Design and synthesis of nature-inspired chromenopyrroles as potential modulators of mitochondrial metabolism

Abstract

Chromenopyrrole derivatives with multiple stereocenters and variable ring fusion pattern are found in many natural products and biologically appealing molecules. By employing a build/couple/pair strategy, we have recently reported on the discovery of a serendipitous cascade to access a diverse collection of chromenopyrroles. This protocol features a one-pot cascade that includes the generation of azomethine ylide and intramolecular [3 + 2]-cycloaddition. Phenotypic screening of the developed pilot library enabled the identification of chemical probes that efficiently suppress mitochondrial membrane potential, elevate reactive oxygen species content, and deplete ATP content in a hepatoma cell line (Hepa1-6), without affecting the proliferation of T- or B-cells. This selective targeting represents a new approach for the treatment of cancer.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Scheme 1
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. 1.

    Clemons PA, Wilson JA, Dancik V, Muller S, Carrinski HA, Wagner BK, et al. Quantifying structure and performance diversity for sets of small molecules comprising small-molecule screening collections. Proc Natl Acad Sci USA. 2011;108:6817–22.

    CAS  PubMed  Google Scholar 

  2. 2.

    Luker T, Alcaraz L, Chohan KK, Blomberg N, Brown DS, Butlin RJ, et al. Strategies to improve in vivo toxicology outcomes for basic candidate drug molecules. Bioorg Med Chem Lett. 2011;21:5673–79.

    CAS  PubMed  Google Scholar 

  3. 3.

    O’Connor CJ, Laraia L, Spring DR. Chemical genetics. Chem Soc Rev. 2011;40:4332–45.

    PubMed  Google Scholar 

  4. 4.

    Ritchie TJ, Macdonald SJ. The impact of aromatic ring count on compound developability–are too many aromatic rings a liability in drug design? Drug Disco Today. 2009;14:1011–20.

    CAS  Google Scholar 

  5. 5.

    Kidd SL, Osberger TJ, Mateu N, Sore HF, Spring DR. Recent applications of diversity-oriented synthesis toward novel, 3-dimensional fragment collections. Front Chem. 2018;6:460.

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Ward SE, Beswick P. What does the aromatic ring number mean for drug design? Expert Opin Drug Dis. 2014;9:995–1003.

    CAS  Google Scholar 

  7. 7.

    Lebold TP, Wood JL, Deitch J, Lodewyk MW, Tantillo DJ, Sarpong R. A divergent approach to the synthesis of the yohimbinoid alkaloids venenatine and alstovenine. Nat Chem. 2013;5:126–31.

    CAS  PubMed  Google Scholar 

  8. 8.

    O’Connor CJ, Beckmann HS, Spring DR. Diversity-oriented synthesis: producing chemical tools for dissecting biology. Chem Soc Rev. 2012;41:4444–56.

    Google Scholar 

  9. 9.

    Chen FE, Huang J. Reserpine: a challenge for total synthesis of natural products. Chem Rev. 2005;105:4671–706.

    CAS  PubMed  Google Scholar 

  10. 10.

    Gaich T, Baran PS. Aiming for the ideal synthesis. J Org Chem. 2010;75:4657–73.

    CAS  PubMed  Google Scholar 

  11. 11.

    Galloway WR, Isidro-Llobet A, Spring DR. Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules. Nat Commun. 2010;1:80.

    PubMed  Google Scholar 

  12. 12.

    Haggarty SJ. The principle of complementarity: chemical versus biological space. Curr Opin Chem Biol. 2005;9:296–303.

    CAS  PubMed  Google Scholar 

  13. 13.

    Ibbeson BM, Laraia L, Alza E, OC CJ, Tan YS, Davies HM, et al. Diversity-oriented synthesis as a tool for identifying new modulators of mitosis. Nat Commun. 2014;5:3155.

    PubMed  Google Scholar 

  14. 14.

    Kim J, Kim H, Park SB. Privileged structures: efficient chemical “navigators” toward unexplored biologically relevant chemical spaces. J Am Chem Soc. 2014;136:14629–38.

