1-Tetralone is a reagent used in the synthesis of amino-pyrazolopyridines with anti-NF-κB and pro-apoptotic potential. In terms of its structure, it can also be regarded as benzo-fused cyclohexanone.

1-tetralone chalcone derivatives against LPS-stimulated reactive oxygen species

Inflammation is an important part of the body’s immune response to any kind of infections, injury, pain, toxin, or stimuli. During the processes of wound healing, these responses are of vital importance for removing infections. However, if they persist longer than necessary, can cause harmful effects, resulting in chronic inflammation.  1-Tetralones, also known as 3,4-dihydro-2H-napthalen-1-one, are important class of compounds, and several derivatives of them have shown important biological activities such as anti-tumor, neurological disorders, and antimicrobial activity. Similarly, the novel amine derivatives of 4-amino-3,4-dihydro-2H-napthalen-1-one studied by Barlow et al. displayed significant mast cell stabilizing property, and it was also interesting to know that the 1-tetralone nucleus along with aminocyclopentyl group was necessary for exerting the anti-inflammatory effects. In this present study, we report the design and synthesis of a series of thirty-two 1-tetralone or 6-amino-1-tetralone along with halogenated functionalities on 2-benzylidene moiety at ortho, meta, or para-position which were evaluated for their inhibitory effects against the ROS-production in LPS-stimulated 264.7 macrophages.[1]

SAR was also analyzed by comparing the various rigid chalcone derivatives reported previously by our research group with 1-tetralone and 6-amino-1-tetralone substituted chalcone derivatives. In conclusion, we have systematically designed and synthesized a series of thirty-two halogenated 1-tetralone and 6-amino-1-tetralone chalcone derivatives using Claisen-Schmidt condensation reaction. The synthesized compounds were evaluated for the inhibitory effect on ROS production stimulated by LPS in RAW 264.7 macrophages. Among them, compounds 18 possessing 6-amino-1-tetralone chalcone moiety showed the strongest inhibitory activity of ROS production stimulated by LPS in RAW 264.7 macrophages. SAR study revealed that chalcone derivatives having 1-tetralone skeleton is responsible for exhibiting the potent ROS inhibition than that of previously reported 1-indanone or 4-chromanone skeleton bearing chalcone derivatives. In addition, amino substitution at the 6th position of 1-tetralone skeleton greatly increased inhibitory activity of ROS production stimulated by LPS in RAW 264.7 macrophages. These results would provide new insights to the researchers working to develop novel anti-inflammatory agents.

The evaluation of 1-tetralone derivatives as inhibitors of monoamine oxidase

The monoamine oxidase (MAO) enzymes are of much clinical interest since they metabolise neurotransmitter and dietary amines in the peripheral and central tissues. Based on reports that it act as MAO inhibitors, this study synthesised a series of 1-tetralone derivatives in an effort to expand on the structure–activity relationships (SARs) of MAO inhibition by this class of compounds. In particular, the effect on MAO inhibition of the reduction of the 1-tetralone carbonyl group to the corresponding alcohol was determined. The chemical modifications that were made to it included substitution on C5, C6 and C7 and reduction of the carbonyl to the corresponding alcohol. 4-Chromanone compounds are the corresponding pyranone analogues of 1-tetralone and with appropriate substitution, may be expected to act as suitable scaffolds for the design of MAO inhibitors. The C7 position was selected since substitution of 1-tetralones on C7 yields significantly better MAO inhibition than substitution on C6.[2]

This study investigates the MAO inhibition properties of a series of 1-tetralone and 4-chromanone derivatives and finds that these compounds are specific inhibitors of the MAO-B isoform. Among these series, 28 MAO-B inhibitors with submicromolar inhibition potencies are reported. Good-potency MAO-A inhibitors have also been identified, with eight compounds possessing submicromolar IC50 values. Highly potent MAO-B inhibitors were present among both series with 11 compounds exhibiting IC50?<?0.01 μM. Considering the MAO inhibition data of the 1-tetralone compounds of this study and those that have been reported in the literature, the following key conclusions may be made: (1) It is clear that substitution on C7 yields more potent inhibition of both MAO-A and MAO-B than substitution on C6, which in turn leads to more potent inhibition than substitution on C5. It may also be expected that the addition of a chlorine to the side chain will increase MAO-B inhibition potency since this will lead to additional van der Waals interactions. Similarly, the good MAO-B inhibition observed with the 4-chromanone derivatives may be dependent on the enhanced polarity of this moiety (compared to 1-tetralone) and thus the increased potential for polar interactions in the MAO-B substrate cavity.

Asymmetric Synthesis of 1-Tetralones Bearing A Remote Quaternary Stereocenter

All-carbon quaternary stereocenters commonly exist in natural products and bioactive molecules. On the other hand, carbon?carbon bond (C?C) activation reactions catalyzed by transition metals allow for deconstructive rearrangement of carbon skeletons, thereby enabling new strategic bond disconnections for constructing complex molecules. In this context, 1-tetralones bearing a C4 quaternary center have been found in many bioactive compounds and often serve as important synthetic intermediates; however, they are nontrivial to prepare asymmetrically.  If enantioenriched cyclopentanones that contain a β quaternary stereocenter could be used as substrates, a convenient enantioselective preparation of 1-tetralones bearing a C4 quaternary center would be realized. Here, we describe the development of a catalytic C?C activation approach for constructing remote all-carbon quaternary centers in 1-tetralones.[3]

In summary, scientists have demonstrated a unique approach to access enantioenriched 1-tetralones with an all-carbon quaternary stereocenter that is remote from the carbonyl moiety. Through a two-step sequence of Pd-catalyzed asymmetric conjugate addition and Rh-catalyzed C?C activation, chiral 1-tetralones have been obtained in good overall yields and excellent enantioselectivity from readily available cyclopentenones and arylboronic acids. The scalability and chemoselectivity could make this method attractive for complex molecule synthesis. While the current scope is limited to 1-tetralone products, the strategy–that is forming a proximal stereocenter with established methods and then transporting it to a distal position–could have broad implications beyond this work.

References

[1]Katila P, Shrestha A, Shrestha A, Shrestha R, Park PH, Lee ES. Introduction of amino moiety enhances the inhibitory potency of 1-tetralone chalcone derivatives against LPS-stimulated reactive oxygen species production in RAW 264.7 macrophages. Bioorg Chem. 2019 Jun;87:495-505. doi: 10.1016/j.bioorg.2019.03.055. Epub 2019 Mar 20. PMID: 30927590.

[2]Cloete SJ, N'Da CI, Legoabe LJ, Petzer A, Petzer JP. The evaluation of 1-tetralone and 4-chromanone derivatives as inhibitors of monoamine oxidase. Mol Divers. 2021 Feb;25(1):491-507. doi: 10.1007/s11030-020-10143-w. Epub 2020 Sep 24. PMID: 32970293; PMCID: PMC7512223.

[3]Ochi S, Xia Y, Dong G. Asymmetric Synthesis of 1-Tetralones Bearing A Remote Quaternary Stereocenter through Rh-Catalyzed C-C Activation of Cyclopentanones. Bull Chem Soc Jpn. 2020;93(10):1213-1217. doi: 10.1246/bcsj.20200147. Epub 2020 Jun 5. PMID: 34675442; PMCID: PMC8528243.