Discovery of Di(het)arylmethane and Dibenzoxanthene Derivatives as Potential Anticancer Agents.

A family of bifunctional dihetarylmethanes and dibenzoxanthenes is assembled via a reaction of acetals containing a 2-chloroacetamide moiety with phenols and related oxygen-containing heterocycles. These compounds demonstrated selective antitumor activity associated with the induction of cell apoptosis and inhibition of the process of glycolysis. In particular, bis(heteroaryl)methane containing two 4-hydroxy-6-methyl-2H-pyran-2-one moieties combine excellent in vitro antitumor efficacy with an IC50 of 1.7 µM in HuTu-80 human duodenal adenocarcinoma models with a high selectivity index of 73. Overall, this work highlights the therapeutic potential of dimeric compounds assembled from functionalized acetals and builds a starting point for the development of a new family of anticancer agents.

Dihydroxanthene-based monoamine oxidase A-activated photosensitizers for photodynamic/photothermal therapy of tumors.

Small molecule photosensitizers for combined in vivo tailored cancer diagnostics and photodynamic/photothermal therapy are desperately needed. Monoamine oxidase A (MAO-A)-activated therapeutic and diagnostic compounds provide great selectivity because MAO-A can be employed as a biomarker for associated Tumors. In order to screen photosensitizers with photodynamic therapeutic potential, we have created a range of near-infrared fluorescent molecules in this work by combining dihydroxanthene parent with various heterocyclic fluorescent dyes. The NIR fluorescent diagnostic probe, DHMQ, was created by combining the screened fluorescent dye matrices with the propylamino group, which is the recognition moiety of MAO-A, based on the oxidative deamination mechanism of the enzyme. This probe has a low toxicity level and can identify MAO-A precisely. It has the ability to use fluorescence imaging on mice and cells to track MAO-A activity in real-time. It has strong phototoxicity and can produce singlet oxygen when exposed to laser light. The temperature used in photothermal imaging can get up to 50 °C, which can harm tumor cells permanently and have a positive phototherapeutic impact on tumors grown from SH-SY5Y xenograft mice. The concept of using MAO-A effectively in diseases is expanded by the MAO-A-activated diagnostic-integrated photosensitizers, which offer a new platform for in vivo cancer diagnostics and targeted anticancer treatment.

Developing NIR xanthene-chalcone fluorophores with large Stokes shifts for fluorescence imaging.

A series of novel near-infrared (NIR) xanthene-chalcone fluorophores were constructed through a modular synthesis with the electron-donating xanthene moiety and the electron-withdrawing chalcone moiety. These fluorophores are convenient for fluorescence imaging in living cells, benefiting from their NIR emissions (650-710 nm), large Stokes shifts (>100 nm), moderate quantum yields and low cytotoxicity. The substituted hydroxyl group of the xanthene-chalcone fluorophore HCA-E facilitates the development of multifunctional fluorescent probes. As an example, a highly sensitive and selective probe N-HCA-E for glutathione (GSH) detection was developed based on the fluorophore HCA-E. A 4-nitrobenzenesulfonyl (4-Ns) group was introduced to cage the hydroxyl group of HCA-E, which was used as a selective recognition site for the thiol of GSH and an effective fluorescence quencher. Probe N-HCA-E revealed NIR "turn-on" fluorescence (709 nm) for endogenous and exogenous GSH detection in lysosomes with a large Stokes shift (129 nm) and high anti-interference ability.

Design, synthesis, and biological evaluation of gambogenic acid derivatives: Unraveling their anti-cancer effects by inducing pyroptosis.

Gambogenic acid (GNA), a caged xanthone derived from Garcinia hanburyi, exhibits a wide range of anti-cancer properties. The caged skeleton of GNA serves as the fundamental pharmacophore responsible for its antitumor effects. However, limited exploration has focused on the structural modifications of GNA. This study endeavors to diversify the structure of GNA and enhance its anti-cancer efficacy. Sulfoximines, recognized as pivotal motifs in medicinal chemistry due to their outstanding properties, have featured in several anti-cancer drugs undergoing clinical trials. Accordingly, a series of 33 GNA derivatives combined with sulfoximines were synthesized and evaluated for their anti-cancer effects against MIAPaCa2, MDA-MB-231, and A549 cells in vitro. The activity screening led to the identification of compound 12k, which exhibited the most potent anti-cancer effect. Mechanistic studies revealed that 12k primarily induced pyroptosis in MIAPaCa2 and MDA-MB-231 cells by activating the caspase-3/gasdermin E (GSDME) pathway. These findings suggested that 12k is a promising drug candidate in cancer therapy and highlighted the potential of sulfoximines as a valuable functional group in drug discovery.

