1. Xanthone: The Molecule

The numbering and designation of rings A and B come from the biosynthetic pathways for the compounds from higher plants, A-ring (carbons 1–4) being acetate-derived whereas the shikimic acid pathway gives B-ring (carbons 5–8); the other carbon atoms are numbered according IUPAC 2004 recommendations for structure elucidation purposes.

Figure 1. Structure of xanthone (9H-xanthen-9-one).

X-Ray diffraction data are an important tool, not only for structure elucidation but also to help in understanding the mechanism of action of the wide range of biological and pharmacological activities showed by xanthone derivatives. The crystal structure of 9H-xanthen-9-one (Figure 1) was first reported in 1982 and later, using more accurate experimental techniques, the data have been improved. Considering the molecule of xanthone itself in solid state, it is essentially planar due to the conjugated ring systems, except for the O(11) atom, which deviates 0.13 Å from the plane, with the central pyranoid ring with partial aromatic character. Due to the tricyclic-fused ring system, free rotation is limited. The rigidity of this scaffold contributes to the stability of the compound. For xanthone derivatives, slight differences can be found dependent on the nature of the substituents and their localization on the scaffold. The three-ring system can be slightly twisted along its longitudinal axis due to steric factors associated with the substituents, especially for bulky groups . 

A large amount of research concerning xanthone derivatives has been carried out, not only regarding isolation from terrestrial and marine sources, but also concerning compounds obtained by synthesis and with a large diversity of applications in medicinal, analytical and environmental chemistry. In 2005, one of us (M.M.M.P.) was Guest Editor of a Special issue of Current Medicinal Chemistry, which covered  isolation, synthesis, magnetic resonance spectroscopy and crystal X-ray studies of several xanthone derivatives as well as papers covering their biological activities and mechanisms of action.

Xanthone: A Privileged Scaffold

According the concept of Evans et al. the xanthone nucleus could be considered as a “privileged structure”, taking into account its binding to multiple, unrelated classes of protein receptors as high affinity ligands. Following, several authors associated the “xanthone” to the “privileged structure concept”. This ability of xanthones to interfere with a variety of biological targets is related with some special molecular features such as the presence of a heteroaromatic tricyclic ring system predominantly planar and rigid, a carbonyl group at the central ring able of several interactions, a biaryl ether group contributing to the electronic system, and the xanthone core that accommodates a vast variety of substituents at different positions.

A Library of Natural Mimetic Xanthones Looking for Biological Diversity: From the Land and from the Sea

Our journey through the world of xanthones comprises several stages and objectives. To obtain a library of natural mimetic xanthones we have been working in an interactive way including isolation of new compounds, total synthesis or molecular modifications, screening of biological activities and in-deep studies regarding their absorption, distribution, metabolism, excretion, toxicity (ADMET) properties as well as formulation of new compounds with appropriated drug delivery systems.

This work reviews the contributions of the corresponding author (M.M.M.P.) and her research group to Medicinal Chemistry concerning the isolation from plant and marine sources of xanthone derivatives as well as their synthesis, biological/pharmacological activities, formulation and analytical applications. Xanthone derivatives have a variety of activities with great potential for therapeutic applications due to their versatile framework. The group has contributed with several libraries of xanthones derivatives, with a variety of activities such as antitumor, anticoagulant, antiplatelet, anti-inflammatory, antimalarial, antimicrobial, hepatoprotective, antioxidant, and multidrug resistance reversal effects. Besides therapeutic applications, our group has also developed xanthone derivatives with analytical applications as chiral selectors for liquid chromatography and for maritime application as antifouling agents for marine paints.

Figure 22. Our chemical “family tree” based on xanthone.

In summary, taking into account the chemical “family tree” based on xanthone (Figure 22), our group has:

(1) isolated new compounds from terrestrial and marine sources and/or analyzed species not yet studied with regard to their secondary metabolites;

(2) used Nature-based strategies to guide the synthetic ways whenever possible;

(3) synthesized these compounds for structure elucidation purposes to obtain them through “greener” methods and in quantities suitable for biological/pharmacological assays, as well as to obtain nature-based analogues with improved druglike properties;

(4) contributed with new data in the area of NMR and X-ray crystallography;

(5) evaluated several biological activities for different chemical families of xanthone derivatives; the main focus was in the area of antitumor and antimicrobial agents, especially taking into account MDR, which we believe should be pursuit in Academia; other areas of intervention include cardiovascular, antimalarial, anti-inflammatory, anti-obesity, hepatoprotection, etc. More recently, the area related to the discovery of environmental-benign AF agents was also explored;

(6) explored the mechanisms of action, SAR and structure-activity-properties-relationship (SAPR);

(7) formulated some compounds in nanoparticles, liposomes and proliposomes (drug delivery systems), especially with xanthones with potential antitumor activity;

(8) determined the drug-likeness of some hit compounds (ADMET assays), as this should be carried out as soon as possible in the pipeline of drug discovery and development;

(9) obtained several chiral derivatives of xanthones and studied enantioseparation and enantioselectivity with regard to various biological activities, as well as analytical applications as chiral selectors for liquid chromatography

Given nature of the invitation and the objective of this Special Issue (Contributions of Female Scientists), the authors are only female members of our group. We expect that this review may serve as an inspiration for other groups working with diverse “privileged structures” in an integrative way.

References

1. Biswas, S.C.; Sen, R.K. X-ray crystallographic studies of xanthones. Indian J. Pure Appl. Phys. 1982, 20, 414.

2. Onuma, S.; Iijima, K.; Oonishi, I. Structure of xanthone. Acta Crystallogr. Sect. C 1990, 46, 1725–1727. [CrossRef]

3. Gales, L.; Damas, A.M. Xanthones-A Structural Perspective. Curr. Med. Chem. 2005, 12, 2499–2515. [CrossRef] [PubMed]

4. Hepworth, H. Chemical Synthesis: Studies in the Investigation of Natural Organic Products; Blackie and Son: London, UK, 1924;

Volume 44, pp. 120–121.

5. Henry, L.; Cavenfou, J.-B. J. Pharm. Chim. 1821, 7, 178.

6. Kamal, A.; Husain, S.A.; Noorani, R.; Murtaza, N.; Qureshi, I.H.; Qureshi, A.A. Studies in the biochemistry of microorganisms. XI.

Isolation of tajixanthone, shamixanthone, ajamxanthone, shahenxanthone, najamxanthone, radixanthone and mannitol from

mycelium of Aspergillus stellatus, Curzi. Pak. J. Sci. Indus. Res. 1970, 251–255, in press.

7. Michael, A. On the action of aromatic oxy-acids on phenols. Am. Chem. J. 1883, 5, 81–97.

8. Kostanecki, S.V. Über das Gentisin. Mon. Chem. Verwandte Teile And. Wiss. 1891, 12, 205–210. [CrossRef]

9. Organic Syntheses. Available online: http://online.fliphtml5.com/jocd/yqzh/#p=1 (accessed on 2 December 2020).

10. Goldberg, I. Ueber phenylirungen bei gegenwart von kupfer als katalysator. Ber. Dtsch. Chem. Ges. 1906, 39, 1691–1692. [CrossRef]

11. Schmid, W. Ueber das Mangostin. Justus Liebigs Ann. Chem. 1855, 93, 83–88. [CrossRef]

12. Rai, M.; Chikindas, M.L. Natural Antimicrobials in Food Safety and Quality; CAB International: Wallingford, UK, 2011.

13. Negi, J.S.; Bisht, V.K.; Singh, P.; Rawat, M.S.M.; Joshi, G.P. Naturally Occurring Xanthones: Chemistry and Biology. J. Appl. Chem.

