TY  - CONF
AU  - Bangay, Gabrielle
AU  - Isca, Vera
AU  - Domínguez-Martín, Eva María
AU  - Santos, Daniel J.V.A.
AU  - Díaz-Lanza, Ana María
AU  - Saraiva, Lucília
AU  - Afonso, Carlos A.M.
AU  - Jovanović, Mirna
AU  - Pešić, Milica
AU  - Rijo, Patricia
PY  - 2023
UR  - https://www.thieme-connect.com/products/ejournals/html/10.1055/s-0043-1774270
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6435
AB  - Multidrug resistant (MDR) cancer cases continue to increase, such that the search for novel and more effective anti-cancer therapeutics is of high priority. In some MDR cancers, the overexpression of membrane transport proteins, like P-glycoprotein (P-gp), continues to be a major impediment to successful therapy. Plectranthus genus (Lamiaceae), known for their medicinal and therapeutic properties, is a well-known source of bioactive diterpenoids, such as 7α-acetoxy-6β-hydroxyroyleanone (Roy) and 6,7- dehydroroyleanone (DeRoy). Based on in silico molecular docking studies, a small library of semi-synthetic derivates was prepared. The antitumoural activity of the compounds was assessed in resistant human cancer cell lines NCI-H460/R and DLD1-TxR. Cell viability was assessed using MTT assay and cell death induction by Annexin V/PI. Overall, it was demonstrated that three of the abietane diterpenoid analogues induced P-gp inhibition in MDR cancer cell lines, presenting novel selective compounds for the possible treatment of lung and colon cancer. Moreover, Roy and DeRoy nano-formulations were successfully prepared. DeRoy hybrid nanoparticles significantly increased the efficacy of DeRoy in NCI-H460 and NCI- H460/R. Roy, conjugated with oleic acid afforded self-assembly nanoparticles, to improve aqueous solubility and bioavailability of Roy. This new nano formulation did not decrease cell viability of Vero-E6 cells when compared to Roy with potential as a pro-drug delivery system. Currently, top hit derivatives are being prepared into nano-formulations for prospective pharmaceutical use as P-gp modulators.
PB  - Georg Thieme Verlag KG
C3  - 71st International Congress and Annual Meeting of the Society for Medicinal Plant and Natural Product Research (GA); 2023 Jul 2-5; Dublin, Ireland
T1  - New formulations with royleanone derivatives from Plectranthus spp. to inhibit P-glycoprotein activity
DO  - 10.1055/s-0043-1774270
SP  - 1424
ER  - 

@conference{
author = "Bangay, Gabrielle and Isca, Vera and Domínguez-Martín, Eva María and Santos, Daniel J.V.A. and Díaz-Lanza, Ana María and Saraiva, Lucília and Afonso, Carlos A.M. and Jovanović, Mirna and Pešić, Milica and Rijo, Patricia",
year = "2023",
abstract = "Multidrug resistant (MDR) cancer cases continue to increase, such that the search for novel and more effective anti-cancer therapeutics is of high priority. In some MDR cancers, the overexpression of membrane transport proteins, like P-glycoprotein (P-gp), continues to be a major impediment to successful therapy. Plectranthus genus (Lamiaceae), known for their medicinal and therapeutic properties, is a well-known source of bioactive diterpenoids, such as 7α-acetoxy-6β-hydroxyroyleanone (Roy) and 6,7- dehydroroyleanone (DeRoy). Based on in silico molecular docking studies, a small library of semi-synthetic derivates was prepared. The antitumoural activity of the compounds was assessed in resistant human cancer cell lines NCI-H460/R and DLD1-TxR. Cell viability was assessed using MTT assay and cell death induction by Annexin V/PI. Overall, it was demonstrated that three of the abietane diterpenoid analogues induced P-gp inhibition in MDR cancer cell lines, presenting novel selective compounds for the possible treatment of lung and colon cancer. Moreover, Roy and DeRoy nano-formulations were successfully prepared. DeRoy hybrid nanoparticles significantly increased the efficacy of DeRoy in NCI-H460 and NCI- H460/R. Roy, conjugated with oleic acid afforded self-assembly nanoparticles, to improve aqueous solubility and bioavailability of Roy. This new nano formulation did not decrease cell viability of Vero-E6 cells when compared to Roy with potential as a pro-drug delivery system. Currently, top hit derivatives are being prepared into nano-formulations for prospective pharmaceutical use as P-gp modulators.",
publisher = "Georg Thieme Verlag KG",
journal = "71st International Congress and Annual Meeting of the Society for Medicinal Plant and Natural Product Research (GA); 2023 Jul 2-5; Dublin, Ireland",
title = "New formulations with royleanone derivatives from Plectranthus spp. to inhibit P-glycoprotein activity",
doi = "10.1055/s-0043-1774270",
pages = "1424"
}