THQ-Xanthene: An Emerging Strategy to Create Next-Generation NIR-I/II Fluorophores.

Near-infrared fluorescence imaging is vital for exploring the biological world. The short emissions (<650 nm) and small Stokes shifts (<30 nm) of current xanthene dyes obstruct their biological applications since a long time. Recently, a potent and universal THQ structural modification technique that shifts emission to the NIR-I/II range and enables a substantial Stokes shift (>100 nm) for THQ-modified xanthene dyes is established. Thus, a timely discussion of THQ-xanthene and its applications is extensive. Hence, the advent, working principles, development trajectory, and biological applications of THQ-xanthene dyes, especially in the fields of fluorescence probe-based sensing and imaging, cancer theranostics, and super-resolution imaging, are introduced. It is envisioned that the THQ modification tactic is a simple yet exceptional approach to upgrade the performance of conventional xanthene dyes. THQ-xanthene will advance the strides of xanthene-based potentials in early fluorescent diagnosis of diseases, cancer theranostics, and imaging-guided surgery.

Synthesis of Cyano-Benzylidene Xanthene Synthons Using a Diprotic Brønsted Acid Catalyst, and Their Application as Efficient Inhibitors of Aluminum Corrosion in Alkaline Solutions.

Novel cyano-benzylidene xanthene derivatives were synthesized using one-pot and condensation reactions. A diprotic Brønsted acid (i.e., oxalic acid) was used as an effective catalyst for the promotion of the synthesis process of the new starting xanthene-aldehyde compound. Different xanthene concentrations (ca. 0.1-2.0 mM) were applied as corrosion inhibitors to control the alkaline uniform corrosion of aluminum. Measurements were conducted in 1.0 M NaOH solution using Tafel extrapolation and linear polarization resistance (LPR) methods. The investigated xanthenes acted as mixed-type inhibitors that primarily affect the anodic process. Their inhibition efficiency values were enhanced with inhibitor concentration, and varied according to their chemical structures. At a concentration of 2.0 mM, the best-performing studied xanthene derivative recorded maximum inhibition efficiency values of 98.9% (calculated via the Tafel extrapolation method) and 98.4% (estimated via the LPR method). Scanning electron microscopy (SEM) was used to examine the morphology of the corroded and inhibited aluminum surfaces, revealing strong inhibitory action of each studied compound. High-resolution X-ray photoelectron spectroscopy (XPS) profiles validated the inhibitor compounds' adsorption on the Al surface. Density functional theory (DFT) and Monte Carlo simulations were applied to investigate the distinction of the anticorrosive behavior among the studied xanthenes toward the Al (111) surface. The non-planarity of xanthenes and the presence of the nitrile group were the key players in the adsorption process. A match between the experimental and theoretical findings was evidenced.

Biocompatible silver(I) complexes with heterocyclic thioamide ligands for selective killing of cancer cells and high antimicrobial activity - A combined in vitro and in silico study.

A series of heteroleptic Ag(I) complexes bearing 4,6-dimethyl-2-pyrimidinethiol (dmp2SH), i.e., [AgCl(dmp2SH)(PPh3)2] (1), [Ag(dmp2SH)(PPh3)2]NO3 (2), [Ag(dmp2SΗ)(xantphos)]NO3 (3), [Ag(µ-dmp2S)(PPh3)]2 (4), [Ag(dmp2S)(xantphos)] (5), [Ag(µ-dmp2S)(DPEphos)]2 (6) (xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and DPEPhos = bis[(2-diphenylphosphino)phenyl]ether) were synthesized. The complexes display systematic variation of particular structural characteristics which were proved to have a significant impact on their in vitro cytotoxicity and antimicrobial properties. A moderate-to-high potential for bacteria growth inhibition was observed for all complexes, with 2, 3 and 5 being particularly effective against Gram-(+) bacteria (IC50 = 1.6-4.5 µM). The three complexes exhibit high in vitro cytotoxicity against HeLa and MCF-7 cancer cells (IC50 = 0.32-3.00 µΜ), suggesting the importance of coordination unsaturation and cationic charge for effective bioactivity. A very low cytotoxicity against HDFa normal cells was observed, revealing a high degree of selectivity (selectivity index ~10) and, hence, biocompatibility. Fluorescence microscopy using 2 showed effective targeting on the membrane of the HeLa cancer cells, subsequently inducing cell death. Binding of the complexes to serum albumin proteins is reasonably strong for potential uptake and subsequent release to target sites. A moderate in vitro antioxidant capacity for free radicals scavenging was observed and a low potential to destroy the double-strand structure of calf-thymus DNA by intercalation, suggesting likely implication of these properties in the bioactivity mechanisms of these complexes. Further insight into possible mechanisms of bioactivity was obtained by molecular modeling calculations, by exploring their ability to act as potential inhibitors of DNA-gyrase, human estrogen receptor alpha, human cyclin-dependent kinase 6, and human papillomavirus E6 oncoprotein.