2013, 2013, 621459. [CrossRef]

14. Madalena, M.M.P. Editorial [Hot Topic: Xanthone (Dibenzo-γ-Pyrone): An Interesting Framework In Medicinal Chemistry (Guest

Editor: Madalena M.M. Pinto)]. Curr. Med. Chem. 2005, 12, 2411. [CrossRef]

15. Vieira, L.M.M.; Kijjoa, A. Naturally-Occurring Xanthones: Recent Developments. Curr. Med. Chem. 2005, 12, 2413–2446.

[CrossRef] [PubMed]

16. Sousa, M.E.; Pinto, M.M.M. Synthesis of Xanthones: An Overview. Curr. Med. Chem. 2005, 12, 2447–2479. [CrossRef] [PubMed]

17. Silva, A.M.S.; Pinto, D.C.G.A. Structure Elucidation of Xanthone Derivatives: Studies of Nuclear Magnetic Resonance Spectroscopy. Curr. Med. Chem. 2005, 12, 2481–2497. [CrossRef] [PubMed]

18. Pinto, M.M.M.; Sousa, M.E.; Nascimento, M.S.J. Xanthone Derivatives: New Insights in Biological Activities. Curr. Med. Chem.

2005, 12, 2517–2538. [CrossRef] [PubMed]

19. Riscoe, M.; Kelly, J.X.; Winter, R. Xanthones as Antimalarial Agents: Discovery, Mode of Action, and Optimization. Curr. Med.

Chem. 2005, 12, 2539–2549. [CrossRef] [PubMed]

20. Evans, B.E.; Rittle, K.E.; Bock, M.G.; DiPardo, R.M.; Freidinger, R.M.; Whitter, W.L.; Lundell, G.F.; Veber, D.F.; Anderson, P.S.;

Chang, R.S.L.; et al. Methods for drug discovery: Development of potent, selective, orally effective cholecystokinin antagonists.

J. Med. Chem. 1988, 31, 2235–2246. [CrossRef]

21. Nguyen, H.T.; Lallemand, M.-C.; Boutefnouchet, S.; Michel, S.; Tillequin, F. Antitumor Psoropermum Xanthones and Sarcomelicope Acridones: Privileged Structures Implied in DNA Alkylation. J. Nat. Prod. 2009, 72, 527–539. [CrossRef]

22. Lesch, B.; Bräse, S. A Short, Atom-Economical Entry to Tetrahydroxanthenones. Angew. Chem. Int. Ed. 2004, 43, 115–118.

[CrossRef]

23. Hesham, R.E.-S.; Dina, M.H.E.-G.; Mai, A.E.-B.; Mervat, F.Z.; Ulf, G.; Sonny, L.; Rob, V. Naturally Occurring Xanthones; Latest

Investigations: Isolation, Structure Elucidation and Chemosystematic Significance. Curr. Med. Chem. 2009, 16, 2581–2626.

[CrossRef]

24. Demirkiran, O. Xanthones in Hypericum: Synthesis and BiologicalActivities. In Bioactive Heterocycles III; Khan, M.T.H., Ed.;

Springer: Berlin/Heidelberg, Germany, 2007; pp. 139–178. [CrossRef]

25. Wezeman, T.; Masters, K.-S. Chapter 12 Xanthones are Privileged Scaffolds in Medicinal Chemistry—But are they Over-privileged?

In Privileged Scaffolds in Medicinal Chemistry: Design, Synthesis, Evaluation; The Royal Society of Chemistry: London, UK, 2016;

pp. 312–347. [CrossRef]

26. Peres, V.; Nagem, T.J.; De Oliveira, F.F. Tetraoxygenated naturally occurring xanthones. Phytochemistry 2000, 55, 683–710.

[CrossRef]

27. Loureiro, D.R.P.; Soares, J.X.; Costa, J.C.; Magalhães, Á.F.; Azevedo, C.M.G.; Pinto, M.M.M.; Afonso, C.M.M. Structures, activities

and drug-likeness of anti-infective xanthone derivatives isolated from the marine environment: A review. Molecules 2019, 24, 243.

[CrossRef] [PubMed]

28. Kumla, D.; Dethoup, T.; Gales, L.; Pereira, J.A.; Freitas-Silva, J.; Costa, P.M.; Silva, A.M.S.; Pinto, M.M.M.; Kijjoa, A. Erubescensoic

Acid, a new polyketide and a xanthonopyrone SPF-3059-26 From the culture of the marine sponge-associated fungus penicillium

erubescens KUFA 0220 and Antibacterial activity evaluation of some of its constituents. Molecules 2019, 24, 208. [CrossRef]

[PubMed]

29. Resende, D.; Pereira-Terra, P.; Inácio, Â.; Costa, P.; Pinto, E.; Sousa, E.; Pinto, M. Lichen Xanthones as Models for New Antifungal

Agents. Molecules 2018, 23, 2617. [CrossRef] [PubMed]

30. Pinto, M.M.M.; Castanheiro, R.A.P.; Kijjoa, A. Xanthones from Marine-Derived Microorganisms: Isolation, Structure Elucidation

and Biological Activities. In Encyclopedia of Analytical Chemistry; John Wiley & Sons, Ltd.: Hoboken, NJ, USA, 2006. [CrossRef]

31. Masters, K.-S.; Bräse, S. Xanthones from Fungi, Lichens, and Bacteria: The Natural Products and Their Synthesis. Chem. Rev. 2012,

112, 3717–3776. [CrossRef] [PubMed]

32. Bugni, T.S.; Ireland, C.M. Marine-derived fungi: A chemically and biologically diverse group of microorganisms. Nat. Prod. Rep.

2004, 21, 143–163. [CrossRef]

33. Roberts, J.C. Naturally Occurring Xanthones. Chem. Rev. 1961, 61, 591–605. [CrossRef]

34. Narosa, G.B. (Ed.) Natural Prenylated xanthones: Chemistry and biological activities. In Natural Products: Chemistry, Biochemistry

and Pharmacology; Publishing House PVT: New Dehli, India, 2009.

35. Mesquita, A.A.L.; Gottlieb, O.R.; Madalena, M.D.M. Xanthonolignoids from Kielmeyera coriacea. Phytochemistry 1987, 26,

2045–2048. [CrossRef]

36. Pinto, M.; Nascimento, M.S.J.; Gonzalez, M.J.; Mondranondra, I.-O. Anticomplementary activity and constituents of Cratoxylum

maingayi DYER. Pharm. Pharmacol. Lett. 1997, 7, 128–130.

37. Kijjoa, A.; José, M.; Gonzalez, T.G.; Pinto, M.M.M.; Damas, A.M.; Mondranondra, I.O.; Silva, A.M.S.; Herz, W. Xanthones from

Cratoxylum maingayi. Phytochemistry 1998, 49, 2159–2162. [CrossRef]

38. Gonzalez, M.J.; Nascimento, M.S.J.; Cidade, H.M.; Pinto, M.M.M.; Kijjoa, A.; Anantachoke, C.; Silva, A.M.S.; Herz, W. Immunomodulatory activity of xanthones from Calophyllum teysmannii var. inuphylloide. Planta Med. 1999, 65, 368–371.

[CrossRef] [PubMed]

39. Kijjoa, A.; Gonzalez, M.J.; Pinto, M.M.M.; Silva, A.M.S.; Anantachoke, C.; Herz, W. Xanthones from Calophyllum teysmannii var.

inophylloide. Phytochemistry 2000, 55, 833–836. [CrossRef] [PubMed]

40. Kijjoa, A.; Gonzalez, M.J.; Pinto, M.M.; Nascimento, M.S.J.; Campos, N.; Mondranondra, I.O.; Silva, A.M.S.; Eaton, G.; Herz,

W. Cytotoxicity of prenylated xanthones and other constituents from the wood of Garcinia merguensis. Planta Med. 2008, 74,

864–866. [CrossRef] [PubMed]

41. Freitas, V.L.S.; Ribeiro da Silva, M.D.M.C. Influence of Hydroxyl Functional Group on the Structure and Stability of Xanthone: A

Computational Approach. Molecules 2018, 23, 2962. [CrossRef] [PubMed]

42. Pinto, M.; Nascimento, M.S.J. Anticomplementary activity of hydroxy- and methoxyxanthones. Pharm. Pharmacol. Lett. 1997, 7,

125–127.

