Light-Driven Site-Selective Glycosylation of Native Carbohydrates.

Carbohydrates constitute the largest source of biomass on Earth, but their synthetic modification is highly challenging due to their high content of oxygen functionalities. The site- and stereoselective modification of native sugars is a definitive goal of glycochemistry research. Recent efforts to bypass the need for protecting groups, leveraging selective activation through photochemical mechanisms for site-selective C-C bond formation from native sugars, are likely to largely impact all glycochemistry-related areas. Davis, Koh, and co-workers have recently presented their use of photocatalysis to develop a "cap and glycosylate" approach for the site- and stereoselective C-glycosylation of native sugars. The modernization of a direct radical functionalization of in situ formed thioglycoside using photocatalysis was used in the synthetic manipulation of unprotected carbohydrates. This allowed reaching complex saccharides, and post-translational modification of proteins.

Novel tetrahydroquinoline derivatives induce ROS-mediated apoptosis in glioblastoma cells.

Current treatment for Glioblastoma Multiforme (GBM) is not efficient due to its aggressive nature, tendency to infiltrate surrounding brain tissue, and chemotherapy resistance. Tetrahydroquinoline scaffolds are emerging as a new class of drug for treating many human cancers including GBM. This study investigates the cytotoxicity effect of eight novel derivatives of 2-((3,4-dihydroquinolin-1(2H)-yl)(aryl)methyl)phenol, containing substitute 1 with reduced dihydroquinoline fused with cyclohexene ring and substitute 2 with phenyl and methyl group. The 4-position of the aryl ring was determinant for the desired cytotoxicity, and out of the 8 synthesized compounds, the 4-trifluoromethyl substituted derivative (4ag) exhibited the most anti-GBM potential effect compared to the standard chemotherapeutic agent, temozolomide (TMZ), with IC50 values of 38.3 µM and 40.6 µM in SNB19 and LN229 cell lines, respectively. Our results demonstrated that 4ag triggers apoptosis through the activation of Caspase-3/7. In addition, 4ag induced intracellular reactive oxygen species (iROS) which in turn elevated mitochondrial ROS (mtROS) and causes the disruption of the mitochondrial membrane potential (Δψmt) in both GBM cells. This compound also exhibited anti-migratory properties over the time in both the cell lines. Overall, these findings suggest that tetrahydroquinoline derivative, 4ag could lead to the development of a new drug for treating GBM.

Halimane Derivatives from Plectranthus ornatus Codd. as Novel Anti-cancer Agents.

The Plectranthus genus is often cited for its medicinal properties. Plectranthus ornatus Codd. is traditionally used in Africa for the treatment of gastric and liver diseases and their leaves are used for their antibiotic action. The main constituent of P. ornatus is the halimane compound, 11 R∗-acetoxyhalima-5,13E-dien-15-oic acid (Hal), described for its antimicrobial and anticancer properties. The objective of this work was to improve the activity of the halimane lead molecule. Further physiochemical characterisation was performed on Hal. To the best of our knowledge, this work constitutes the first published data of the absolute configurations by SCXRD and thermal stability of Hal. Using Hal, reactions with different amines were carried out to afford novel semi-synthetic derivatives and their structural elucidation was completed. The cytotoxicity of the derivatives was assessed against three leukaemia cancer cell lines (CCRF-CEM, K562 and HL-60). The antioxidant activity was investigated using H2O2-induced HGF-1 cells and their anti-inflammatory activity was studied using RT-PCR and ELISA. Our data showed that amide derivatives of Hal presented moderate cytotoxicity and more potent activity when compared to the parent molecule, giving insight into the SAR of Hal. The derivatives also displayed protection against oxidative damage to DNA. Finally, the derivatives possessed anti-inflammatory properties at the level of gene and protein expression for the cytokines IL-1ß, TNF-α and IL-6, induced by LPS in normal HGF-1 cells. Overall, our study provides useful insight into the enhanced biological activities of semi-synthetic Hal derivatives, as a starting point for novel drug formulations in cancer therapy.

Cu-Catalyzed Tandem Oxidation-Intramolecular Cannizzaro Reaction of Biorenewables and Bioactive Molecules.

A tandem Cu-catalyzed oxidation-intramolecular Cannizzaro reaction leading to bioactive α-hydroxyesters from α-hydroxyketones is reported. The process uses oxygen as a sole oxidant to achieve the formation of glyoxals, which are efficiently converted in situ to important α-hydroxyesters. The mechanistic insights are provided by isotopic labeling and supported by DFT calculations. The transformation proved a robust synthetic tool to achieve the synthesis of human metabolites and hydroxyl esters of various biologically active steroid derivatives.