A novel, dual action chimera comprising DNA methylating agent and near-IR xanthene-cyanine photosensitizer for combined anticancer therapy.

A facile synthesis, biological evaluation and photodynamic properties of novel activatable anticancer molecular hybrids (chimeras) Ch and I-Ch are described. The chimeras consist of DNA methylating methyl triazene moiety and fluorogenic xanthene-cyanine (XCy) or iodinated xanthene-cyanine (I-XCy) photosensitizer. These two anticancer core structures are bound by means of a self-immolative 4-aminobenzyl alcohol linker. The hydrolytic cleavage of the carbamate protecting group promotes activation of both DNA methylating monomethyl triazene and phototoxic xanthene-cyanine dye providing, in addition, a near-IR emission signal for detection of the drug activation events. Preliminary antiproliferative assay demonstrates that the developed chimeras exhibit higher antitumor activity in the breast cancer cell line upon near-IR light irradiation compared to their structural constituents, xanthene-cyanine photosensitizer and monomethyl triazene substance.

Discovery of potent antiproliferative agents from selected oxygen heterocycles as EGFR tyrosine kinase inhibitors from the U.S. National Cancer Institute database by in silico screening and bioactivity evaluation.

A similarity search was conducted on the U.S. Enhanced National Cancer Institute Database Browser 2.2 to find structures related to 1,5-dihydroxy-9H-xanthen-9-one, a previously established EGFR-TK inhibitor. Compounds were virtually screened and selected for bioactivity testing revealed 5 candidates, mostly displayed stronger antiproliferative activities than erlotinib with IC50 values between 0.95 and 17.71 µM against overexpressed EGFR-TK cancer cell lines: A431 and HeLa. NSC107228 displayed the strongest antiproliferative effects with IC50 values of 2.84 and 0.95 µM against A431 and HeLa cancer cell lines, respectively. Three compounds, NSC81111, NSC381467 and NSC114126 inhibited EGFR-TK with IC50 values between 0.15 and 30.18 nM. NSC81111 was the best inhibitor with IC50 = 0.15 nM. Molecular docking analysis of the 3 compounds predicted hydrogen bonding and hydrophobic interactions with key residues were important for the bioactivities observed. Furthermore, calculations of the physicochemical properties suggest the compounds are drug-like and are potentially active orally.

Facile and divergent optimization of chromazonarol enabled the identification of simplified drimane meroterpenoids as novel pharmaceutical leads.

The diversity of drimane hydroquinones was significantly expanded by the facile construction of (+)-chromazonarol relevant natural products, isomers, and analogues for the discovery of new pharmaceutical leads. The structure-activity relationship of (+)-chromazonarol relevant (non)-natural products was delineated via the synergistic interaction of the programmable synthesis and bioactivity-guided screening. The first divergent derivatization of (+)-chromazonarol demonstrated that the phenolic hydroxyl group is one inviolable requirement for antifungal effect. Pinpoint modification of (+)-yahazunol manifested the position of hydroxyl group was crucial for both antifungal and antitumor activities. (+)-Albaconol, (+)-neoalbaconol, and two (+)-yahazunol isomers (24 and 25) proved to be the novel pharmaceutical leads. The probable macromolecular targets were estimated to deliver new information about the biological potentials resident in (+)-yahazunol relevant products. This work also featured the first synthesis of (+)-albaconol and (+)-neoalbaconol, the first biological exploration of (+)-dictyvaric acid and improved preparation of (+)-8-epi-puupehedione and a promising pelorol analogue.