43. Fernandes, E.G.R.; Silva, A.M.S.; Cavaleiro, J.A.S.; Silva, F.M.; Fernanda, M.; Borges, M.; Pinto, M.M.M. 1H and 13C NMR

Spectroscopy of mono-, di-, tri- and tetrasubstituted xanthones. Magn. Reson. Chem. 1998, 36, 305–309. [CrossRef]

44. Gales, L.; De Sousa, M.E.; Pinto, M.M.M.; Kijjoa, A.; Damas, A.M. Naturally occurring 1,2,8-trimethoxy-xanthone and biphenyl

ether intermediates leading to 1,2-dimethoxy-xanthone. Acta Crystallogr. Sect. C Cryst. Struct. Commun. 2001, 57, 1319–1323.

[CrossRef]

45. Gales, L.; Sousa, M.E.; Pinto, M.M.M.; Damas, A.M. 3,4-Dihydroxy-9H-xanthen-9-one trihydrate. Acta Crystallogr. Sect. E Struct.

Rep. Online 2005, 61, o2213–o2215. [CrossRef]

46. Resende, D.I.S.P.; Durães, F.; Maia, M.; Sousa, E.; Pinto, M.M.M. Recent advances in the synthesis of xanthones and azaxanthones.

Org. Chem. Front. 2020. [CrossRef]

47. Teixeira, M.; Afonso, C.M.; Pinto, M.M.; Barbosa, C.M. A validated HPLC method for the assay of xanthone and 3-

methoxyxanthone in PLGA nanocapsules. J. Chromatogr. Sci. 2003, 41, 371–376. [CrossRef]

48. Pedro, M.; Cerqueira, F.; Sousa, M.E.l.; Nascimento, M.S.J.; Pinto, M. Xanthones as inhibitors of growth of human cancer cell lines

and Their effects on the proliferation of human lymphocytes In Vitro. Bioorg. Med. Chem. 2002, 10, 3725–3730. [CrossRef]

49. Cidade, H.; Rocha, V.; Palmeira, A.; Marques, C.; Tiritan, M.E.; Ferreira, H.; Lobo, J.S.; Almeida, I.F.; Sousa, M.E.; Pinto, M. In

silico and in vitro antioxidant and cytotoxicity evaluation of oxygenated xanthone derivatives. Arab. J. Chem. 2017. [CrossRef]

50. Fernandes, E.R.; Carvalho, F.D.; Remião, F.G.; Bastos, M.L.; Pinto, M.M.; Gottlieb, O.R. Hepatoprotective Activity of Xanthones

and Xanthonolignoids Against tert-Butylhydroperoxide-Induced Toxicity in Isolated Rat Hepatocytes—Comparison with Silybin.

Pharm. Res. Off. J. Am. Assoc. Pharm. Sci. 1995, 12, 1756–1760. [CrossRef]

51. Pinto, E.; Afonso, C.; Duarte, S.; Vale-Silva, L.; Costa, E.; Sousa, E.; Pinto, M. Antifungal Activity of Xanthones: Evaluation of

their Effect on Ergosterol Biosynthesis by High-performance Liquid Chromatography. Chem. Biol. Drug Des. 2011, 77, 212–222.

[CrossRef] [PubMed]

52. Bessa, L.J.; Palmeira, A.; Gomes, A.S.; Vasconcelos, V.; Sousa, E.; Pinto, M.; Da Costa, P.M. Synergistic effects between thioxanthones and oxacillin against methicillin-resistant staphylococcus aureus. Microb. Drug Resist. 2015, 21, 404–415. [CrossRef]

[PubMed]

53. Resende, D.I.S.P.; Pereira-Terra, P.; Moreira, J.; Freitas-Silva, J.; Lemos, A.; Gales, L.; Pinto, E.; De Sousa, M.E.; Da Costa, P.M.;

Pinto, M.M.M. Synthesis of a Small Library of Nature-Inspired Xanthones and Study of Their Antimicrobial Activity. Molecules

2020, 25, 2405. [CrossRef]

54. Urbatzka, R.; Freitas, S.; Palmeira, A.; Almeida, T.; Moreira, J.; Azevedo, C.; Afonso, C.; Correia-da-Silva, M.; Sousa, E.; Pinto, M.;

et al. Lipid reducing activity and toxicity profiles of a library of polyphenol derivatives. Eur. J. Med. Chem. 2018, 151, 272–284.

[CrossRef]

55. Almeida, J.R.; Palmeira, A.; Campos, A.; Cunha, I.; Freitas, M.; Felpeto, A.B.; Turkina, M.V.; Vasconcelos, V.; Pinto, M.; Correia-Dasilva, M.; et al. Structure-antifouling activity relationship and molecular targets of bio-inspired(Thio)xanthones. Biomolecules 2020,

10, 1126. [CrossRef]

56. Gnerre, C.; Thull, U.; Gaillard, P.; Carrupt, P.-A.; Testa, B.; Fernandes, E.; Silva, F.; Pinto, M.; Pinto, M.M.M.; Wolfender, J.-L.; et al.

Natural and Synthetic Xanthones as Monoamine Oxidase Inhibitors: Biological Assay and 3D-QSAR. Helv. Chim. Acta 2001, 84,

552–570. [CrossRef]

57. Silva, R.; Sousa, E.; Carmo, H.; Palmeira, A.; Barbosa, D.J.; Gameiro, M.; Pinto, M.; De Lourdes Bastos, M.; Remião, F. Induction

and activation of P-glycoprotein by dihydroxylated xanthones protect against the cytotoxicity of the P-glycoprotein substrate

paraquat. Arch. Toxicol. 2014, 88, 937–951. [CrossRef]

58. Martins, E.; Silva, V.; Lemos, A.; Palmeira, A.; Puthongking, P.; Sousa, E.; Rocha-Pereira, C.; Ghanem, C.I.; Carmo, H.; Remião,

F.; et al. Newly Synthesized Oxygenated Xanthones as Potential P-Glycoprotein Activators: In Vitro, Ex Vivo, and In Silico

Studies. Molecules 2019, 24, 707. [CrossRef] [PubMed]

59. Saraiva, L.; Fresco, P.; Pinto, E.; Sousa, E.; Pinto, M.; Gonçalves, J. Synthesis and in vivo modulatory activity of protein kinase C of

xanthone derivatives. Bioorg. Med. Chem. 2002, 10, 3219–3227. [CrossRef]

60. Saraiva, L.; Fresco, P.; Pinto, E.; Sousa, E.; Pinto, M.; Gonçalves, J. Inhibition of protein kinase C by synthetic xanthone derivatives.

Bioorg. Med. Chem. 2003, 11, 1215–1225. [CrossRef]

61. Rosa, G.P.; Palmeira, A.; Resende, D.I.S.P.; Almeida, I.F.; Kane-Pagès, A.; Barreto, M.C.; Sousa, E.; Pinto, M.M.M. Xanthones for

melanogenesis inhibition: Molecular docking and QSAR studies to understand their anti-tyrosinase activity. Bioorg. Med. Chem.

2021, 29, 115873. [CrossRef] [PubMed]

62. Sousa, E.P.; Silva, A.M.S.; Pinto, M.M.M.; Pedro, M.M.; Cerqueira, F.A.M.; Nascimento, M.S.J. Isomeric Kielcorins and Dihydroxyxanthones: Synthesis, Structure Elucidation, and Inhibitory Activities of Growth of Human Cancer Cell Lines and on the

Proliferation of Human Lymphocytes In Vitro. Helv. Chim. Acta 2002, 85, 2862–2876. [CrossRef]

63. Gomes, S.; Raimundo, L.; Soares, J.; Loureiro, J.B.; Leão, M.; Ramos, H.; Monteiro, M.N.; Lemos, A.; Moreira, J.; Pinto, M.; et al.

New inhibitor of the TAp73 interaction with MDM2 and mutant p53 with promising antitumor activity against neuroblastoma.

Cancer Lett. 2019, 446, 90–102. [CrossRef] [PubMed]

64. Silva, V.; Cerqueira, F.; Nazareth, N.; Medeiros, R.; Sarmento, A.; Sousa, E.; Pinto, M. 1,2-Dihydroxyxanthone: Effect on A375-C5

Melanoma Cell Growth Associated with Interference with THP-1 Human Macrophage Activity. Pharmaceuticals 2019, 12, 85.

