChemProp on the publicly available METLIN SMRT dataset, it performed impressively with an average error of 38.70 s. These results highlight the efficacy of molecular graph neural networks, especially ChemProp, in diverse RT prediction scenarios, thereby enhancing the efficiency of chromatographic analysis.

Direct Deaminative Functionalization.

Selective functional group interconversions in complex molecular settings underpin many of the challenges facing modern organic synthesis. Currently, a privileged subset of functional groups dominates this landscape, while others, despite their abundance, are sorely underdeveloped. Amines epitomize this dichotomy; they are abundant but otherwise intransigent toward direct interconversion. Here, we report an approach that enables the direct conversion of amines to bromides, chlorides, iodides, phosphates, thioethers, and alcohols, the heart of which is a deaminative carbon-centered radical formation process using an anomeric amide reagent. Experimental and computational mechanistic studies demonstrate that successful deaminative functionalization relies not only on outcompeting the H-atom transfer to the incipient radical but also on the generation of polarity-matched, productive chain-carrying radicals that continue to react efficiently. The overall implications of this technology for interconverting amine libraries were evaluated via high-throughput parallel synthesis and applied in the development of one-pot diversification protocols.

High-Throughput Preparation of Supramolecular Nanostructures on Metal Surfaces.

One of the contemporary challenges in materials science lies in the rapid materials screening and discovery. Experimental sample libraries can be generated by high-throughput parallel synthesis to map the composition space for rapid material discoveries. Molecular self-assembly on surfaces has proved a useful way to construct nanostructures with interesting topologies or properties. Despite the strong dependence of molecular stoichiometry on the structures, high-throughput preparations of supramolecular surface nanostructures have been far less explored. Here, by integrating a physical mask into the standard ultra-high-vacuum (UHV) molecular preparation system we show a high-throughput approach for preparing supramolecular nanostructures of continuous composition spreads on metal surfaces. The spatially addressable sample libraries of supramolecular self-assemblies are characterized by high-resolution scanning probe microscopy. We could explore different binary nanostructures of varying molecular ratios on one single substrate. Moreover, we use the minimum spanning tree approach to qualitatively and quantitatively study the structural properties of the formed nanostructures. This high-throughput approach may accelerate the screening and exploration of surface-supported, low-dimensional nanostructures not limited to supramolecular interactions.

Efficient molecular encoding in multifunctional self-immolative urethanes

SUMMARYMolecular encoding in sequence-defined polymers shows promise as a new paradigm for data storage. Here, we report what is, to our knowledge, the first use of self-immolative oligourethanes for storing and reading encoded information. As a proof of principle, we describe how a text passage from Jane Austen’s Mansfield Park was encoded in sequence-defined oligourethanes and reconstructed via self-immolative sequencing. We develop Mol.E-coder, a software tool that uses a Huffman encoding scheme to convert the character table to hexadecimal. The oligourethanes are then generated by a high-throughput parallel synthesis. Sequencing of the oligourethanes by self-immolation is done concurrently in a parallel fashion, and the liquid chromatography-mass spectrometry (LC-MS) information decoded by our Mol.E-decoder software. The passage is capable of being reproduced wholly intact by a third-party, without any purifications or the use of tandem MS (MS/MS), despite multiple rounds of compression, encoding, and synthesis.

Research Progress on High Throughput Parallel Synthesis of Micro-nano Powders Libraries

Research Progress on High Throughput Parallel Synthesis of Micro-nano Powders Libraries

Abstract 4789: Clinical candidate DBPR112: A novel epidermal growth factor receptor inhibitor as a promising treatment for non-small cell lung cancer

