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Synthesis of 1-(4-hydroxy-3-methoxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid derivatives as mast cell stabilizers

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Abstract

The role of mast cells can be protective or harmful; depending upon the physiological/pathological condition in which they get activated. The latter role is due to mast cell degranulation and release of an array of incendiary mediators. Mast cells have a well-established role in diseases like allergy, eczema, anaphylactic shock, mastocytosis, and other miscellaneous mast cell diseases. Previously, we have shown that spiro-β-carboline alkylated analogs have mast cells stabilization activity. Recently, tryptophan has been reported to suppress the mast cell activation. Indeed, vanillin analogs were reported to inhibit degranulation. Hence, it is worthwhile to synthesize 21 constrained analogs of tryptophan with vanillin which are derivatives of 2,3,4,9-tetrahydro-β-carboline-3-carboxylic acid and their evaluation for ex-vivo inhibition of the compound 48/80 induced mast degranulation activity. By comparing IC50 (µM) values with standard drug cromolyn sodium (IC50 = 0.486 ± 0.003 µM), the bulky group compounds like tri-substituted isopropyl (compound 7; cis-1-(4-Isopropoxy-3-methoxyphenyl)-2,9-diisopropyl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid; IC50 = 0.389 ± 0.015 µM) and tri-substituted octyl (compound 17; cis-1-(3’-Methoxy-4’-(octyloxy)phenyl)-2,9-dioctyl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid; IC50 = 0.237 ± 0.031 µM) were found to be equipotent. Furthermore, the polar group SO2 containing compound tosyl derivative (compound 21; cis-1-(4’-hydroxy-3’-methoxyphenyl)-2-tosyl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid; IC50 = 1.16 ± 0.080 µM) also showed marked potency. This is an important study of β-carboline derivatives showing mast cell stabilization having a wider scope in mast cell research, although their mechanism remains to be unknown.

Highlights

  • Diastereoselective Pictet–Spengler cyclization to form tetrahydro β-carboline derivatives.

  • Constrained analogs of tryptophan and vanillin.

  • Cis and trans isomers.

  • Mast cells stabilization.

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Acknowledgements

We would like to thank University Grant Commission, New Delhi for providing research grant (F.No. 41-1378/2012) for mast cell stabilizers research. The authors sought to sincerely thank S. Avtar Singh for his erudition towards NMR (SAIF, Panjab University, Chandigarh). We would also like to thank the Department of Chemistry & Biochemistry, Brigham Young University, Provo, Utah for their help. Moreover, we would like to thank Dr Amandeep Gargi (PhD Microbiology, USA), Miss Amanpreet Kaur and Miss Sheenam Goyal, Mr Jaskaran Walia and Mr Karan Dutt (Punjabi University, Patiala).

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  1. These authors contributed equally to the research work and to drafting the manuscript: Karan Saini, Jatinder Singh, Ramanpreet Shah

Authors and Affiliations

  1. Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, 147002, India

    Karan Saini, Jatinder Singh, Ramanpreet Shah, Jaspreet Kaur, Dhandeep Singh, Nirmal Singh, Amteshwar Singh Jaggi & Dimple Sethi Chopra

  2. Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT, 84602, United States

    Jatinder Singh

  3. Department of Biotechnology, Punjabi University, Patiala, Punjab, 147002, India

    Ram Sarup Singh

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Saini, K., Singh, J., Shah, R. et al. Synthesis of 1-(4-hydroxy-3-methoxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid derivatives as mast cell stabilizers. Med Chem Res 29, 1400–1412 (2020). https://doi.org/10.1007/s00044-020-02555-y

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