[CrossRef]

65. Gomes, A.S.; Brandão, P.; Fernandes, C.S.G.; Da Silva, M.; De Sousa, M.; Pinto, M.M.M. Drug-like Properties and ADME of

Xanthone Derivatives: The Antechamber of Clinical Trials. Curr. Med. Chem. 2016, 23, 3654–3686. [CrossRef]

66. Sousa, E.; Palmeira, A.; Cordeiro, A.S.; Sarmento, B.; Ferreira, D.; Lima, R.T.; Helena Vasconcelos, M.; Pinto, M. Bioactive

xanthones with effect on P-glycoprotein and prediction of intestinal absorption. Med. Chem. Res. 2013, 22, 2115–2123. [CrossRef]

67. Resende, D.I.S.P.; Almeida, M.C.; Maciel, B.; Carmo, H.; Sousa Lobo, J.; Dal Pozzo, C.; Cravo, S.M.; Rosa, G.P.; Kane-Pagès, A.; Do

Carmo Barreto, M.; et al. Efficacy, Stability, and Safety Evaluation of New Polyphenolic Xanthones Towards Identification of

Bioactive Compounds to Fight Skin Photoaging. Molecules 2020, 25, 2782. [CrossRef]

68. Phyo, Y.Z.; Teixeira, J.; Tiritan, M.E.; Cravo, S.; Palmeira, A.; Gales, L.; Silva, A.M.S.; Pinto, M.M.M.; Kijjoa, A.; Fernandes, C. New

chiral stationary phases for liquid chromatography based on small molecules: Development, enantioresolution evaluation and

chiral recognition mechanisms. Chirality 2020, 32, 81–97. [CrossRef] [PubMed]

69. Fernandes, C.; Tiritan, M.E.; Cravo, S.; Phyo, Y.Z.; Kijjoa, A.; Silva, A.M.S.; Cass, Q.B.; Pinto, M.M.M. New chiral stationary

phases based on xanthone derivatives for liquid chromatography. Chirality 2017, 29, 430–442. [CrossRef] [PubMed]

70. Teixeira, M.; Pedro, M.; Nascimento, M.S.J.; Pinto, M.M.M.; Barbosa, C.M. Development and characterization of PLGA nanoparticles containing 1,3-dihydroxy-2-methylxanthone with improved antitumor activity on a human breast cancer cell line. Pharm.

Dev. Technol. 2019, 24, 1104–1114. [CrossRef] [PubMed]

71. Teixeira, M.; Alonso, M.J.; Pinto, M.M.M.; Barbosa, C.M. Development and characterization of PLGA nanospheres and nanocapsules containing xanthone and 3-methoxyxanthone. Eur. J. Pharm. Biopharm. 2005, 59, 491–500. [CrossRef] [PubMed]

72. Malta, R.; Loureiro, J.B.; Costa, P.; Sousa, E.; Pinto, M.; Saraiva, L.; Amaral, M.H. Development of lipid nanoparticles containing

the xanthone LEM2 for topical treatment of melanoma. J. Drug Deliv. Sci. Technol. 2020. [CrossRef]

73. Loureiro, D.R.P.; Magalhães, Á.F.; Soares, J.X.; Pinto, J.; Azevedo, C.M.G.; Vieira, S.; Henriques, A.; Ferreira, H.; Neves, N.;

Bousbaa, H.; et al. Yicathins B and C and Analogues: Total Synthesis, Lipophilicity and Biological Activities. ChemMedChem 2020,

15, 749–755. [CrossRef]

74. Silva, V.; Gil-Martins, E.; Rocha-Pereira, C.; Lemos, A.; Palmeira, A.; Puthongking, P.; Sousa, E.; De Lourdes Bastos, M.; Remião, F.;

Silva, R. Oxygenated xanthones as P-glycoprotein modulators at the intestinal barrier: In vitro and docking studies. Med. Chem.

Res. 2020, 29, 1041–1057. [CrossRef]

75. Baell, J.; Walters, M.A. Chemistry: Chemical con artists foil drug discovery. Nature 2014, 513, 481–483. [CrossRef]

76. Baell, J.B.; Nissink, J.W.M. Seven Year Itch: Pan-Assay Interference Compounds (PAINS) in 2017—Utility and Limitations. ACS

Chem. Biol. 2018, 13, 36–44. [CrossRef]

77. Pinto, M.M.M.; Castanheiro, R.A.P. Synthesis of prenylated xanthones: An overview. Curr. Org. Chem. 2009, 13, 1215–1240.

[CrossRef]

78. Azevedo, C.M.G.; Afonso, C.M.M.; Soares, J.X.; Reis, S.; Sousa, D.; Lima, R.T.; Vasconcelos, M.H.; Pedro, M.; Barbosa, J.; Gales,

L.; et al. Pyranoxanthones: Synthesis, growth inhibitory activity on human tumor cell lines and determination of their lipophilicity

in two membrane models. Eur. J. Med. Chem. 2013, 69, 798–816. [CrossRef] [PubMed]

79. Castanheiro, R.A.P.; Pinto, M.M.M.; Cravo, S.M.M.; Pinto, D.C.G.A.; Silva, A.M.S.; Kijjoa, A. Improved methodologies for

synthesis of prenylated xanthones by microwave irradiation and combination of heterogeneous catalysis (K10 clay) with

microwave irradiation. Tetrahedron 2009, 65, 3848–3857. [CrossRef]

80. Azevedo, C.M.G.; Afonso, C.M.M.; Sousa, D.; Lima, R.T.; Helena Vasconcelos, M.; Pedro, M.; Barbosa, J.; Corrêa, A.G.; Reis,

S.; Pinto, M.M.M. Multidimensional optimization of promising antitumor xanthone derivatives. Bioorg. Med. Chem. 2013, 21,

2941–2959. [CrossRef] [PubMed]

81. França, F.; Silva, P.M.A.; Soares, J.X.; Henriques, A.C.; Loureiro, D.R.P.; Azevedo, C.M.G.; Afonso, C.M.M.; Bousbaa, H. A

Pyranoxanthone as a Potent Antimitotic and Sensitizer of Cancer Cells to Low Doses of Paclitaxel. Molecules 2020, 25, 5845.

[CrossRef] [PubMed]

82. Epifano, F.; Genovese, S.; Menghini, L.; Curini, M. Chemistry and pharmacology of oxyprenylated secondary plant metabolites.

Phytochemistry 2007, 68, 939–953. [CrossRef]

83. Nakatani, K.; Nakahata, N.; Arakawa, T.; Yasuda, H.; Ohizumi, Y. Inhibition of cyclooxygenase and prostaglandin E2 synthesis by γ-mangostin, a xanthone derivative in mangosteen, in C6 rat glioma cells11Abbreviations: AA, arachidonic acid;

BSA, bovine serum albumin; COX, cyclooxygenase; COX-1, constitutive COX.; COX-2, inducible COX; cPLA2, cytosolic PLA2;

EMEM, Eagle’s minimum essential medium; ERK, extracellular signal regulated kinase; HEPES, 2-[4-(2-Hydroxyethyl)-1-

piperazinyl]ethanesulfonic acid; MAPK, mitogen-activated protein kinase;PGE2, prostaglandin E2; sPLA2, secretory phospholipase A2; TBST, Tris-buffered saline containing 0.05% Tween 20. Biochem. Pharmacol. 2002, 63, 73–79. [CrossRef]

84. Castanheiro, R.A.P.; Pinto, M.M.M.; Silva, A.M.S.; Cravo, S.M.M.; Gales, L.; Damas, A.M.; Nazareth, N.; Nascimento, M.S.J.;

Eaton, G. Dihydroxyxanthones prenylated derivatives: Synthesis, structure elucidation, and growth inhibitory activity on human

tumor cell lines with improvement of selectivity for MCF-7. Bioorg. Med. Chem. 2007, 15, 6080–6088. [CrossRef]

85. Castanheiro, R.A.P.; Silva, A.M.S.; Campos, N.A.N.; Nascimento, M.S.J.; Pinto, M.M.M. Antitumor activity of some prenylated

xanthones. Pharmaceuticals 2009, 2, 33–43. [CrossRef]

86. Palmeira, A.; Paiva, A.; Sousa, E.; Seca, H.; Almeida, G.M.; Lima, R.T.; Fernandes, M.X.; Pinto, M.; Vasconcelos, M.H. Insights into

the in vitro antitumor mechanism of action of a new pyranoxanthone. Chem. Biol. Drug Des. 2010, 76, 43–58. [CrossRef]

87. Paiva, A.M.; Sousa, M.E.; Camões, A.; Nascimento, M.S.J.; Pinto, M.M.M. Prenylated xanthones: Antiproliferative effects and

enhancement of the growth inhibitory action of 4-hydroxytamoxifen in estrogen receptor-positive breast cancer cell line. Med.