A novel EGFR inhibitor, HNPMI, regulates apoptosis and oncogenesis by modulating BCL-2/BAX and p53 in colon cancer.

BACKGROUND AND PURPOSE: Colorectal cancer (CRC) is the second most lethal disease, with high mortality due to its heterogeneity and chemo-resistance. Here, we have focused on the epidermal growth factor receptor (EGFR) as an effective therapeutic target in CRC and studied the effects of polyphenols known to modulate several key signalling mechanisms including EGFR signalling, associated with anti-proliferative and anti-metastatic properties. EXPERIMENTAL APPROACH: Using ligand- and structure-based cheminformatics, we developed three potent, selective alkylaminophenols, 2-[(3,4-dihydroquinolin-1(2H)-yl)(p-tolyl)methyl]phenol (THTMP), 2-[(1,2,3,4-tetrahydroquinolin-1-yl)(4-methoxyphenyl)methyl]phenol (THMPP) and N-[2-hydroxy-5-nitrophenyl(4'-methylphenyl)methyl]indoline (HNPMI). These alkylaminophenols were assessed for EGFR interaction, EGFR-pathway modulation, cytotoxic and apoptosis induction, caspase activation and transcriptional and translational regulation. The lead compound HNPMI was evaluated in mice bearing xenografts of CRC cells. KEY RESULTS: Of the three alkylaminophenols tested, HNPMI exhibited the lowest IC50 in CRC cells and potential cytotoxic effects on other tumour cells. Modulation of EGFR pathway down-regulated protein levels of osteopontin, survivin and cathepsin S, leading to apoptosis. Cell cycle analysis revealed that HNPMI induced G0/G1 phase arrest in CRC cells. HNPMI altered the mRNA for and protein levels of several apoptosis-related proteins including caspase 3, BCL-2 and p53. HNPMI down-regulated the proteins crucial to oncogenesis in CRC cells. Assays in mice bearing CRC xenografts showed that HNPMI reduced the relative tumour volume. CONCLUSIONS AND IMPLICATIONS: HNPMI is a promising EGFR inhibitor for clinical translation. HNPMI regulated apoptosis and oncogenesis by modulating BCL-2/BAX and p53 in CRC cell lines, showing potential as a therapeutic agent in the treatment of CRC.

Methanodibenzo[b,f][1,5]dioxocins as Novel Glutaminase Inhibitor with Anti-Glioblastoma Potential.

Glutamine metabolism is an important hallmark of several cancers with demonstrated antitumor activity in glioblastoma cancer cells (GBM). GBM cells regulate glutamine and use it as a major energy source for their proliferation through the glutaminolysis process. Enzymes, such as glutaminase in glutaminolysis, can be targeted by small-molecule inhibitors, thus exhibiting promising anticancer properties. The resistance to glutaminolysis demands the development of new therapeutic molecules to overcome drug resistance. Herein, we have reported a novel library of constrained methanodibenzo[b,f][1,5]dioxocin derivatives as glutaminase (GLS) inhibitors and their anti-GBM potential. The library consisting of seven molecules was obtained through self-condensation of 2'-hydroxyacetophenones, out of which three molecules, namely compounds 3, 5, and 6, were identified with higher binding energy values ranging between -10.2 and -9.8 kcal/mol with GLS (PDB ID; 4O7D). Pharmacological validation of these compounds also showed a higher growth inhibition effect in GBM cells than the standard drug temozolomide (TMZ). The most promising compound, 6, obeyed Lipinski's rule of five and was identified to interact with key residues Arg307, Asp326, Lys328, Lys399, and Glu403 of GLS. This compound exhibited the best cytotoxic effect with IC50 values of 63 µM and 83 µM in LN229 and SNB19 cells, respectively. The potential activation of GLS by the best-constrained dibenzo[b,f][1,5]dioxocin in the tested series increased apoptosis via reactive oxygen species production in both GBM cells, and exhibited anti-migratory and anti-proliferative properties over time in both cell lines. Our results highlight the activation mechanism of a dibenzo[b,f][1,5]dioxocin from the structural basis and demonstrate that inhibition of glutaminolysis may facilitate the pharmacological intervention for GBM treatment.

Ru-Catalyzed Isomerization of Achmatowicz Derivatives: A Sustainable Route to Biorenewables and Bioactive Lactones.