Abstract Lung cancer is one of the chief causes of cancer death in the world; in addition, non-small cell lung cancer (NSCLC) accounts for 85% of the lung cancer deaths. The development of tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) have shown remarkable effects in patients but some acquired resistance after treatment. Therefore, the discovery of efficacious EGFR-TKIs poses an utmost priority. Our team at IBPR has designed and synthesized a series of compounds by high throughput parallel synthesis platform. In the subsequent structure-activity relationship study (SAR) and lead optimization, approximate 150 compounds were synthesized, which concluded that the presence of an N,N-dimethyl functional group on the Michael acceptor and the S-chirality of the phenylaminoethanol side chain were both essential. Consequently, DBPR112 was identified as a potent EGFR-TKI clinical candidate showing excellent inhibitory ability on EGFRL858R/T790M and EGFR exon 20 insertion. DBPR112 was orally effective against the growth of human lung H1975 tumors subcutaneously xenografted in nude mice. A dramatic reduction in tumor size was noted with DBPR112 treatment, while displaying negligible body weight loss in all dosing groups. Furthermore, DBPR112 was more tolerable than afatinib in mice. To date, all pre-clinical studies were completed, and the IND application of DBPR112 was approved by US FDA in 2016 and the Phase I clinical trial has been initiated since July 2017 in Taiwan. Citation Format: Hsing-Pang Hsieh, Jang-Yang Chang, Ching-Chuan Kuo, John Hsu. Clinical candidate DBPR112: A novel epidermal growth factor receptor inhibitor as a promising treatment for non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4789.

Facile synthesis of semi-library of low charge density cationic polyesters from poly(alkylene maleate)s for efficient local gene delivery

Cationic polymers are one of the main non-viral vectors for gene therapy, but their applications are hindered by the toxicity and inefficient transfection, particularly in the presence of serum or other biological fluids. While rational design based on the current understanding of gene delivery process has produced various cationic polymers with improved overall transfection, high-throughput parallel synthesis of libraries of cationic polymers seems a more effective strategy to screen out efficacious polymers. Herein, we demonstrate a novel platform for parallel synthesis of low cationic charge-density polyesters for efficient gene delivery. Unsaturated polyester poly(alkylene maleate) (PAM) readily underwent Michael-addition reactions with various mercaptamines to produce polyester backbones with pendant amine groups, poly(alkylene maleate mercaptamine)s (PAMAs). Variations of the alkylenes in the backbone and the mercaptamines on the side chain produced PAMAs with tunable hydrophobicity and DNA-condensation ability, the key parameters dominating transfection efficiency of the resulting polymer/DNA complexes (polyplexes). A semi-library of such PAMAs was exampled from 7 alkylenes and 18 mercaptamines, from which a lead PAMA, G-1, synthesized from poly(1,4-phenylene bis(methylene) maleate) and N,N-dimethylcysteamine, showed remarkable transfection efficiency even in the presence of serum, owing to its efficient lysosome-circumventing cellular uptake. Furthermore, G-1 polyplexes efficiently delivered the suicide gene pTRAIL to intraperitoneal tumors and elicited effective anticancer activity.

Abstract 2530: Optimization of 5,6-fused pyrimidine-based kinase inhibitors by computer-aided drug design for the treatment of AML

Abstract FMS-like receptor tyrosine kinase-3 (FLT3), a member of the class III tyrosine kinase receptor family, is expressed by immature hematopoietic cells, and highly associates with acute myeloid leukemia (AML). While acquired resistance to selective FLT3 inhibitors, the treatment became inefficient. Many literatures suggested that dual FLT3-Aurora inhibition may overcome selective FLT3 inhibitor resistance, in part due to inhibition of Aurora kinase, and may benefit patients with FLT3-mutated AML. Thus, utilizing dual FLT3-Aurora inhibitors may be the viable therapy for the treatment of AML. Recently, our group reported a novel AURKA inhibitor by using high-throughput parallel synthesis and structure-based drug design (SBDD). Based on this, we wanted to modify the selective AURKA inhibitor to maintain its Aurora A inhibition as well as improve its FLT3 activity to develop dual FLT3-Aurora kinase inhibitors. Through rapid construction of the platform of FLT3 virtual screening, the lead was quickly and efficiently identified. Proceeding investigation of structure-activity relationship could lead to 6-phenyl pyrrolopyrimidine analogue, showing FLT3 inhibition with an IC50 of 101 nM as well as Aurora kinase A inhibition with an IC50 of 33 nM. To further increase the level of inhibition of FLT3, binding energy calculations and docking study of FLT3 model were introduced to select terminal groups of the side chain with high priority. The selected compounds were synthesized and evaluated the bioactivity. The dramatic antiproliferation of the dual FLT3-AURKA inhibitor against MOLM-13 and MV4-11 (FLT3-ITD (+) human AML cell lines) was observed, and its biologic mechanism of inhibition of FLT3 and Aurora kinase A was proved the by significant evidence of biomarker. For this finding, this novel inhibitor holds potential for further development of preclinical investigations as an anti-AML drug candidate. Citation Format: Yung Chang Hsu, Hui-Yi Shiao, Yi-Yu Ke, John T. A. Hsu, Wen-Hsing Lin, Chun-Hwa Chen, Hsing-Pang Hsieh. Optimization of 5,6-fused pyrimidine-based kinase inhibitors by computer-aided drug design for the treatment of AML. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2530. doi:10.1158/1538-7445.AM2014-2530