Chem. Res. 2012, 21, 552–558. [CrossRef]

88. Leão, M.; Gomes, S.; Pedraza-Chaverri, J.; Machado, N.; Sousa, E.; Pinto, M.; Inga, A.; Pereira, C.; Saraiva, L. α-Mangostin

and Gambogic Acid as Potential Inhibitors of the p53–MDM2 Interaction Revealed by a Yeast Approach. J. Nat. Prod. 2013, 76,

774–778. [CrossRef] [PubMed]

89. Lemos, A.; Leão, M.; Soares, J.; Palmeira, A.; Pinto, M.; Saraiva, L.; Sousa, M.E. Medicinal Chemistry Strategies to Disrupt the

p53–MDM2/MDMX Interaction. Med. Chem. Res. 2016, 36, 789–844. [CrossRef] [PubMed]

90. Inga, A.; Pinto, M.M.d.M.; Saraiva, L.H.A.; Sousa, M.E.d.S.P.d.; Pereira, C.I.F.; Paiva, A.M.G.; Leão, M.V.C.F. Inhibitors of

p53-mdm2 Interaction. WO/2013/105037, 7 February 2013.

91. Liu, J.; Zhou, F.; Zhang, L.; Wang, H.; Zhang, J.; Zhang, C.; Jiang, Z.; Li, Y.; Liu, Z.; Chen, H. DMXAA-pyranoxanthone hybrids

enhance inhibition activities against human cancer cells with multi-target functions. Eur. J. Med. Chem. 2018, 143, 1768–1778.

[CrossRef] [PubMed]

92. Paiva, A.M.; Pinto, R.A.; Teixeira, M.; Barbosa, C.M.; Lima, R.T.; Vasconcelos, M.H.; Sousa, E.; Pinto, M. Development of

noncytotoxic PLGA nanoparticles to improve the effect of a new inhibitor of p53-MDM2 interaction. Int. J. Pharm. 2013, 454,

394–402. [CrossRef]

93. Paiva, A.M.; Teixeira, M.; Pereira, R.; Barbosa, C.M.; Sousa, E.; Pinto, M.M.M. Development and validation of an HPLC method

for the quantification of a cytotoxic dihydropyranoxanthone in biodegradable nanoparticles. Int. J. Drug Deliv. 2013, 5, 224–232.

94. Pedro Gonçalves, A.; Silva, N.; Oliveira, C.; Kowbel, D.J.; Glass, N.L.; Kijjoa, A.; Palmeira, A.; Sousa, E.; Pinto, M.; Videira, A.

Transcription profiling of the Neurospora crassa response to a group of synthetic (thio)xanthones and a natural acetophenone.

Genom. Data 2015, 4, 26–32. [CrossRef] [PubMed]

95. Le Pogam, P.; Boustie, J. Xanthones of Lichen Source: A 2016 Update. Molecules 2016, 21, 294. [CrossRef] [PubMed]

96. Dayan, F.E.; Romagni, J.G. Lichens as a potential source of pesticides. Pestic. Outlook 2001, 12, 229–232. [CrossRef]

97. Sousa, E.; Paiva, A.; Nazareth, N.; Gales, L.; Damas, A.M.; Nascimento, M.S.J.; Pinto, M. Bromoalkoxyxanthones as promising

antitumor agents: Synthesis, crystal structure and effect on human tumor cell lines. Eur. J. Med. Chem. 2009, 44, 3830–3835.

[CrossRef]

98. Sun, R.-R.; Miao, F.-P.; Zhang, J.; Wang, G.; Yin, X.-L.; Ji, N.-Y. Three new xanthone derivatives from an algicolous isolate of

Aspergillus wentii. Magn. Reson. Chem. 2013, 51, 65–68. [CrossRef]

99. Cruz, M.I.; Cidade, H.; Pinto, M. Dual/multitargeted xanthone derivatives for Alzheimer’s disease: Where do we stand? Future

Med. Chem. 2017, 9, 1611–1630. [CrossRef] [PubMed]

100. Cruz, I.; Puthongking, P.; Cravo, S.; Palmeira, A.; Cidade, H.; Pinto, M.; Sousa, E. Xanthone and Flavone Derivatives as Dual

Agents with Acetylcholinesterase Inhibition and Antioxidant Activity as Potential Anti-Alzheimer Agents. J. Chem. 2017, 2017, 16.

[CrossRef]

101. Lemos, A.; Gomes, A.S.; Loureiro, J.B.; Brandão, P.; Palmeira, A.; Pinto, M.M.M.; Saraiva, L.; Sousa, M.E. Synthesis, Biological

Evaluation, and In Silico Studies of Novel Aminated Xanthones as Potential p53-Activating Agents. Molecules 2019, 24, 1975.

[CrossRef] [PubMed]

102. Portela, C.; Afonso, C.M.M.; Pinto, M.M.M.; João Ramos, M. Definition of an electronic profile of compounds with inhibitory

activity against hematin aggregation in malaria parasite. Bioorg. Med. Chem. 2004, 12, 3313–3321. [CrossRef] [PubMed]

103. Portela, C.; Afonso, C.M.M.; Pinto, M.M.M.; Ramos, M.J. Receptor–drug association studies in the inhibition of the hematin

aggregation process of malaria. FEBS Lett. 2003, 547, 217–222. [CrossRef]

104. Portela, C.; Afonso, C.M.M.; Pinto, M.M.M.; João Ramos, M. Computational studies of new potential antimalarial compounds—

Stereoelectronic complementarity with the receptor. J. Comput.-Aided Mol. Des. 2003, 17, 583–595. [CrossRef] [PubMed]

105. Portela, C.; Afonso, C.M.M.; Pinto, M.M.M.; Lopes, D.; Nogueira, F.; Do Rosário, V. Synthesis and Antimalarial Properties of New

Chloro-9H-xanthones with an Aminoalkyl Side Chain. Chem. Biodivers. 2007, 4, 1508–1519. [CrossRef]

106. Neves, A.R.; Correia-da-Silva, M.; Sousa, E.; Pinto, M. Strategies to overcome heparins’ low oral bioavailability. Pharmaceuticals

2016, 9, 37. [CrossRef]

107. Desai, U.R. The promise of sulfated synthetic small molecules as modulators of glycosaminoglycan function. Future Med. Chem.

2013, 5, 1363–1366. [CrossRef]

108. Correia-da-Silva, M.; Sousa, E.; Duarte, B.; Marques, F.; Carvalho, F.; Cunha-Ribeiro, L.M.; Pinto, M.M.M. Polysulfated Xanthones:

Multipathway Development of a New Generation of Dual Anticoagulant/Antiplatelet Agents. J. Med. Chem. 2011, 54, 5373–5384.

[CrossRef]

109. Imran, M.; Arshad, M.S.; Butt, M.S.; Kwon, J.-H.; Arshad, M.U.; Sultan, M.T. Mangiferin: A natural miracle bioactive compound

against lifestyle related disorders. Lipids Health Dis. 2017, 16, 84. [CrossRef] [PubMed]

110. Rashid, Q.; Abid, M.; Jairajpuri, M. Elucidating the specificity of non-heparin-based conformational activators of antithrombin for

factor Xa inhibition. J. Nat. Sci. Biol. Med. 2014, 5, 36–42. [CrossRef] [PubMed]

111. Pinto, M.; Sousa, M.E.; Da Silva, M.C.; Marques, F.; Carvalho, F. Patente Portuguesa Nº 104739: Xantonas Sulfatadas e Análogos

Xantónicos Glicosilados Sulfatados com Actividade Anticoagulante e Processos Para a Sua Preparação. Portuguese Patent nº

104739, Boletim da Propriedade Industrial nº 47/2011, 9 March 2011.