A Ru-catalyzed isomerization of Achmatowicz derivatives that opens unexplored routes to diversify the biogenic furanic platform is reported. The mechanistic insights of this formally redox-neutral intramolecular process were studied computationally and by deuterium labeling. The transformation proved to be a robust synthetic tool to achieve the synthesis of bioderived-monomers and a series of 4-keto-δ-valerolactones that further enabled the development of a flexible strategy for the synthesis of acetogenins. A concise and protective group-free asymmetric total synthesis of two natural products, namely, (S,S)-muricatacin and the (S,S)-L-factor, is also described.

Functionalized Cyclopentenes via the Formal [4+1] Cycloaddition of Photogenerated Siloxycarbenes from Acyl Silanes.

This work describes the first formal cycloaddition reaction of photogenerated nucleophilic carbenes derived from acylsilanes with electrophilic dienes. The resulting transient donor-acceptor cyclopropane rearranges to its stable and highly functionalized cyclopentene isomer in an unprecedented metal-free process. The cyclopropanation-vinyl cyclopropane rearrangement sequence was corroborated by computational calculations. The cyclopropane formation corresponds to a higher energetic barrier, and the vinylcyclopropane-cyclopentene rearrangement proceeds through different mechanisms, although of comparable energies, depending on the stereochemistry of the cyclopropane.

C20-nor-Abietane and Three Abietane Diterpenoids from Plectranthus mutabilis Leaves as P-Glycoprotein Modulators.

In this study, a bioguided fractionation of Plectranthus mutabilis extract was performed by chromatographic methods. It yielded one new nor-abietane diterpene, mutabilol (1), and three known abietanes, coleon-U-quinone (2), 8α,9α-epoxycoleon-U-quinone (3), and coleon U (4). The abietane diterpenoid 5 was also tentatively identified using HPLC-MS/MS. Moreover, the extract profile and quantification of each isolated compound were determined by HPLC-DAD. Compound 4 was the major compound in the extract. Compounds 2-4 were found to be selective toward cancer cell lines and were able to inhibit P-glycoprotein (P-gp) activity in NCI-H460/R cells at longer exposure of 72 h and consequently revert doxorubicin (DOX) resistance in subsequent combined treatment. None of the compounds influenced the P-gp expression in NCI-H460/R cells, while the extract significantly increased it.

Diketopyrrolo[3,4-c]pyrrole derivative as a promising ligand for the stabilization of G-quadruplex DNA structures.

Telomerase, oncogenes and tumor suppressors are closely associated with tumour occurrence, therefore these structures are being recognized as targets for the development of new anticancer drugs. The efficacy of several molecules in telomerase inhibition and regulation of genes expression, by adduct formation with G-quadruplexes (G4), has been studied by biophysical and biochemical methods with promising results. We report here the synthesis and structural characterization of a small positively charged diketopyrrolo[3,4-c]pyrrole derivative, identified as DPP(PyMe)2, that showed very promising results as G4 stabilizing ligand. The data obtained from UV-Vis and fluorescence experiments suggest that DPP(PyMe)2 presents high affinity to G4 structures. Docking studies and molecular dynamics simulations unraveled the binding modes of the ligand with four G4 structures. The obtained results also allowed us to conclude that the DPP(PyMe)2 ligand binds into the top G-tetrad or in a mixed binding mode depending on the GQ structure. A remarkable selectivity of DPP(PyMe)2 for c-MYC and KRAS 32R in the presence of ds26 was observed by circular dichroism (CD) and fluorescence resonance energy transfer (FRET) melting experiments. CD titrations revealed a stabilization higher than 30 °C in the case of c-MYC G4 structure and, for the same sequence, DPP(PyMe)2 showed the ability to block the activity of Taq polymerase in a dose-dependent manner. The subcellular localization obtained with confocal microscopy corroborates the results obtained by the other techniques and the obtained data suggest that DPP(PyMe)2 is an attractive ligand for the development of G4 labelling probes.

P2Y1 agonist HIC in combination with androgen receptor inhibitor abiraterone acetate impairs cell growth of prostate cancer.