Bangay, G., Isca, V., Domínguez-Martín, E. M., Santos, D. J.V.A., Díaz-Lanza, A. M., Saraiva, L., Afonso, C. A.M., Jovanović, M., Pešić, M.,& Rijo, P.. (2023). New formulations with royleanone derivatives from Plectranthus spp. to inhibit P-glycoprotein activity. in 71st International Congress and Annual Meeting of the Society for Medicinal Plant and Natural Product Research (GA); 2023 Jul 2-5; Dublin, Ireland
Georg Thieme Verlag KG., 1424.
https://doi.org/10.1055/s-0043-1774270

Bangay G, Isca V, Domínguez-Martín EM, Santos DJ, Díaz-Lanza AM, Saraiva L, Afonso CA, Jovanović M, Pešić M, Rijo P. New formulations with royleanone derivatives from Plectranthus spp. to inhibit P-glycoprotein activity. in 71st International Congress and Annual Meeting of the Society for Medicinal Plant and Natural Product Research (GA); 2023 Jul 2-5; Dublin, Ireland. 2023;:1424.
doi:10.1055/s-0043-1774270 .

Bangay, Gabrielle, Isca, Vera, Domínguez-Martín, Eva María, Santos, Daniel J.V.A., Díaz-Lanza, Ana María, Saraiva, Lucília, Afonso, Carlos A.M., Jovanović, Mirna, Pešić, Milica, Rijo, Patricia, "New formulations with royleanone derivatives from Plectranthus spp. to inhibit P-glycoprotein activity" in 71st International Congress and Annual Meeting of the Society for Medicinal Plant and Natural Product Research (GA); 2023 Jul 2-5; Dublin, Ireland (2023):1424,
https://doi.org/10.1055/s-0043-1774270 . .

TY  - CONF
AU  - Bangay, Gabrielle
AU  - Isca, Vera M. S.
AU  - Dos Santos, Daniel J. V. A.
AU  - Ferreira, Ricardo J.
AU  - Princiotto, Salvatore
AU  - Jovanović, Mirna
AU  - Pešić, Milica
AU  - Rijo, Patricia
PY  - 2022
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5471
AB  - The number of multidrug resistant (MDR) cancer cases across the globe is continuing to rise,
such that the search for novel anti-cancer therapeutics is paramount. For instance, the overexpression
of membrane transport proteins, such as P-glycoprotein (P-gp), or the selective modulation of protein
kinases C (PKC) isoforms continues to be a major impediment to effective therapy. Known for
their medicinal properties, species from Plectranthus have been reported to have cytotoxicity against
various cancer cell lines due to diterpenes, such as 7 -acetoxy-6 -hydroxyroyleanone (Roy) and 6,7-
dehydroroyleanone (DeRoy). Based on molecular docking simulations, 10 semi-synthetic derivatives
of Roy that displayed strong P-gp interactions in silico were prepared. The antitumoral activity was
evaluated in resistant human cancer cell lines NCI-H460/R and DLD1-TxR, showing three derivatives
having the most prominent selectivity towards cancer cells, compared to normal lung fibroblasts
MRC5. Moreover, they showed a reduction in P-gp activity in Rho123 accumulation and indicated
P-gp inhibition in the DOX accumulation assay using the same resistant cell lines. Overall, it was
demonstrated that three abietane diterpenoids induced P-gp inhibition in MDR cancer cell lines. As
regards the PKC activity, further analogues were tested as PKC ( ,  I,  , " and  ) modulators; one
benzoylated derivative showed the ability to selectively activate PKC- , while the natural compound
DeRoy displayed improved PKC activity, compared with the positive control, in all tested isoforms.
Further investigations are ongoing to prepare analogues of other biologically active diterpenoids to
obtain potential hits as P-gp and PKC modulators.
PB  - Basel: MDPI
C3  - The 8th International Electronic Conference on Medicinal Chemistry; 2022 Nov 1-30; Virtual Event
T1  - Royleanone Analogues from Plectranthus spp. Demonstrate P-gp Inhibition and PKC Modulation
DO  - 10.3390/ECMC2022-13459
SP  - 144
ER  - 