112. Neves, A.R.; Correia-Da-Silva, M.; Sousa, E.; Pinto, M. Structure-activity relationship studies for multitarget antithrombotic drugs.

Future Med. Chem. 2016, 8, 2305–2355. [CrossRef] [PubMed]

113. Rashid, Q.; Singh, P.; Abid, M.; Jairajpuri, M.A. Limitations of conventional anticoagulant therapy and the promises of non-heparin

based conformational activators of antithrombin. J. Thromb. Thrombolysis 2012, 34, 251–259. [CrossRef]

114. Kaltenbach, D.D.; Jaishankar, D.; Hao, M.; Beer, J.C.; Volin, M.V.; Desai, U.R.; Tiwari, V. Sulfotransferase and Heparanase:

Remodeling Engines in Promoting Virus Infection and Disease Development. Front. Pharmacol. 2018, 9. [CrossRef]

115. Daniel, K.A.; Rami, A.A.-H. Sulfated Non-Saccharide Glycosaminoglycan Mimetics as Novel Drug Discovery Platform for

Various Pathologies. Curr. Med. Chem. 2020, 27, 3412–3447. [CrossRef]

116. Lima, R.T.; Seca, H.; Palmeira, A.; Fernandes, M.X.; Castro, F.; Correia-da-Silva, M.; Nascimento, M.S.J.; Sousa, E.; Pinto, M.;

Vasconcelos, M.H. Sulfated small molecules targeting EBV in Burkitt lymphoma: From in silico screening to the evidence of

in vitro effect on viral episomal DNA. Chem. Biol. Drug Des. 2013, 81, 631–644. [CrossRef]

117. Vilas-Boas, C.; Sousa, E.; Pinto, M.; Correia-da-Silva, M. An antifouling model from the sea: A review of 25 years of zosteric acid

studies. Biofouling 2017, 33, 927–942. [CrossRef]

118. Almeida, J.R.; Correia-Da-Silva, M.; Sousa, E.; Antunes, J.; Pinto, M.; Vasconcelos, V.; Cunha, I. Antifouling potential of

Nature-inspired sulfated compounds. Sci. Rep. 2017, 7. [CrossRef]

119. Alves, A.; Correia-da-Silva, M.; Nunes, C.; Campos, J.; Sousa, E.; Silva, P.M.A.; Bousbaa, H.; Rodrigues, F.; Ferreira, D.; Costa,

P.C.; et al. Discovery of a new xanthone against glioma: Synthesis and Development of (Pro)liposome Formulations. Molecules

2019, 24, 409. [CrossRef]

120. Neves, A.R.; Correia-da-Silva, M.; Silva, P.M.A.; Ribeiro, D.; Sousa, E.; Bousbaa, H.; Pinto, M. Synthesis of new glycosylated

flavonoids with inhibitory activity on cell growth. Molecules 2018, 23, 1093. [CrossRef] [PubMed]

121. Tiritan, M.E.; Ribeiro, A.R.; Fernandes, C.; Pinto, M.M.M. Chiral pharmaceuticals. In Encyclopedia of Chemical Technology;

Kirk-Othmer, M., Ed.; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2016.

122. Lanzotti, V. Drugs based on natural compounds: Recent achievements and future perspectives. Phytochem. Rev. 2014, 13, 725–726.

[CrossRef]

123. Carlos Miguel Goncalves, A.; Carlos Manuel Magalhaes, A.; Madalena Maria Magalhaes, P. Routes to Xanthones: An Update on

the Synthetic Approaches. Curr. Org. Chem. 2012, 16, 2818–2867. [CrossRef]

124. Blaser, H.-U. Chirality and its implications for the pharmaceutical industry. Rend. Lincei 2013, 24, 213–216. [CrossRef]

125. Fernandes, C.; Carraro, M.L.; Ribeiro, J.; Araujo, J.; Tiritan, M.E.; Pinto, M.M.M. Synthetic chiral derivatives of xanthones:

Biological activities and enantioselectivity studies. Molecules 2019, 24, 791. [CrossRef] [PubMed]

126. Araújo, J.; Fernandes, C.; Pinto, M.; Elizabeth Tiritan, M. Chiral derivatives of xanthones with antimicrobial activity. Molecules

2019, 24, 314. [CrossRef]

127. Pinto, M.M.M.; Sousa, E.P. Natural and synthetic xanthonolognoids: Chemistry and biological activities. Curr. Med. Chem. 2003,

10, 1–12. [CrossRef]

128. Fernandes, E.G.R.; Pinto, M.M.M.; Silva, A.M.S.; Cavaleiro, J.A.S.; Gottlieb, O.R. Synthesis and structural elucidation of

xanthonolignoids: Trans-(±)- kielcorin B and trans-(±)-isokielcorin B. Heterocycles 1999, 51, 821–828. [CrossRef]

129. Emília Sousa, M.; Afonso, C.M.M.; Pinto, M.M.M. Quantitative Analysis of Kielcorins in Biomimetic Synthesis by Liquid

Chromatography/UV Detection. J. Liq. Chromatogr. Relat. Technol. 2003, 26, 29–41. [CrossRef]

130. Saraiva, L.; Fresco, P.; Pinto, E.; Sousa, E.; Pinto, M.; Gonçalves, J. Inhibition of α, βI, δ, η and ζ protein kinase C isoforms by

xanthonolignoids. J. Enzym. Inhib. Med. Chem. 2003, 18, 357–370. [CrossRef]

131. Sousa, E.P.; Tiritan, M.E.; Oliveira, R.V.; Afonso, C.M.M.; Cass, Q.B.; Pinto, M.M.M. Enantiomeric resolution of kielcorin

derivatives by HPLC on polysaccharide stationary phases using multimodal elution. Chirality 2004, 16, 279–285. [CrossRef]

[PubMed]

132. Silva, B.; Pereira, J.A.; Cravo, S.; Araújo, A.M.; Fernandes, C.; Pinto, M.M.M.; De Pinho, P.G.; Remião, F. Multi-milligram

resolution and determination of absolute configuration of pentedrone and methylone enantiomers. J. Chromatogr. B Anal. Technol.

Biomed. Life Sci. 2018, 1100–1101, 158–164. [CrossRef] [PubMed]

133. Pinto, M.M.M.; Fernandes, C.; Tiritan, M.E. Chiral Separations in Preparative Scale: A Medicinal Chemistry Point of View.

Molecules 2020, 25, 1931. [CrossRef] [PubMed]

134. Sousa, M.E.; Tiritan, M.E.; Belaz, K.R.A.; Pedro, M.; Nascimento, M.S.J.; Cass, Q.B.; Pinto, M.M.M. Multimilligram enantioresolution of low-solubility xanthonolignoids on polysaccharide chiral stationary phases using a solid-phase injection system. J.

Chromatogr. A 2006, 1120, 75–81. [CrossRef] [PubMed]

135. Fernandes, C.; Masawang, K.; Tiritan, M.E.; Sousa, E.; De Lima, V.; Afonso, C.; Bousbaa, H.; Sudprasert, W.; Pedro, M.; Pinto,

M.M. New chiral derivatives of xanthones: Synthesis and investigation of enantioselectivity as inhibitors of growth of human

tumor cell lines. Bioorg. Med. Chem. 2014, 22, 1049–1062. [CrossRef] [PubMed]

136. Carraro, M.L.; Marques, S.; Silva, A.S.; Freitas, B.; Silva, P.M.A.; Pedrosa, J.; De Marco, P.; Bousbaa, H.; Fernandes, C.; Tiritan,

M.E.; et al. Synthesis of New Chiral Derivatives of Xanthones with Enantioselective Effect on Tumor Cell Growth and DNA

Crosslinking. ChemistrySelect 2020, 5, 10285–10291. [CrossRef]

137. Fernandes, C.; Oliveira, L.; Tiritan, M.E.; Leitao, L.; Pozzi, A.; Noronha-Matos, J.B.; Correia-de-Sa, P.; Pinto, M.M. Synthesis of

new chiral xanthone derivatives acting as nerve conduction blockers in the rat sciatic nerve. Eur. J. Med. Chem. 2012, 55, 1–11.