P2Y receptors belong to the large superfamily of G-protein-coupled receptors and play a crucial role in cell death and survival. P2Y1 receptor has been identified as a marker for prostate cancer (PCa). A previously unveiled selective P2Y1 receptor agonist, the indoline-derived HIC (1-(1-((2-hydroxy-5-nitrophenyl)(4-hydroxyphenyl)methyl)indoline-4-carbonitrile), induces a series of molecular and biological responses in PCa cells PC3 and DU145, but minimal toxicity to normal cells. Here, we evaluated the combinatorial effect of HIC with abiraterone acetate (AA) targeted on androgen receptor (AR) on the inhibition of PCa cells. Here, the presence of HIC and AA significantly inhibited cell proliferation of PC3 and DU145 cells with time-dependent manner as a synerfistic combination. Moreover, it was also shown that the anticancer and antimetastasis effects of the combinratorial drugs were noticed through a decrease in colony-forming ability, cell migration, and cell invasion. In addition, the HIC + AA induced apoptotic population of PCa cells as well as cell cycle arrest in G1 progression phase. In summary, these studies show that the combination of P2Y1 receptor agonist, HIC and AR inhibitor, AA, effectively improved the antitumor activity of each drug. Thus, the combinatorial model of HIC and AA should be a novel and promising therapeutic strategy for treating prostate cancer.

GPR17 signaling activation by CHBC agonist induced cell death via modulation of MAPK pathway in glioblastoma.

AIM: Glioblastoma multiforme (GBM) is the most common and aggressive primary adult brain tumor. GBM is characterized by a heterogeneous population of cells that are resistant to chemotherapy. Recently, we have synthesized CHBC, a novel indole derivative targeted to GBM biomarker G-protein-coupled receptor 17 and inhibitor of GBM cells. In this study, CHBC was further investigated to characterize the efficiency of this agonist at the molecular level and its underlying mechanism in GBM cell death induction. MATERIALS AND METHODS: The effect of CHBC and TMZ was determined using time dependent inhibitor assay in glioblastoma cells, LN229 and SNB19. Drug induced cell cycle arrest was measured using PI staining followed by image analysis. The induction of apoptosis and mechanism of action of CHBC was studied using apoptosis, caspase 3/7 and mitochondrial membrane permeability assays. Modulation of the key genes involved in MAPK signaling pathway was also measured using immunoblotting array. KEY FINDINGS: The inhibitory kinetic study has revealed that CHBC inhibited SNB19 and LN229 cell growth in a time-dependent manner. Furthermore, CHBC with the IC50 of 85 µM, mediated cell death through an apoptosis mechanism in both studied cell lines. The study also has revealed that CHBC targets GPR17 leading to the induction of apoptosis via the activation of Caspase 3/7 and dysfunction of mitochondrial membrane potential. In addition, CHBC treatment led to marked G2/M cell cycle arrest. The protein array has confirmed the anticancer effect of CHBC by the disruption of the mitogen-activated protein kinase pathway (MAPK). SIGNIFICANCE: Taken together, these results demonstrated that CHBC induced G2/M cell cycle arrest and apoptosis by disrupting MAPK signaling in human glioblastoma cells. This study concludes that CHBC represent a class of compounds for treating glioblastoma.

Functional characterization of HIC, a P2Y1 agonist, as a p53 stabilizer for prostate cancer cell death induction.

Background: (1-(2-hydroxy-5-nitrophenyl)(4-hydroxyphenyl)methyl)indoline-4-carbonitrile (HIC), an agonist of the P2Y1 receptor (P2Y1R), induces cell death in prostate cancer cells. However, the molecular mechanism behind the inhibition of HIC in prostate cancer remains elusive. Methods & results: Here, to outline the inhibitory role of HIC on prostate cancer cells, PC-3 and DU145 cell lines were treated with the respective IC50 concentrations, which reduced cell proliferation, adherence properties and spheroid formation. HIC was able to arrest the cell cycle at G1/S phase and also induced apoptosis and DNA damage, validated by gene expression profiling. HIC inhibited the prostate cancer cells' migration and invasion, revealing its antimetastatic ability. P2Y1R-targeted HIC affects p53, MAPK and NF-κB protein expression, thereby improving the p53 stabilization essential for G1/S arrest and cell death. Conclusion: These findings provide an insight on the potential use of HIC, which remains the mainstay treatment for prostate cancer.

Alkylaminophenol and GPR17 Agonist for Glioblastoma Therapy: A Combinational Approach for Enhanced Cell Death Activity.