@conference{
author = "Bangay, Gabrielle and Isca, Vera M. S. and Dos Santos, Daniel J. V. A. and Ferreira, Ricardo J. and Princiotto, Salvatore and Jovanović, Mirna and Pešić, Milica and Rijo, Patricia",
year = "2022",
abstract = "The number of multidrug resistant (MDR) cancer cases across the globe is continuing to rise,
such that the search for novel anti-cancer therapeutics is paramount. For instance, the overexpression
of membrane transport proteins, such as P-glycoprotein (P-gp), or the selective modulation of protein
kinases C (PKC) isoforms continues to be a major impediment to effective therapy. Known for
their medicinal properties, species from Plectranthus have been reported to have cytotoxicity against
various cancer cell lines due to diterpenes, such as 7 -acetoxy-6 -hydroxyroyleanone (Roy) and 6,7-
dehydroroyleanone (DeRoy). Based on molecular docking simulations, 10 semi-synthetic derivatives
of Roy that displayed strong P-gp interactions in silico were prepared. The antitumoral activity was
evaluated in resistant human cancer cell lines NCI-H460/R and DLD1-TxR, showing three derivatives
having the most prominent selectivity towards cancer cells, compared to normal lung fibroblasts
MRC5. Moreover, they showed a reduction in P-gp activity in Rho123 accumulation and indicated
P-gp inhibition in the DOX accumulation assay using the same resistant cell lines. Overall, it was
demonstrated that three abietane diterpenoids induced P-gp inhibition in MDR cancer cell lines. As
regards the PKC activity, further analogues were tested as PKC ( ,  I,  , " and  ) modulators; one
benzoylated derivative showed the ability to selectively activate PKC- , while the natural compound
DeRoy displayed improved PKC activity, compared with the positive control, in all tested isoforms.
Further investigations are ongoing to prepare analogues of other biologically active diterpenoids to
obtain potential hits as P-gp and PKC modulators.",
publisher = "Basel: MDPI",
journal = "The 8th International Electronic Conference on Medicinal Chemistry; 2022 Nov 1-30; Virtual Event",
title = "Royleanone Analogues from Plectranthus spp. Demonstrate P-gp Inhibition and PKC Modulation",
doi = "10.3390/ECMC2022-13459",
pages = "144"
}

Bangay, G., Isca, V. M. S., Dos Santos, D. J. V. A., Ferreira, R. J., Princiotto, S., Jovanović, M., Pešić, M.,& Rijo, P.. (2022). Royleanone Analogues from Plectranthus spp. Demonstrate P-gp Inhibition and PKC Modulation. in The 8th International Electronic Conference on Medicinal Chemistry; 2022 Nov 1-30; Virtual Event
Basel: MDPI., 144.
https://doi.org/10.3390/ECMC2022-13459

Bangay G, Isca VMS, Dos Santos DJVA, Ferreira RJ, Princiotto S, Jovanović M, Pešić M, Rijo P. Royleanone Analogues from Plectranthus spp. Demonstrate P-gp Inhibition and PKC Modulation. in The 8th International Electronic Conference on Medicinal Chemistry; 2022 Nov 1-30; Virtual Event. 2022;:144.
doi:10.3390/ECMC2022-13459 .

Bangay, Gabrielle, Isca, Vera M. S., Dos Santos, Daniel J. V. A., Ferreira, Ricardo J., Princiotto, Salvatore, Jovanović, Mirna, Pešić, Milica, Rijo, Patricia, "Royleanone Analogues from Plectranthus spp. Demonstrate P-gp Inhibition and PKC Modulation" in The 8th International Electronic Conference on Medicinal Chemistry; 2022 Nov 1-30; Virtual Event (2022):144,
https://doi.org/10.3390/ECMC2022-13459 . .