ChemInform Abstract: Use of Ionic Liquids as Neoteric Solvents in the Synthesis of Fused Heterocycles

AbstractReview: [125 refs.

Use of ionic liquids as neoteric solvents in the synthesis of fused heterocycles.

Medicinal chemistry has been benefited by combinatorial chemistry and high-throughput parallel synthesis. Ionic liquids reduce the materials and energy intensity of chemical processes and products, minimize or eliminate the dispersion of harmful chemicals in the environment, maximize the use of renewable resources and extend the durability and recyclability of products. It is possible to tune the physical and chemical properties by varying the nature of the cations and anions. Ionic liquids can be easily recovered, cleaned up, and reused repeatedly.

ChemInform Abstract: Relevance of Sonochemistry or Ultrasound (US) as a Proficient Means for the Synthesis of Fused Heterocycles

AbstractReview: 52 refs.

Discovery and optimization of a new class of potent and non-chiral indole-3-carboxamide-based renin inhibitors

Selective inhibition of the aspartyl protease renin has gained attraction as an interesting approach to control hypertension and associated cardiovascular risk factors given its unique position in the renin–angiotensin system. Using a combination of high-throughput screening, parallel synthesis, X-ray crystallography and structure-based design, we identified and optimized a novel series of potent and non-chiral indole-3-carboxamides with remarkable potency for renin. The most potent compound 5k displays an IC 50 value of 2 nM.

ChemInform Abstract: Comparison of Monomode and Multimode Microwave Equipment in Suzuki—Miyaura Reactions — en Route to High Throughput Parallel Synthesis under Microwave Conditions.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Comparison of monomode and multimode microwave equipment in Suzuki–Miyaura reactions— en route to high throughput parallel synthesis under microwave conditions

The microwave heated Suzuki–Miyaura cross-coupling reaction of boronic acids, boronic esters and organotrifluoroborates served as a model reaction in a singlemode equipment. The reaction conditions were optimized with respect to temperature and reaction time and were transferred to multimode equipment which is well suited for multiparallel synthesis in a larger scale. The source of the Pd species chosen included immobilized Pd complexes and Pd particles. In fact the increased time to reach the required reaction time in multimode chambers suitable for 48 parallel reactions has to be taken into account. The nature of the boronic acid has no impact on the efficiency of the catalytic process. However, heterogenized Pd species perform less well in multimode chambers with larger vial volumes, which we ascribe to diffusion phenomena.

Composition-spread thin films of pentacene and 6,13-pentacenequinone fabricated by using continuous-wave laser molecular beam epitaxy

Synthesis of continuous composition-spread (CCS) thin films is widely recognized in combinatorial material science as a powerful technique for rapidly investigating the properties of new functional materials. However, there are very few reports of CCS organic thin films due to the fact that the thermal evaporation method with Knudsen cells, which is commonly used to fabricate organic thin films in vacuum, does not offer the necessary level of deposition rate control as, for example, does pulsed laser deposition (PLD). We have successfully fabricated organic CCS thin films of pentacene and 6,13-pentacenequinone by continuous-wave laser molecular beam epitaxy (CWL-MBE), which we developed as a new fabrication method for organic thin films. The composition-spread films were characterized systematically by ultraviolet–visible spectroscopy, Fourier transform infrared spectroscopy, X-ray diffraction, atomic force microscopy, and two-probe conductivity measurements. The present work brings the advantages of high-throughput parallel synthesis and systematic characterization to the field of organic electronics, allowing for quick exploration and rapid optimization of organic functional materials and devices.