Drug resistance and tumor heterogeneity limits the therapeutic efficacy in treating glioblastoma, an aggressive infiltrative type of brain tumor. GBM cells develops resistance against chemotherapeutic agent, temozolomide (TMZ), which leads to the failure in treatment strategies. This enduring challenge of GBM drug resistance could be rational by combinatorial targeted therapy. Here, we evaluated the combinatorial effect of phenolic compound (2-(3,4-dihydroquinolin-1(2H)-yl)(p-tolyl)methyl)phenol (THTMP), GPR17 agonist 2-({5-[3-(Morpholine-4-sulfonyl)phenyl]-4-[4-(trifluoromethoxy)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)-N-[4-(propan-2-yl)phenyl]acetamide (T0510.3657 or T0) with the frontline drug, TMZ, on the inhibition of GBM cells. Mesenchymal cell lines derived from patients' tumors, MMK1 and JK2 were treated with the combination of THTMP + T0, THTMP + TMZ and T0 + TMZ. Cellular migration, invasion and clonogenicity assays were performed to check the migratory behavior and the ability to form colony of GBM cells. Mitochondrial membrane permeability (MMP) assay and intracellular calcium, [Ca2+]i, assay was done to comprehend the mechanism of apoptosis. Role of apoptosis-related signaling molecules was analyzed in the induction of programmed cell death. In vivo validation in the xenograft models further validates the preclinical efficacy of the combinatorial drug. GBM cells exert better synergistic effect when exposed to the cytotoxic concentration of THTMP + T0, than other combinations. It also inhibited tumor cell proliferation, migration, invasion, colony-forming ability and cell cycle progression in S phase, better than the other combinations. Moreover, the combination of THTMP + T0 profoundly increased the [Ca2+]i, reactive oxygen species in a time-dependent manner, thus affecting MMP and leading to apoptosis. The activation of intrinsic apoptotic pathway was regulated by the expression of Bcl-2, cleaved caspases-3, cytochrome c, HSP27, cIAP-1, cIAP-2, p53, and XIAP. The combinatorial drug showed promising anti-tumor efficacy in GBM xenograft model by reducing the tumor volume, suggesting it as an alternative drug to TMZ. Our findings indicate the coordinated administration of THTMP + T0 as an efficient therapy for inhibiting GBM cell proliferation.

Synthesis and Preclinical Validation of Novel Indole Derivatives as a GPR17 Agonist for Glioblastoma Treatment.

The discovery of a potential ligand-targeting G protein-coupled receptor 17 (GPR17) is important for developing chemotherapeutic agents against glioblastoma multiforme (GBM). We used the integration of ligand- and structure-based cheminformatics and experimental approaches for identifying the potential GPR17 ligand for GBM treatment. Here, we identified a novel indoline-derived phenolic Mannich base as an activator of GPR17 using molecular docking of over 6000 indoline derivatives. One of the top 10 hit molecules, CHBC, with a glide score of -8.390 was synthesized through a multicomponent Petasis borono-Mannich reaction. The CHBC-GPR17 interaction leads to a rapid decrease of cAMP and Ca2+. CHBC exhibits the cytotoxicity effect on GBM cells in a dose-dependent manner with an IC50 of 85 µM, whereas the known agonist MDL29,951 showed a negligible effect. Our findings suggest that the phenolic Mannich base could be a better GPR17 agonist than MDL29,951, and further uncovering their pharmacological properties could potentiate an inventive GBM treatment.

O,O-Silyl Group Migrations in Quinic Acid Derivatives: An Opportunity for Divergent Synthesis.

The O,O-silyl group migrations on a quinic acid-derived cyclitol have been studied, and the ease of migration was observed to be dependent on the silicon substituents and reaction conditions. Conditions were found to improve the formation of a main isomer during the O,O-silyl group migrations that could be integrated into the formal synthesis of vitamin D receptor modulator VS-105 and in the first total synthesis of a metabolite from the African ant Crematogaster nigriceps.

Modulation of Human Phenylalanine Hydroxylase by 3-Hydroxyquinolin-2(1H)-One Derivatives.

Phenylketonuria (PKU) is a genetic disease caused by deficient activity of human phenylalanine hydroxylase (hPAH) that, when untreated, can lead to severe psychomotor impairment. Protein misfolding is recognized as the main underlying pathogenic mechanism of PKU. Therefore, the use of stabilizers of protein structure and/or activity is an attractive therapeutic strategy for this condition. Here, we report that 3-hydroxyquinolin-2(1H)-one derivatives can act as protectors of hPAH enzyme activity. Electron paramagnetic resonance spectroscopy demonstrated that the 3-hydroxyquinolin-2(1H)-one compounds affect the coordination of the non-heme ferric center at the enzyme active-site. Moreover, surface plasmon resonance studies showed that these stabilizing compounds can be outcompeted by the natural substrate l-phenylalanine. Two of the designed compounds functionally stabilized hPAH by maintaining protein activity. This effect was observed on the recombinant purified protein and in a cellular model. Besides interacting with the catalytic iron, one of the compounds also binds to the N-terminal regulatory domain, although to a different location from the allosteric l-Phe binding site, as supported by the solution structures obtained by small-angle X-ray scattering.