TY  - JOUR
AU  - Isca, Vera M. S.
AU  - Ferreira, Ricardo J.
AU  - Garcia, Catarina
AU  - Monteiro, Carlos M.
AU  - Dinić, Jelena
AU  - Holmstedt, Suvi
AU  - André, Vânia
AU  - Pešić, Milica
AU  - Dos Santos, Daniel J. V. A.
AU  - Candeias, Nuno R.
AU  - Afonso, Carlos A. M.
AU  - Rijo, Patrícia
PY  - 2020
UR  - https://pubs.acs.org/doi/10.1021/acsmedchemlett.9b00642
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3820
AB  - The development of multidrug resistance (MDR) is a major cause of failure in cancer chemotherapy. Several abietane diterpenes with antitumoral activities have been isolated from Plectranthus spp. such as 6,7-dehydroroyleanone (DHR, 1) and 7α-acetoxy-6β-hydroxyroyleanone (AHR, 2). Several royleanone derivatives were prepared through hemisynthesis from natural compounds 1 and 2 to achieve a small library of products with enhanced anti-P-glycoprotein activity. Nonetheless, some derivatives tend to be unstable. Therefore, to reason such lack of stability, the electron density based local reactivity descriptors condensed Fukui functions and dual descriptor were calculated for several derivatives of DHR. Additionally, molecular docking and molecular dynamics studies were performed on several other derivatives to clarify the molecular mechanisms by which they may exert their inhibitory effect in P-gp activity. The analysis on local reactivity descriptors was important to understand possible degradation pathways and to guide further synthetic approaches toward new royleanone derivatives. A molecular docking study suggested that the presence of aromatic moieties increases the binding affinity of royleanone derivatives toward P-gp. It further suggests that one royleanone benzoylated derivative may act as a noncompetitive efflux modulator when bound to the M-site. The future generation of novel royleanone derivatives will involve (i) a selective modification of position C-12 with chemical moieties smaller than unsubstituted benzoyl rings and (ii) the modification of the substitution pattern of the benzoyloxy moiety at position C-6.
PB  - Washington : ACS Publications
T2  - ACS Medicinal Chemistry Letters
T1  - Molecular Docking Studies of Royleanone Diterpenoids from Plectranthus spp. as P-Glycoprotein Inhibitors
IS  - 5
VL  - 11
DO  - 10.1021/acsmedchemlett.9b00642
SP  - 839
EP  - 845
ER  - 

@article{
author = "Isca, Vera M. S. and Ferreira, Ricardo J. and Garcia, Catarina and Monteiro, Carlos M. and Dinić, Jelena and Holmstedt, Suvi and André, Vânia and Pešić, Milica and Dos Santos, Daniel J. V. A. and Candeias, Nuno R. and Afonso, Carlos A. M. and Rijo, Patrícia",
year = "2020",
abstract = "The development of multidrug resistance (MDR) is a major cause of failure in cancer chemotherapy. Several abietane diterpenes with antitumoral activities have been isolated from Plectranthus spp. such as 6,7-dehydroroyleanone (DHR, 1) and 7α-acetoxy-6β-hydroxyroyleanone (AHR, 2). Several royleanone derivatives were prepared through hemisynthesis from natural compounds 1 and 2 to achieve a small library of products with enhanced anti-P-glycoprotein activity. Nonetheless, some derivatives tend to be unstable. Therefore, to reason such lack of stability, the electron density based local reactivity descriptors condensed Fukui functions and dual descriptor were calculated for several derivatives of DHR. Additionally, molecular docking and molecular dynamics studies were performed on several other derivatives to clarify the molecular mechanisms by which they may exert their inhibitory effect in P-gp activity. The analysis on local reactivity descriptors was important to understand possible degradation pathways and to guide further synthetic approaches toward new royleanone derivatives. A molecular docking study suggested that the presence of aromatic moieties increases the binding affinity of royleanone derivatives toward P-gp. It further suggests that one royleanone benzoylated derivative may act as a noncompetitive efflux modulator when bound to the M-site. The future generation of novel royleanone derivatives will involve (i) a selective modification of position C-12 with chemical moieties smaller than unsubstituted benzoyl rings and (ii) the modification of the substitution pattern of the benzoyloxy moiety at position C-6.",
publisher = "Washington : ACS Publications",
journal = "ACS Medicinal Chemistry Letters",
title = "Molecular Docking Studies of Royleanone Diterpenoids from Plectranthus spp. as P-Glycoprotein Inhibitors",
number = "5",
volume = "11",
doi = "10.1021/acsmedchemlett.9b00642",
pages = "839-845"
}