Optimization of Thermoelectric Properties of Ni-Cu based Alloy through Combinatorial Approach

AbstractThe thermoelectric properties of Ni1-xCux (0<x<1) alloy are measured from 323K to 950K. The sample with optimized composition, Ni70Cu30 is found to possess large power factor value of 0.012 Wm−1K−2 at around 950K. Estimated figure of merit value ZT is 0.21 for Ni50Cu50 and 0.18 for Ni70Cu30 at the same temperature. A novel attempt of high-throughput parallel synthesis using multiple-wells is carried out to test the feasibility of combinatorial approach in this material system. The Seebeck coefficient is visualized over the multiple-wells combinatorial library and the other Ni-Cu composition-spread, and it is proved that further enhancement of throughput could be possible by conducting systematic experiments based on the combinatorial approaches performed in this study.

Rapid synthesis and fluorous-phase purification of α-perfluorohexyloligothiophenes

A high-throughput methodology that facilitates the synthesis, purification and characterisation of π-conjugated oligothiophenes has been developed. α-Perfluorohexyltetrathiophene was synthesised by sequential α-bromination and microwave promoted Stille cross-coupling reactions. Each synthetic transformation was followed by a fluorous solid-phase extraction (F-SPE) procedure to isolate the desired α-perfluorohexyloligothiophene. After a single F-SPE, each oligomer gave essentially one peak by GC–MS, which enabled stepwise growth of a tetrathiophene with no additional purification of the intermediate building blocks required. We anticipate that microwave accelerated synthesis in conjunction with fluorous-phase purification of π-conjugated systems will find generic application in the high-throughput parallel-synthesis of novel organic materials for semiconductor applications.

One-minute full-gradient HPLC/UV/ELSD/MS analysis to support high-throughput parallel synthesis.

High-throughput parallel synthesis of library compounds for early drug discovery requires high-throughput analytical methods to confirm synthesis, identify reaction products, and determine purity. An ultrafast 1.0-min HPLC/UV/ELSD/MS method was developed and compared to our standard 2.5- and 5.0-min methods in order to determine if the faster method was appropriate to evaluate compound synthesis and determine purity. In addition to using standard test mixtures, a 400-member library produced by high-throughput parallel synthesis was used for comparing the various methods. Mass spectrometric detection was used for compound identification, while UV and ELSD data offered purity assessment. Compared to our longer separations, chromatographic separation achieved using the 1.0-min method was sufficient for compound evaluation and purity assessment. This ultrafast 1.0-min HPLC/UV/ELSD/MS method is expected to increase analytical throughput tremendously, provide important information faster, and reduce the overall cycle time from synthesis to screening.

Automation highlights from literature

Automation highlights from literature

Optimizing Preparative LC/MS Configurations and Methods for Parallel Synthesis Purification

Preparative LC/MS is widely employed to address the high-throughput purification demands of parallel synthesis. However, conflicting chromatography requirements and the complexities of applying MS-directed fractionation can limit its effectiveness in high-throughput parallel synthesis schemes. We report here an at-column dilution small-scale preparative LC configuration which satisfies the mass loading (>20 mg) and small fraction volume (<1.5 mL) requirements of discovery parallel synthesis schemes employing plate mapping. We also present a protocol for compound-specific optimization of the preparative gradient LC method and MS threshold for fractionation from a “prepreparative” LC/MS analysis of the crude material. We will demonstrate significantly improved preparative separations (relative to “universal” prep LC methods) and the selection of reliable and effective fraction threshold methods for diverse libraries. The methods and configurations are simple to implement and are equally suited for “open acc...