    CAS  PubMed  Google Scholar 

  15. 15.

    Moffat JG, Rudolph J, Bailey D. Phenotypic screening in cancer drug discovery - past, present and future. Nat Rev Drug Disco. 2014;13:588–602.

    CAS  Google Scholar 

  16. 16.

    Nie F, Kunciw DL, Wilcke D, Stokes JE, Galloway WR, Bartlett S, et al. A multidimensional diversity-oriented synthesis strategy for structurally diverse and complex macrocycles. Angew Chem Int Ed Engl. 2016;55:11139–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Swinney DC, Anthony J. How were new medicines discovered? Nat Rev Drug Disco. 2011;10:507–19.

    CAS  Google Scholar 

  18. 18.

    Badillo JJ, Arevalo GE, Fettinger JC, Franz AK. Titanium-catalyzed stereoselective synthesis of spirooxindole oxazolines. Org Lett. 2011;13:418–21.

    CAS  PubMed  Google Scholar 

  19. 19.

    Dhanasekar E, Kannan T, Venkatesan R, Perumal PT, Kamalraja J. Metal-Free and Regioselective Synthesis of Substituted and Fused Chromenopyrrole Scaffolds via the Divergent Reactivity of α-Azido Ketones in Water. J Org Chem. 2020;85:9631–49.

    CAS  PubMed  Google Scholar 

  20. 20.

    Fan H, Peng J, Hamann MT, Hu JF. Lamellarins and related pyrrole-derived alkaloids from marine organisms. Chem Rev. 2008;108:264–87.

    CAS  PubMed  Google Scholar 

  21. 21.

    Purushothaman S, Prasanna R, Niranjana P, Raghunathan R, Nagaraj S, Rengasamy R. Stereoselective synthesis of hexahydro-3-methyl-1-arylchromeno[3,4-b]pyrrole and its annulated heterocycles as potent antimicrobial agents for human pathogens. Bioorg Med Chem Lett. 2010;20:7288–91.

    CAS  PubMed  Google Scholar 

  22. 22.

    Arumugam N, Raghunathan R, Almansour AI, Karama U. An efficient synthesis of highly functionalized novel chromeno[4,3-b]pyrroles and indolizino[6,7-b]indoles as potent antimicrobial and antioxidant agents. Bioorg Med Chem Lett. 2012;22:1375–9.

    CAS  PubMed  Google Scholar 

  23. 23.

    Khiati S, Seol Y, Agama K, Dalla Rosa I, Agrawal S, Fesen K, et al. Poisoning of mitochondrial topoisomerase I by lamellarin D. Mol Pharm. 2014;86:193–9.

    Google Scholar 

  24. 24.

    Srinivasulu V, Sieburth SM, El-Awady R, Kariem NM, Tarazi H, O’Connor MJ, et al. Post-ugi cascade transformations for accessing diverse chromenopyrrole collections. Org Lett. 2018;20:836–9.

    CAS  PubMed  Google Scholar 

  25. 25.

    Porporato PE, Filigheddu N, Pedro JMB, Kroemer G, Galluzzi L. Mitochondrial metabolism and cancer. Cell Res. 2018;28:265–80.

    CAS  PubMed  Google Scholar 

  26. 26.

    Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell. 2012;21:297–308.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Zong WX, Rabinowitz JD, White E. Mitochondria and cancer. Mol Cell. 2016;61:667–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer. 2011;11:85–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Sabharwal SS, Schumacker PT. Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles’ heel? Nat Rev Cancer. 2014;14:709–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Tait SW, Green DR. Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol. 2010;11:621–32.

    CAS  PubMed  Google Scholar 

  31. 31.

    Weinberg SE, Chandel NS. Targeting mitochondria metabolism for cancer therapy. Nat Chem Biol. 2015;11:9–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Wang L, Zhang X, Cui G, Chan JY, Wang L, Li C, et al. A novel agent exerts antitumor activity in breast cancer cells by targeting mitochondrial complex II. Oncotarget. 2016;7:32054–64.