Isca, V. M. S., Ferreira, R. J., Garcia, C., Monteiro, C. M., Dinić, J., Holmstedt, S., André, V., Pešić, M., Dos Santos, D. J. V. A., Candeias, N. R., Afonso, C. A. M.,& Rijo, P.. (2020). Molecular Docking Studies of Royleanone Diterpenoids from Plectranthus spp. as P-Glycoprotein Inhibitors. in ACS Medicinal Chemistry Letters
Washington : ACS Publications., 11(5), 839-845.
https://doi.org/10.1021/acsmedchemlett.9b00642

Isca VMS, Ferreira RJ, Garcia C, Monteiro CM, Dinić J, Holmstedt S, André V, Pešić M, Dos Santos DJVA, Candeias NR, Afonso CAM, Rijo P. Molecular Docking Studies of Royleanone Diterpenoids from Plectranthus spp. as P-Glycoprotein Inhibitors. in ACS Medicinal Chemistry Letters. 2020;11(5):839-845.
doi:10.1021/acsmedchemlett.9b00642 .

Isca, Vera M. S., Ferreira, Ricardo J., Garcia, Catarina, Monteiro, Carlos M., Dinić, Jelena, Holmstedt, Suvi, André, Vânia, Pešić, Milica, Dos Santos, Daniel J. V. A., Candeias, Nuno R., Afonso, Carlos A. M., Rijo, Patrícia, "Molecular Docking Studies of Royleanone Diterpenoids from Plectranthus spp. as P-Glycoprotein Inhibitors" in ACS Medicinal Chemistry Letters, 11, no. 5 (2020):839-845,
https://doi.org/10.1021/acsmedchemlett.9b00642 . .

TY  - JOUR
AU  - Isca, Vera M. S.
AU  - Ferreira, Ricardo J.
AU  - Garcia, Catarina
AU  - Monteiro, Carlos M.
AU  - Dinić, Jelena
AU  - Holmstedt, Suvi
AU  - André, Vânia
AU  - Pešić, Milica
AU  - Dos Santos, Daniel J. V. A.
AU  - Candeias, Nuno R.
AU  - Afonso, Carlos A. M.
AU  - Rijo, Patrícia
PY  - 2020
UR  - https://pubs.acs.org/doi/10.1021/acsmedchemlett.9b00642
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3817
AB  - The development of multidrug resistance (MDR) is a major cause of failure in cancer chemotherapy. Several abietane diterpenes with antitumoral activities have been isolated from Plectranthus spp. such as 6,7-dehydroroyleanone (DHR, 1) and 7α-acetoxy-6β-hydroxyroyleanone (AHR, 2). Several royleanone derivatives were prepared through hemisynthesis from natural compounds 1 and 2 to achieve a small library of products with enhanced anti-P-glycoprotein activity. Nonetheless, some derivatives tend to be unstable. Therefore, to reason such lack of stability, the electron density based local reactivity descriptors condensed Fukui functions and dual descriptor were calculated for several derivatives of DHR. Additionally, molecular docking and molecular dynamics studies were performed on several other derivatives to clarify the molecular mechanisms by which they may exert their inhibitory effect in P-gp activity. The analysis on local reactivity descriptors was important to understand possible degradation pathways and to guide further synthetic approaches toward new royleanone derivatives. A molecular docking study suggested that the presence of aromatic moieties increases the binding affinity of royleanone derivatives toward P-gp. It further suggests that one royleanone benzoylated derivative may act as a noncompetitive efflux modulator when bound to the M-site. The future generation of novel royleanone derivatives will involve (i) a selective modification of position C-12 with chemical moieties smaller than unsubstituted benzoyl rings and (ii) the modification of the substitution pattern of the benzoyloxy moiety at position C-6.
PB  - Washington : ACS Publications
T2  - ACS Medicinal Chemistry Letters
T1  - Molecular Docking Studies of Royleanone Diterpenoids from Plectranthus spp. as P-Glycoprotein Inhibitors
IS  - 5
VL  - 11
DO  - 10.1021/acsmedchemlett.9b00642
SP  - 839
EP  - 845
ER  - 

