4‐Methyltetrahydropyran (4‐MeTHP): Application as an Organic Reaction Solvent

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a promising target for anticancer therapy due to its ability to counter the effects topoisomerase 1 (Top1) poison, such as topotecan, thus, decreasing their efficacy. Compounds containing adamantane and monoterpenoid residues connected via 1,2,4-triazole or 1,3,4-thiadiazole linkers were synthesized and tested against Tdp1. All the derivatives exhibited inhibition at low micromolar or nanomolar concentrations with the most potent inhibitors having IC50 values in the 0.35–0.57 µM range. The cytotoxicity was determined in the HeLa, HCT-116 and SW837 cancer cell lines; moderate CC50 (µM) values were seen from the mid-teens to no effect at 100 µM. Furthermore, citral derivative 20c, α-pinene-derived compounds 20f, 20g and 25c, and the citronellic acid derivative 25b were found to have a sensitizing effect in conjunction with topotecan in the HeLa cervical cancer and colon adenocarcinoma HCT-116 cell lines. The ligands are predicted to bind in the catalytic pocket of Tdp1 and have favorable physicochemical properties for further development as a potential adjunct therapy with Top1 poisons.

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“…(E)-1-Bromo-3,7-dimethylocta-2,6-diene 19c, yield 84%. The spectral data were consistent with those in the literature [49].…”

Section: General Procedures For Synthesis Of Bromidessupporting

confidence: 90%

Novel Tdp1 Inhibitors Based on Adamantane Connected with Monoterpene Moieties via Heterocyclic Fragments

et al. 2021

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“…Green chemistry is an increasing trend not only in chemical industry but also in academia. 59 − 62 Despite the environmental needs and the availability of many alternative solvents such as water, 63 ethyl acetate, 64 , 65 dimethyl carbonate, 66 , 67 2-MeTHF, 68 , 69 and 4-MeTHP, 61 , 70 the usage of green solvent for olefin metathesis is relatively scarce. We therefore screened both the general-purpose Hoveyda–Grubbs second-generation catalyst ( Ru1 , see Figure 1 ) and the tagged StickyCat PF 6 ( Ru2 ) in RCM of diethyl diallylmalonate ( 1 ) used as a model substrate, in two solvent systems—DCM (not green) and EtOAc (green).…”

Section: Results and Discussionmentioning

confidence: 99%

Olefin Metathesis in Continuous Flow Reactor Employing Polar Ruthenium Catalyst and Soluble Metal Scavenger for Instant Purification of Products of Pharmaceutical Interest

Toh

Patrzałek

Nienałtowski

et al. 2021

ACS Sustainable Chem. Eng.

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In recent years, the development of continuous-flow reactors has attracted growing attention from the synthetic community. Moreover, findings in the precise control of the reaction parameters and improved mass/heat transfer have made the flow setup an attractive alternative to batch reactors, both in academia and industry, enabling safe and easy scaling-up of synthetic processes. Even though a majority of the pharmaceutical industry currently rely on batch reactors or semibatch reactors, many are integrating flow technology because of easier maintenance and lower risks. Herein, we demonstrate an operationally simple flow setup for homogeneous ring-closing metathesis, which is applicable to the synthesis of active pharmaceutical ingredients precursors or analogues with high efficiency, low residence time, and in a green solvent. Furthermore, through the addition of a soluble metal scavenger in the subsequent step within the flow system, the level of ruthenium contamination in the final product can be greatly reduced (to less than 5 ppm). To ensure that this method is applicable for industrial usage, an upscale process including a 24 h continuous-flow reaction for more than 60 g of a Sildenafil analogue was achieved in a continuous-flow fashion by adjusting the tubing size and flow rate accordingly.

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“…4-MeTHP can be utilized under acidic or alkaline conditions, thus it is being used as a solvent in esterifications, radical reactions, Grignard and Wittig reactions, halogen-metal exchange, in reductions and oxidations, including epoxidation, and many other organic reactions. 45 Due to all these advantages and green chemistry perspectives, it is expected that this solvent will find a broad range of applications, especially in industrial processes, as it was suggested in an elegant exploratory study by Kobayashi et al 45 To the best of our knowledge, however, 4-MeTHP has not yet been tested in olefin metathesis reactions promoted by modern second-generation catalysts. 46…”

Section: Introductionmentioning

confidence: 99%

4-Methyltetrahydropyran as a Convenient Alternative Solvent for Olefin Metathesis Reaction: Model Studies and Medicinal Chemistry Applications

Nienałtowski

Krzesiński

Baumert

et al. 2020

ACS Sustainable Chem. Eng.

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A number of metathesis reactions were successfully conducted in 4-methyltetrahydropyran, including both standard model dienes, as well as more complex substrates, such as analogues of biologically active compounds and active pharmaceutical ingredients. To place this solvent in a context of pharmaceutical R + D, larger-scale syntheses of SUAM 1221, a prolyl endopeptidase inhibitor with potential application in Alzheimer disease treatment, and a derivative of sildenafil, an analogue of the popular Viagra drug, were executed. In the latter case, despite all the setup being made in air, the metathesis reaction at a 33 g scale proceeded very well with relatively low catalyst loading and without need of aqueous workup or column chromatography.

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4‐Methyltetrahydropyran (4‐MeTHP): Application as an Organic Reaction Solvent

Cited by 21 publications

References 65 publications

Novel Tdp1 Inhibitors Based on Adamantane Connected with Monoterpene Moieties via Heterocyclic Fragments

Novel Tdp1 Inhibitors Based on Adamantane Connected with Monoterpene Moieties via Heterocyclic Fragments

Olefin Metathesis in Continuous Flow Reactor Employing Polar Ruthenium Catalyst and Soluble Metal Scavenger for Instant Purification of Products of Pharmaceutical Interest

4-Methyltetrahydropyran as a Convenient Alternative Solvent for Olefin Metathesis Reaction: Model Studies and Medicinal Chemistry Applications

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