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Boland ML, Chourasia AH, Macleod KF. Mitochondrial dysfunction in cancer. Front Oncol. 2013;3:292.

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Vyas S, Zaganjor E, Haigis MC. Mitochondria and cancer. Cell. 2016;166:555–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Giampazolias E, Tait SW. Mitochondria and the hallmarks of cancer. FEBS J. 2016;283:803–14.

    CAS  PubMed  Google Scholar 

  36. 36.

    Whitaker RM, Corum D, Beeson CC, Schnellmann RG. Mitochondrial biogenesis as a pharmacological target: a new approach to acute and chronic diseases. Annu Rev Pharm Toxicol. 2016;56:229–49.

    CAS  Google Scholar 

  37. 37.

    Fulda S, Galluzzi L, Kroemer G. Targeting mitochondria for cancer therapy. Nat Rev Drug Disco. 2010;9:447–64.

    CAS  Google Scholar 

  38. 38.

    Seyfried TN. Cancer as a mitochondrial metabolic disease. Front Cell Dev Biol. 2015;3:43.

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    Scarpulla RC. Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim Biophys Acta. 2011;1813:1269–78.

    CAS  PubMed  Google Scholar 

  40. 40.

    Zhang G, Frederick DT, Wu L, Wei Z, Krepler C, Srinivasan S, et al. Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors. J Clin Invest. 2016;126:1834–56.

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Webb M, Sideris DP, Biddle M. Modulation of mitochondrial dysfunction for treatment of disease. Bioorg Med Chem Lett. 2019;29:1270–7.

    CAS  PubMed  Google Scholar 

  42. 42.

    Andreux PA, Houtkooper RH, Auwerx J. Pharmacological approaches to restore mitochondrial function. Nat Rev Drug Disco. 2013;12:465–83.

    CAS  Google Scholar 

  43. 43.

    Aminzadeh-Gohari S, Weber DD, Vidali S, Catalano L, Kofler B, Feichtinger RG. From old to new - Repurposing drugs to target mitochondrial energy metabolism in cancer. Semin Cell Dev Biol. 2020;98:211–23.

    CAS  PubMed  Google Scholar 

  44. 44.

    Lunt SY, Vander Heiden MG. Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol. 2011;27:441–64.

    CAS  PubMed  Google Scholar 

  45. 45.

    Andreux PA, Mouchiroud L, Wang X, Jovaisaite V, Mottis A, Bichet S, et al. A method to identify and validate mitochondrial modulators using mammalian cells and the worm C. elegans. Sci Rep. 2014;4:5285.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Wallace KB. Mitochondrial off targets of drug therapy. Trends Pharm Sci. 2008;29:361–6.

    CAS  PubMed  Google Scholar 

  47. 47.

    Omar HA, Arafa el SA, Maghrabi IA, Weng JR. Sensitization of hepatocellular carcinoma cells to Apo2L/TRAIL by a novel Akt/NF-kappaB signalling inhibitor. Basic Clin Pharm Toxicol. 2014;114:464–71.

    CAS  Google Scholar 

  48. 48.

    Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol. 2019;16:589–604.

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Bertuccio P, Turati F, Carioli G, Rodriguez T, La Vecchia C, Malvezzi M, et al. Global trends and predictions in hepatocellular carcinoma mortality. J Hepatol. 2017;67:302–9.

    PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from Terry Fox Foundation (grant number 120403), the Research Funding Department at the University of Sharjah (grant number 1801110125-P), and a research grant (BBRI-AS0215) to A.F.M. and I.A.A. from the American University of Sharjah.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Taleb H. Al-Tel.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The authors declare full compliance with ethical standards.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Schilf, P., Srinivasulu, V., Bolognesi, M.L. et al. Design and synthesis of nature-inspired chromenopyrroles as potential modulators of mitochondrial metabolism. Med Chem Res 30, 635–646 (2021). https://doi.org/10.1007/s00044-020-02669-3

Download citation

Keywords

  • Chromenopyrroles
  • Phenotypic screening
  • Mitochondrial metabolism
  • Anticancer activity
  • Hepatoma cells
  • Immunotherapy