[CrossRef]

138. Ribeiro, J.; Veloso, C.; Fernandes, C.; Tiritan, M.E.; Pinto, M.M.M. Carboxyxanthones: Bioactive agents and molecular scaffold for

synthesis of analogues and derivatives. Molecules 2019, 24, 180. [CrossRef]

139. Twibanire, J.-d.K.; Grindley, T.B. Efficient and Controllably Selective Preparation of Esters Using Uronium-Based Coupling

Agents. Org. Lett. 2011, 13, 2988–2991. [CrossRef]

140. Fernandes, C.; Palmeira, A.; Ramos, I.I.; Carneiro, C.; Afonso, C.; Tiritan, M.E.; Cidade, H.; Pinto, P.C.A.G.; Saraiva, M.L.M.F.S.;

Reis, S.; et al. Chiral derivatives of xanthones: Investigation of the effect of enantioselectivity on inhibition of cyclooxygenases

(COX-1 and COX-2) and binding interaction with human serum albumin. Pharmaceuticals 2017, 10, 50. [CrossRef]

141. Santos, Á.; Soares, J.X.; Cravo, S.; Tiritan, M.E.; Reis, S.; Afonso, C.; Fernandes, C.; Pinto, M.M.M. Lipophilicity assessement in

drug discovery: Experimental and theoretical methods applied to xanthone derivatives. J. Chromatogr. B Anal. Technol. Biomed.

Life Sci. 2018, 1072, 182–192. [CrossRef] [PubMed]

142. Fernandes, C.; Palmeira, A.; Santos, A.; Tiritan, M.E.; Afonso, C.; Pinto, M.M. Enantioresolution of Chiral Derivatives of

Xanthones on (S,S)-Whelk-O1 and l-Phenylglycine Stationary Phases and Chiral Recognition Mechanism by Docking Approach

for (S,S)-Whelk-O1. Chirality 2013, 25, 89–100. [CrossRef] [PubMed]

143. Carraro, M.L.; Palmeira, A.; Tiritan, M.E.; Fernandes, C.; Pinto, M.M.M. Resolution, determination of enantiomeric purity and

chiral recognition mechanism of new xanthone derivatives on (S,S)-whelk-O1 stationary phase. Chirality 2017, 29, 247–256.

[CrossRef] [PubMed]

144. Fernandes, C.; Tiritan, M.E.; Cass, Q.; Kairys, V.; Fernandes, M.X.; Pinto, M. Enantioseparation and chiral recognition mechanism

of new chiral derivatives of xanthones on macrocyclic antibiotic stationary phases. J. Chromatogr. A 2012, 1241, 60–68. [CrossRef]

[PubMed]

145. Phyo, Y.Z.; Cravo, S.; Palmeira, A.; Tiritan, M.E.; Kijjoa, A.; Pinto, M.M.M.; Fernandes, C. Enantiomeric Resolution and Docking

Studies of Chiral Xanthonic Derivatives on Chirobiotic Columns. Molecules 2018, 23, 142. [CrossRef] [PubMed]

146. Do Carmo, J.P.; Phyo, Y.Z.; Palmeira, A.; Tiritan, M.E.; Afonso, C.; Kijjoa, A.; M Pinto, M.M.; Fernandes, C. Enantioseparation,

recognition mechanisms and binding of xanthones on human serum albumin by liquid chromatography. Bioanalysis 2019, 11,

1255–1274. [CrossRef]

147. Pinto, M.; Tiritan, M.E.; Fernandes, C.; Cass, Q. Fases Estacionárias Quirais baseadas em Derivados Xantónicos. WO/2011/010284A2,

27 January 2011.

148. Fernandes, C.; Tiritan, M.E.; Pinto, M. Small Molecules as Chromatographic Tools for HPLC Enantiomeric Resolution: Pirkle-Type

Chiral Stationary Phases Evolution. Chromatographia 2013, 76, 871–897. [CrossRef]

149. Corbett, T.H.; Panchapor, C.; Polin, L.; Lowichik, N.; Pugh, S.; White, K.; Kushner, J.; Meyer, J.; Czarnecki, J.; Chinnukroh, S.; et al.

Preclinical efficacy of thioxanthone SR271425 against transplanted solid tumors of mouse and human origin. Investig. New Drugs

1999, 17, 17–27. [CrossRef]

150. Stevenson, J.P.; DeMaria, D.; Reilly, D.; Purvis, J.D.; Graham, M.A.; Lockwood, G.; Drozd, M.; O’Dwyer, P.J. Phase

I/pharmacokinetic trial of the novel thioxanthone SR233377 (WIN33377) on a 5-day schedule. Cancer Chemother. Pharmacol. 1999,

44, 228–234. [CrossRef]

151. Pica-Mattoccia, L.; Cioli, D. Studies on the Mode of Action of Oxamniquine and Related Schistosomicidal Drugs. Am. J. Trop. Med.

Hyg. 1985, 34, 112–118. [CrossRef]

152. Rosi, D.; Peruzzotti, G.; Dennis, E.W.; Berberian, D.A.; Freele, H.; Tullar, B.F.; Archer, S. Hycanthone,1 a New Active Metabolite of

Lucanthone2. J. Med. Chem. 1967, 10, 867–876. [CrossRef] [PubMed]

153. Naidu, M.D.; Agarwal, R.; Pena, L.A.; Cunha, L.; Mezei, M.; Shen, M.; Wilson, D.M., III; Liu, Y.; Sanchez, Z.; Chaudhary, P.; et al.

Lucanthone and Its Derivative Hycanthone Inhibit Apurinic Endonuclease-1 (APE1) by Direct Protein Binding. PLoS ONE 2011,

6, e23679. [CrossRef] [PubMed]

154. Cioli, D.; Pica-Mattoccia, L.; Archer, S. Antischistosomal drugs: Past, present . . . and future? Pharmacol. Ther. 1995, 68, 35–85.

[CrossRef]

155. Ong, T.m.; De Serres, F.J. Mutagenic evaluation of antischistosomal drugs and their derivatives in Neurospora crassa. J. Toxicol.

Environ. Health 1975, 1, 271–279. [CrossRef] [PubMed]

156. LoRusso, P.M.; Foster, B.J.; Wozniak, A.; Heilbrun, L.K.; McCormick, J.I.; Ruble, P.E.; Graham, M.A.; Purvis, J.; Rake, J.; Drozd,

M.; et al. Phase I Pharmacokinetic Study of the Novel Antitumor Agent SR233377. Clin. Cancer Res. 2000, 6, 3088–3094. [PubMed]

157. Goncalves, P.H.; High, F.; Juniewicz, P.; Shackleton, G.; Li, J.; Boerner, S.; LoRusso, P.M. Phase I dose-escalation study of the

thioxanthone SR271425 administered intravenously once every 3 weeks in patients with advanced malignancies. Investig. New

Drugs 2008, 26, 347–354. [CrossRef]

158. Lockhart, A.C.; Calvo, E.; Tolcher, A.W.; Rowinsky, E.K.; Shackleton, G.; Morrison, J.G.; Rafi, R.; VerMeulen, W.; Rothenberg, M.L.

A Phase I Dose-Escalation Study of SR271425, an Intravenously Dosed Thioxanthone Analog, Administered Weekly in Patients

With Refractory Solid Tumors. Am. J. Clin. Oncol. 2009, 32, 9–14. [CrossRef]

159. Soria, J.-C.; Dieras, V.; Girre, V.; Yovine, A.; Mialaret, K.; Armand, J.-P. QTc Monitoring During a Phase I Study: Experience With

SR271425. Am. J. Clin. Oncol. 2007, 30, 106–112. [CrossRef]

160. Mansoori, B.; Mohammadi, A.; Davudian, S.; Shirjang, S.; Baradaran, B. The Different Mechanisms of Cancer Drug Resistance: A

Brief Review. Adv. Pharm. Bull. 2017, 7, 339–348. [CrossRef]

161. Kim, Y.; Chen, J. Molecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation. Science 2018, 359,

915–919. [CrossRef]

162. Ambudkar, S.V.; Kimchi-Sarfaty, C.; Sauna, Z.E.; Gottesman, M.M. P-glycoprotein: From genomics to mechanism. Oncogene 2003,

22, 7468–7485. [CrossRef] [PubMed]

163. Palmeira, A.; Sousa, E.; Helena Vasconcelos, M.; Pinto, M.; Fernandes, M.X. Structure and Ligand-based design of P-glycoprotein

inhibitors: A historical perspective. Curr. Pharm. Des. 2012, 18, 4197–4214. [CrossRef] [PubMed]

164. McDevitt, C.A.; Callaghan, R. How can we best use structural information on P-glycoprotein to design inhibitors? Pharmacol.