Insights into Ergochromes of the Plant Pathogen Claviceps purpurea.

Claviceps purpurea is an ergot fungus known for its neurotropic alkaloids, which have been identified as the main cause of ergotism, a livestock and human disease triggered by ergot consumption. Tetrahydroxanthone dimers, the so-called ergopigments, presumably also contribute to this toxic effect. Overexpression of the cluster-specific transcription factor responsible for the formation of these pigments in C. purpurea led to the isolation of three new metabolites (8-10). The new pigments were characterized utilizing HRMS, NMR techniques, and CD spectroscopy and shown to be xanthone dimers. Secalonic acid A and its 2,4'- and 4,4'-linked isomers were also isolated, and their absolute configuration was investigated. The contribution of secalonic acid A, its isomers, and new metabolites to the toxicity of C. purpurea was investigated in HepG2 and CCF-STTG1 cells. Along with cytotoxic properties, secalonic acid A was found to inhibit topoisomerase I and II activity.

An activatable near-infrared fluorescent probe facilitated high-contrast lipophagic imaging in live cells.

A new fluorescent probe (Q-lipo) was developed by conjugating a xanthene scaffold with a quinoline moiety for activatable imaging of lipophagy. Q-lipo with acidic pH activated near infrared fluorescence and the lipid droplet targeting ability allowed activatable fluorescence imaging and flow cytometry detection of lipophagy in live cells with high contrast. It was further utilized to study the effect of tumor-microenvironment related conditions on lipophagy. Q-lipo would provide a useful tool for studying lipophagy in live cells.

Separation of three chromones from Saposhnikovia divaricata using macroporous resins followed by preparative high-performance liquid chromatography.

Prim-O-glucosylcimifugin, cimifugin, and 5-O-methylvisamminoside are three major chromone derivatives of Saposhnikovia divaricata that have many pharmacological activities, such as anti-inflammatory and antitumor activities. In the present work, an effective method for the simultaneous separation of prim-O-glucosylcimifugin, cimifugin, and 5-O-methylvisamminoside with high purities was established using HPD-300 resin coupled with preparative high-performance liquid chromatography. The adsorption kinetics curves of the three compounds on the HPD-300 resin were studied and found to fit well according to the pseudo-second-order equation. The adsorption isotherm results indicated that the adsorption process of the three compounds was exothermic. After a one-run treatment with the resin, the contents of prim-O-glucosylcimifugin, cimifugin, and 5-O-methylvisamminoside increased from 0.29, 0.06, and 0.37% to 13.07, 2.83, and 16.91% with recovery yields of 76.38, 78.25, and 76.73%, respectively. Finally, the purities of the three compounds were found to reach more than 95% after further separation using preparative high-performance liquid chromatography. The method developed in this study was effective and could simultaneously separate three chromones from Saposhnikovia divaricate. The experimental results also showed that the HPD-300 resin is suitable for the separation of chromone derivatives.

Gambogic acid and gambogenic acid induce a thiol-dependent heat shock response and disrupt the interaction between HSP90 and HSF1 or HSF2.

Cancer cells rely on heat shock proteins (HSPs) for growth and survival. Especially HSP90 has multiple client proteins and plays a critical role in malignant transformation, and therefore different types of HSP90 inhibitors are being developed. The bioactive natural compound gambogic acid (GB) is a prenylated xanthone with antitumor activity, and it has been proposed to function as an HSP90 inhibitor. However, there are contradicting reports whether GB induces a heat shock response (HSR), which is cytoprotective for cancer cells and therefore a potentially problematic feature for an anticancer drug. In this study, we show that GB and a structurally related compound, called gambogenic acid (GBA), induce a robust HSR, in a thiol-dependent manner. Using heat shock factor 1 (HSF1) or HSF2 knockout cells, we show that the GB or GBA-induced HSR is HSF1-dependent. Intriguingly, using closed form ATP-bound HSP90 mutants that can be co-precipitated with HSF1, a known facilitator of cancer, we show that also endogenous HSF2 co-precipitates with HSP90. GB and GBA treatment disrupt the interaction between HSP90 and HSF1 and HSP90 and HSF2. Our study implies that these compounds should be used cautiously if developed for cancer therapies, since GB and its derivative GBA are strong inducers of the HSR, in multiple cell types, by involving the dissociation of a HSP90-HSF1/HSF2 complex.