Increased antibacterial properties of indoline-derived phenolic Mannich bases.

The search for antibacterial agents for the combat of nosocomial infections is a timely problem, as antibiotic-resistant bacteria continue to thrive. The effect of indoline substituents on the antibacterial properties of aminoalkylphenols was studied, leading to the development of a library of compounds with minimum inhibitory concentrations (MICs) as low as 1.18 µM. Two novel aminoalkylphenols were identified as particularly promising, after MIC and minimum bactericidal concentrations (MBC) determination against a panel of reference strain Gram-positive bacteria, and further confirmed against 40 clinical isolates (Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium, and Listeria monocytogenes). The same two aminoalkylphenols displayed low toxicity against two in vivo models (Artemia salina brine shrimp and Saccharomyces cerevisiae). The in vitro cytotoxicity evaluation (on human keratinocytes and human embryonic lung fibroblast cell lines) of the same compounds was also carried out. They demonstrated a particularly toxic effect on the fibroblast cell lines, with IC50 in the 1.7-5.1 µM range, thus narrowing their clinical use. The desired increase in the antibacterial properties of the aminoalkylphenols, particularly indoline-derived phenolic Mannich bases, was reached by introducing an additional nitro group in the indolinyl substituent or by the replacement of a methyl by a bioisosteric trifluoromethyl substituent in the benzyl group introduced through use of boronic acids in the Petasis borono-Mannich reaction. Notably, the introduction of an additional nitro moiety did not confer added toxicity to the aminoalkylphenols.

Erratum: Viswanathan, A., et al. Battling Glioblastoma: A Novel Tyrosine Kinase Inhibitor with Multi-Dimensional Anti-Tumor Effect (Running Title: Cancer Cells Death Signalling Activation). Cells 2019, 8, 1624.

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Royleanone Derivatives From Plectranthus spp. as a Novel Class of P-Glycoprotein Inhibitors.

Cancer is among the leading causes of death worldwide. One of the most challenging obstacles in cancer treatment is multidrug resistance (MDR). Overexpression of P-glycoprotein (P-gp) is associated with MDR. The growing incidence of cancer and the development of MDR drive the search for novel and more effective anticancer drugs to overcome the MDR problem. Royleanones are natural bioactive compounds frequently found in Plectranthus spp. The cytotoxic diterpene 6,7-dehydroroyleanone (1) is the main component of the P. madagascariensis (Pers.) Benth. essential oil, while 7α-acetoxy-6ß-hydroxyroyleanone (2) can be isolated from acetonic extracts of P. grandidentatus Gürke. The reactivity of the natural royleanones 1 and 2 was explored to obtain a small library of new P-gp inhibitors. Four new derivatives (6,7-dehydro-12-O-tert-butyl-carbonate-royleanone (20), 6,7-dehydro-12-O-methylroyleanone (21), 6,7-dehydro-12-O-benzoylroyleanone (22), and 7α-acetoxy-6ß-hydroxy-12-O-benzoylroyleanone (23) were obtained as pure with overall modest to excellent yields (21-97%). P-gp inhibition potential of the derivatives 20-23 was evaluated in human non-small cell lung carcinoma NCI-H460 and its MDR counterpart NCI-H460/R with the P-gp overexpression, through MTT assay. Previously prepared diterpene 7α-acetoxy-6ß-benzoyloxy-12-O-(4-chloro)benzoylroyleanone (4), has also been tested. The P-gp inhibiting effects of compounds 1-4 were also assessed through a Rhodamine 123 accumulation assay. Derivatives 4 and 23 have significant P-gp inhibitory potential. Regarding stability and P-gp inhibition potential, results suggest that the formation of benzoyl esters is a more convenient approach for future derivatives with enhanced effect on the cell viability decrease. Compound 4 presented higher anti-P-gp potential than the natural diterpenes 1, 2, and 3, with comparable inhibitory potential to Dexverapamil. Moreover, derivative 4 showed the ability to sensitize the resistant NCI-H460/R cells to doxorubicin.