Ther. 2007, 113, 429–441. [CrossRef] [PubMed]

165. Wang, R.B.; Kuo, C.L.; Lien, L.L.; Lien, E.J. Structure–activity relationship: Analyses of p-glycoprotein substrates and inhibitors.

J. Clin. Pharm. Ther. 2003, 28, 203–228. [CrossRef] [PubMed]

166. Palmeira, A.; Sousa, E.; Vasconcelos, M.H.; Pinto, M.M. Three decades of P-gp Inhibitors: Skimming through several generations

and scaffolds. Curr. Med. Chem. 2012, 19, 1946–2025. [CrossRef]

167. Morphy, R.; Kay, C.; Rankovic, Z. From magic bullets to designed multiple ligands. Drug Discov. Today 2004, 9, 641–651. [CrossRef]

168. Richard, M.; Zoran, R. Designing Multiple Ligands—Medicinal Chemistry Strategies and Challenges. Curr. Pharm. Des. 2009, 15,

587–600. [CrossRef]

169. Ramsay, R.R.; Popovic-Nikolic, M.R.; Nikolic, K.; Uliassi, E.; Bolognesi, M.L. A perspective on multi-target drug discovery and

design for complex diseases. Clin. Transl. Med. 2018, 7, 3. [CrossRef]

170. Palmeira, A.; Vasconcelos, M.H.; Paiva, A.; Fernandes, M.X.; Pinto, M.; Sousa, E. Dual inhibitors of P-glycoprotein and tumor cell

growth: (Re)discovering thioxanthones. Biochem. Pharmacol. 2012, 83, 57–68. [CrossRef]

171. Palmeira, A.; Rodrigues, F.; Sousa, E.; Pinto, M.; Vasconcelos, M.H.; Fernandes, M.X. New Uses for Old Drugs: PharmacophoreBased Screening for the Discovery of P-Glycoprotein Inhibitors. Chem. Biol. Drug Des. 2011, 78, 57–72. [CrossRef]

172. Garrigos, M.; Mir, L.M.; Orlowski, S. Competitive and Non-Competitive Inhibition of the Multidrug-Resistance-Associated

P-glycoprotein ATPase. Eur. J. Biochem. 1997, 244, 664–673. [CrossRef] [PubMed]

173. Litman, T.; Zeuthen, T.; Skovsgaard, T.; Stein, W.D. Competitive, non-competitive and cooperative interactions between substrates

of P-glycoprotein as measured by its ATPase activity. Biochim. Biophys. Acta (BBA) Mol. Basis Dis. 1997, 1361, 169–176. [CrossRef]

174. Silva, R.; Carmo, H.; Vilas-Boas, V.; Barbosa, D.J.; Palmeira, A.; Sousa, E.; Carvalho, F.; Bastos, M.d.L.; Remião, F. Colchicine

effect on P-glycoprotein expression and activity: In silico and in vitro studies. Chem. Biol. Interact. 2014, 218, 50–62. [CrossRef]

[PubMed]

175. Barbosa, J.; Lima, R.T.; Sousa, D.; Gomes, A.S.; Palmeira, A.; Seca, H.; Choosang, K.; Pakkong, P.; Bousbaa, H.; Pinto, M.M.; et al.

Screening a small library of xanthones for antitumor activity and identification of a hit compound which induces apoptosis.

Molecules 2016, 21, 81. [CrossRef] [PubMed]

176. Safety and Efficacy Study of Lucanthone When Used in Combination With Temozolomide(TMZ) and Radiation to Treat Glioblastoma Multiforme(GBM). Available online: https://clinicaltrials.gov/ct2/show/NCT01587144 (accessed on 25 November 2020).

177. Lima, R.T.; Sousa, D.; Paiva, A.M.; Palmeira, A.; Barbosa, J.; Pedro, M.; Pinto, M.M.; Sousa, E.; Vasconcelos, M.H. Modulation of

autophagy by a thioxanthone decreases the viability of melanoma cells. Molecules 2016, 21, 1343. [CrossRef] [PubMed]

178. Lima, R.T.; Sousa, D.; Gomes, A.S.; Mendes, N.; Matthiesen, R.; Pedro, M.; Marques, F.; Pinto, M.M.; Sousa, E.; Helena Vasconcelos,

M. The antitumor activity of a lead thioxanthone is associated with alterations in cholesterol localization. Molecules 2018, 23, 3301.

[CrossRef]

179. Palmeira, A.; Sousa, E.; Fernandes, M.X.; Pinto, M.M.; Helena Vasconcelos, M. Multidrug resistance reversal effects of aminated

thioxanthones and interaction with cytochrome P450 3A4. J. Pharm. Pharm. Sci. 2011, 15, 31–45. [CrossRef]

180. Kannan, P.; Telu, S.; Shukla, S.; Ambudkar, S.V.; Pike, V.W.; Halldin, C.; Gottesman, M.M.; Innis, R.B.; Hall, M.D. The “Specific”

P-Glycoprotein Inhibitor Tariquidar Is Also a Substrate and an Inhibitor for Breast Cancer Resistance Protein (BCRP/ABCG2).

ACS Chem. Neurosci. 2011, 2, 82–89. [CrossRef]

181. Lopes, A.; Martins, E.; Silva, R.; Pinto, M.M.M.; Remião, F.; Sousa, E.; Fernandes, C. Chiral Thioxanthones as Modulators of

P-glycoprotein: Synthesis and Enantioselectivity Studies. Molecules 2018, 23, 626. [CrossRef]

182. Silva, R.; Vilas-Boas, V.; Carmo, H.; Dinis-Oliveira, R.J.; Carvalho, F.; De Lourdes Bastos, M.; Remião, F. Modulation of Pglycoprotein efflux pump: Induction and activation as a therapeutic strategy. Pharmacol. Ther. 2015, 149, 1–123. [CrossRef]

183. Maglich, J.M.; Stoltz, C.M.; Goodwin, B.; Hawkins-Brown, D.; Moore, J.T.; Kliewer, S.A. Nuclear Pregnane X Receptor and

Constitutive Androstane Receptor Regulate Overlapping but Distinct Sets of Genes Involved in Xenobiotic Detoxification. Mol.

Pharmacol. 2002, 62, 638–646. [CrossRef] [PubMed]

184. Silva, R.; Palmeira, A.; Carmo, H.; Barbosa, D.J.; Gameiro, M.; Gomes, A.; Paiva, A.M.; Sousa, E.; Pinto, M.; Bastos, M.L.; et al.

P-glycoprotein induction in Caco-2 cells by newly synthetized thioxanthones prevents paraquat cytotoxicity. Arch. Toxicol. 2015,

89, 1783–1800. [CrossRef] [PubMed]

185. Ferreira, A.F.; Ponte, F.; Silva, R.; Rocha-Pereira, C.; Sousa, E.; Pinto, M.; Bastos, M.D.L.; Remião, F. Quantification of 1-(propan-2-

ylamino)-4-propoxy-9H-thioxanthen-9-one (TX5), a newly synthetized P-glycoprotein inducer/activator, in biological samples:

Method development and validation. Biomed. Chromatogr. 2017, 31. [CrossRef] [PubMed]

186. Silva, V.; Gil-Martins, E.; Silva, B.; Rocha-Pereira, C.; Sousa, M.E.; Remião, F.; Silva, R. Xanthones as P-glycoprotein modulators

and their impact on drug bioavailability. Expert Opin. Drug Metab. Toxicol. 2020. [CrossRef]