ChCl: Gly (DESs) Promote Environmentally Benign Synthesis of Xanthene Derivatives and Their Antitubercular Activity.

A ChCl: Gly (DESs) promoted environmentally benign method was developed for the first time using the reaction of aryl aldehydes and dimedone to give excellent yields of xanthene analogues. The major application of this present protocol is the use of green solvent, a wide range of substrate, short reaction times, ease of recovery, the recyclability of the catalyst, high reaction yield, and ChCl: Gly as an alternative catalyst and solvent. In addition to this, all the synthesized compounds were evaluated for their in vitro antimycobacterial activity against M. tuberculosis H37Ra (MTB) and M. bovis BCG strains. The compounds 3d, 3e, 3f, and 3j showed significant antitubercular activity against MTB and M. bovis strains with minimum inhibitory concentration (MIC) values of 2.5-15.10 µg/mL and 0.26-14.92 µg/mL, respectively. The compounds 3e, 3f, and 3j were found to be nontoxic against MCF-7, A549, HCT 116, and THP-1 cell lines. All the prepared compounds were confirmed by 1H NMR and 13C NMR analysis.

Xanthenylacetic Acid Derivatives Effectively Target Lysophosphatidic Acid Receptor 6 to Inhibit Hepatocellular Carcinoma Cell Growth.

Despite the increasing incidence of hepatocellular carcinoma (HCC) worldwide, current pharmacological treatments are still unsatisfactory. We have previously shown that lysophosphatidic acid receptor 6 (LPAR6) supports HCC growth and that 9-xanthenylacetic acid (XAA) acts as an LPAR6 antagonist inhibiting HCC growth without toxicity. Here, we synthesized four novel XAA derivatives, (±)-2-(9H-xanthen-9-yl)propanoic acid (compound 4 - MC9), (±)-2-(9H-xanthen-9-yl)butanoic acid (compound 5 - MC6), (±)-2-(9H-xanthen-9-yl)hexanoic acid (compound 7 - MC11), and (±)-2-(9H-xanthen-9-yl)octanoic acid (compound 8 - MC12, sodium salt) by introducing alkyl groups of increasing length at the acetic α-carbon atom. Two of these compounds were characterized by X-ray powder diffraction and quantum mechanical calculations, while molecular docking simulations suggested their enantioselectivity for LPAR6. Biological data showed anti-HCC activity for all XAA derivatives, with the maximum effect observed for MC11. Our findings support the view that increasing the length of the alkyl group improves the inhibitory action of XAA and that enantioselectivity can be exploited for designing novel and more effective XAA-based LPAR6 antagonists.

Application of cyclohexane-1,3-diones for six-membered oxygen-containing heterocycles synthesis.

Cyclohexan-1,3-dione derivatives are versatile scaffolds for the synthesis of a variety of value-added organic molecules including heterocycles and natural products. Six-membered oxygen heterocycles prepared from cyclohexan-1,3-diones are of much importance as they are intermediate for the synthesis of a number of natural products and several other valuable bioactive molecules which shows anti-viral, anti-bacterial, analgesic, antimalarial, anti-inflammatory, anti-allergic, anti-tumor and anti-cancer activities. These advantages have inspired us to write a detailed survey on the newly developed methods which are very essential in the construction of six-membered oxygen heterocycles. Further, the versatility in the chemistry of cyclohexan-1,3-dione and its derivatives is due to the presence of highly active methylene moiety and its active di-carbonyl groups. Recently, reactions of cyclohexane-1,3-dione and its derivatives with other substrates for instance aldehydes, malononitriles, NMSM, chalcones, isatin etc. have been established for the construction of a variety of six-membered oxygen heterocycles. The studies reported in this review article involved the synthesis of six-membered oxygen-containing heterocycles which includes 4H-chromen-5(6H)-one, 2H-xanthen-1(9H)-one, 2H-xanthen-1,8(5H,9H)-dione, 6H-chromen-2,5-dione derivatives and natural products having six-membered oxygen heterocycles from cyclohexane-1,3-dione and its derivatives as one of the substrate.

Real-time imaging of alkaline phosphatase activity of diabetes in mice via a near-infrared fluorescent probe.