@article{
author = "Isca, Vera M. S. and Ferreira, Ricardo J. and Garcia, Catarina and Monteiro, Carlos M. and Dinić, Jelena and Holmstedt, Suvi and André, Vânia and Pešić, Milica and Dos Santos, Daniel J. V. A. and Candeias, Nuno R. and Afonso, Carlos A. M. and Rijo, Patrícia",
year = "2020",
abstract = "The development of multidrug resistance (MDR) is a major cause of failure in cancer chemotherapy. Several abietane diterpenes with antitumoral activities have been isolated from Plectranthus spp. such as 6,7-dehydroroyleanone (DHR, 1) and 7α-acetoxy-6β-hydroxyroyleanone (AHR, 2). Several royleanone derivatives were prepared through hemisynthesis from natural compounds 1 and 2 to achieve a small library of products with enhanced anti-P-glycoprotein activity. Nonetheless, some derivatives tend to be unstable. Therefore, to reason such lack of stability, the electron density based local reactivity descriptors condensed Fukui functions and dual descriptor were calculated for several derivatives of DHR. Additionally, molecular docking and molecular dynamics studies were performed on several other derivatives to clarify the molecular mechanisms by which they may exert their inhibitory effect in P-gp activity. The analysis on local reactivity descriptors was important to understand possible degradation pathways and to guide further synthetic approaches toward new royleanone derivatives. A molecular docking study suggested that the presence of aromatic moieties increases the binding affinity of royleanone derivatives toward P-gp. It further suggests that one royleanone benzoylated derivative may act as a noncompetitive efflux modulator when bound to the M-site. The future generation of novel royleanone derivatives will involve (i) a selective modification of position C-12 with chemical moieties smaller than unsubstituted benzoyl rings and (ii) the modification of the substitution pattern of the benzoyloxy moiety at position C-6.",
publisher = "Washington : ACS Publications",
journal = "ACS Medicinal Chemistry Letters",
title = "Molecular Docking Studies of Royleanone Diterpenoids from Plectranthus spp. as P-Glycoprotein Inhibitors",
number = "5",
volume = "11",
doi = "10.1021/acsmedchemlett.9b00642",
pages = "839-845"
}

Isca, V. M. S., Ferreira, R. J., Garcia, C., Monteiro, C. M., Dinić, J., Holmstedt, S., André, V., Pešić, M., Dos Santos, D. J. V. A., Candeias, N. R., Afonso, C. A. M.,& Rijo, P.. (2020). Molecular Docking Studies of Royleanone Diterpenoids from Plectranthus spp. as P-Glycoprotein Inhibitors. in ACS Medicinal Chemistry Letters
Washington : ACS Publications., 11(5), 839-845.
https://doi.org/10.1021/acsmedchemlett.9b00642

Isca VMS, Ferreira RJ, Garcia C, Monteiro CM, Dinić J, Holmstedt S, André V, Pešić M, Dos Santos DJVA, Candeias NR, Afonso CAM, Rijo P. Molecular Docking Studies of Royleanone Diterpenoids from Plectranthus spp. as P-Glycoprotein Inhibitors. in ACS Medicinal Chemistry Letters. 2020;11(5):839-845.
doi:10.1021/acsmedchemlett.9b00642 .

Isca, Vera M. S., Ferreira, Ricardo J., Garcia, Catarina, Monteiro, Carlos M., Dinić, Jelena, Holmstedt, Suvi, André, Vânia, Pešić, Milica, Dos Santos, Daniel J. V. A., Candeias, Nuno R., Afonso, Carlos A. M., Rijo, Patrícia, "Molecular Docking Studies of Royleanone Diterpenoids from Plectranthus spp. as P-Glycoprotein Inhibitors" in ACS Medicinal Chemistry Letters, 11, no. 5 (2020):839-845,
https://doi.org/10.1021/acsmedchemlett.9b00642 . .