A novel water-soluble near-infrared fluorescent probe named QX-P with simple synthesis is developed. QX-P has high sensitivity and selectivity to ALP. Moreover, the probe can not only visualize ALP activity in four cell lines, but also real-time image ALP activity during the diagnosis and treatment of diabetes in mice.

Activated Carbon/MoO3: Efficient Catalyst for Green Synthesis of Chromeno[d]pyrimidinediones and Xanthenones.

BACKGROUND: Nanoscale metal oxide catalysts have been extensively employed in organic reactions because they have been found to influence the chemical and physical properties of bulk material. The chromene (benzopyran) nucleus constitutes the core structure in a major class of many biologically active compounds, and interest in their chemistry consequently continues because of their numerous biological activities. The xanthene (dibenzopyran) derivatives are classified as highly significant compounds which display a number of various bioactive properties. Pyrimidinones have also gained interest due to their remarkable biological utilization, such as antiviral, antibacterial, antihypertensive, antitumor, and calcium blockers effects. OBJECTIVE: The aim of this work presented herein was to prepare activated carbon/MoO3 nanocomposite and explore its role as a green and recyclable catalyst for the synthesis of chromeno[d]pyrimidinediones and xanthenones under ethanol-drop grinding at room temperature. METHODS: The activated carbon/MoO3 nanocomposite was prepared successfully via a simple route in which the carbonization of gums as new natural precursors was used for the synthesis of activated carbon. This nanocomposite was then effectively used in a reaction of 3,4-methylenedioxyphenol, aromatic aldehydes, and active methylene compounds, including 1,3-dimethylbarbituric acid and dimedone, to synthesize a series of chromeno[d]pyrimidinediones and xanthenones in high yields. The synthesized catalyst was characterized by Fourier transform infrared spectroscopy (FT-IR), Powder x-ray diffractometry (XRD), Scanning electron microscope (SEM), Raman spectroscopy, and also by TGA analysis. Confirmation of the structures of compounds 5(a-g) and 6(a-g) were also established with IR, 1H NMR, and 13C NMR spectroscopic data and also by elemental analyses. RESULTS: A number of 6,8-dimethyl-10-phenyl-6,10-dihydro-7H-[1,3]dioxolo[4´,5´:6,7]chromeno[2,3- d]pyrimidine-7,9(8H)-diones and 7,7-dimethyl-10-(4-methylphenyl)-6,7,8,10-tetrahydro-9H-[1,3]dioxolo[ 4,5-b]xanthen-9-ones were effectively synthesized using activated carbon/MoO3 nanocomposite (0.05 gr) as a catalyst under ethanol-drop grinding at room temperature. The desired products were obtained in high yields (93-97%) within short reaction times (15-20 min). CONCLUSION: This paper investigates the catalytic potential of the synthesized activated carbon/MoO3 nanocomposite for the preparation of chromeno[d]pyrimidinediones and xanthenones under the ethanol-drop grinding procedure. The mildness of the reaction conditions, high yields of products, short reaction times, experimental simplicity, and avoiding the use of harmful solvents or reagents makes this procedure preferable for the synthesis of these compounds.

Xanthenes in Medicinal Chemistry - Synthetic strategies and biological activities.

BACKGROUND: Xanthenes are a special class of oxygen-incorporating tricyclic compounds. Structurally related to xanthones, the presence of different substituents in position 9 strongly influences their physical and chemical properties, as well as their biological applications. This review explores the synthetic methodologies developed to obtain 9H-xanthene, 9-hydroxyxanthene and xanthene-9-carboxylic acid, as well as respective derivatives, from simple starting materials or through modification of related structures. Azaxanthenes, bioisosteres of xanthenes, are also explored. Efficiency, safety, ecological impact and applicability of the described synthetic methodologies are discussed. Synthesis of multi-functionalized derivatives with drug-likeness properties are also reported and their activities explored. Synthetic methodologies for obtaining (aza)xanthenes from simple building blocks are available, and electrochemical and/or metal free procedures recently developed arise as greener and efficient methodologies. Nonetheless, the synthesis of xanthenes through the modification of the carbonyl in position 9 of xanthones represents the most straightforward procedure to easily obtain a variety of (aza)xanthenes. (Aza)xanthene derivatives displayed biological activity as neuroprotector, antitumor, antimicrobial, among others, proving the versatility of this nucleus for different biological applications. However, in some cases their chemical structures suggest a lack of pharmacokinetic properties being associated with safety concerns, which should be overcome if intended for clinical evaluation.