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Influence of partially hydrogenated pyridines (derivatives of cyanothioacetamide) on blood indicators of rats with acute tetrachloromethane hepatitis
Published: 30 October 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5

Currently, a focused search for new and safe hepatoprotective agents is highly relevant. Studies of six partially hydrogenated pyridines, derivatives of cyanothioacetamide, on a model of acute tetracycline hepatitis indicated a high hepatoprotective and detoxifying activity for all compounds. They stabilized the level of biochemical blood parameters, keeping them at the normal level in terms of hepatotoxicity induced by the use of high dosages of CCl4 in vivo.

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Targeting neuroblastoma with a new inhibitor of the TAp73 interaction with MDM2 and mutant p53
Published: 30 October 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5

TAp73 is a key tumour suppressor protein, regulating the transcription of unique and shared p53 target genes with crucial roles in tumorigenesis and therapeutic response. As such, in tumours with impaired p53 signalling, like neuroblastoma (NBL), TAp73 activation represents an encouraging strategy, alternative to p53 activation, to suppress tumour growth and chemoresistance [1]. Actually, NBL represents one of the most common childhood solid cancers but despite the available treatments, the high-risk patients are still characterized by low survival rates, making the search of new therapeutic options an urgent need [2].

In this work, we report the synthesis and biological evaluation of a new TAp73-activating agent, the 1-carbaldehyde-3,4-dimethoxyxanthone (LEM2), as a potent antitumour agent either alone or in combination with conventional drugs [3]. LEM2 anticancer activity was evaluated in the wild-type p53 expressing human colon adenocarcinoma HCT116 cells (HCT116 p53+/+) and in the respective p53-null isogenic derivative cells (HCT116 p53-/-), by sulforhodamine B assay. Results showed that LEM2 had potent p53-independent tumour growth inhibitory effect, with similar IC50values in p53+/+(0.98 ± 0.12 μM) and p53−/−(0.68 ± 0.08 μM) HCT116 cells. The antiproliferative effect of LEM2 on the growth of human tumour cells expressing distinct mutant p53 forms was also investigated, with IC50values around 1–3 μM. LEM2 antitumor effect was associated with enhanced TAp73 transcriptional activity, cell cycle arrest, and apoptosis in p53-null and mutant p53-expressing tumour cells. Importantly, the LEM2 antiproliferative effect was not associated with genotoxicity. Mechanistically, LEM2 was able to disrupt the TAp73 interaction with MDM2 and mutant p53, both in yeast and in human tumour cells. Additionally, by cellular thermal shift assay (CETSA), it was verified that LEM2 induced thermal stabilization of TAp73α but not of MDM2 or mutant p53, suggesting the potential interaction of LEM2 with TAp73α. LEM2 also displayed potent antitumour activity against immortalized and patient-derived NBL cells [4,5], consistent with an activation of the TAp73 pathway. LEM2 alcohol and carboxylic acid derivativeswere also tested to support that the LEM2 biological activity was due to the molecule itself and not to its potential derivatives. Indeed, both the alcohol 1-(hydroxymethyl)-3,4-dimethoxy-9H-xanthen-9-one (LEMred) and the carboxylic acid 3,4-dimethoxy-9-oxo-9H-xanthene-1-carboxylic acid (LEMox) presented a much lower activity when compared to LEM2 and were unable to inhibit the TAp73-MDM2 interaction.

The antiproliferative effect of LEM2, alone and in combination with doxorubicin and cisplatin, was analysed by MTT assay and the synergistic effect was evaluated through determination of combination and dose reduction index values. The results showed a potent TAp73-dependent cytotoxic activity of LEM2, superior to that of nutlin-3a (a known TAp73 activator), associated with induction of cell cycle arrest and apoptosis and upregulation of TAp73 target genes, in NBL cells. Also, we observed a pronounced synergistic effect between doxorubicin/cisplatin and LEM2, which may result from enhancing TAp73 activation through alternative pathways.

In conclusion, besides its relevant contribution to the advance of TAp73 pharmacology, LEM2 may pave the way to improved therapeutic alternatives against NBL, both alone and in combination with conventional chemotherapeutics.

1 – Wolter J et al. Future Oncol., 2010; 6: 429-444; 2- Nakagawara A et al. Jpn. J. Clin. Oncol., 2018; 48:214-24; 3 – Gomes S et al. Cancer letters., 2019; 0304-3835; 4 - Veselska R et al.Cancer, 2006 6: 32; 5 - Veselska R et al. BMC Cancer, 2008; 8: 300

This work received financial support from PT national funds (FCT/MCTES, Fundação para a Ciência e Tecnologia and Ministério da Ciência, Tecnologia e Ensino Superior) through grant UID/QUI/50006/2019. This work received financial support from the European Union (FEDER funds through the Operational Competitiveness Program (COMPETE) POCI-01-0145-FEDER-006684/POCI-01-0145-FEDER-007440 and (3599-PPCDT) PTDC/DTP-FTO/1981/2014 – POCI-01-0145-FEDER-016581) and the FCT grants PTDC/QUIQOR/29664/2017, POCI-01-0145-FEDER-028736 (PTDC/SAU-PUB/28736/2017). We thank FCT and ESF (European Social Fund) through POCH (Programa Operacional Capital Humano) for: L. Raimundo PhD grant ref. SFRH/BD/117949/2016; J. Loureiro PhD grant ref SFRH/BD/128673/2017; H. Ramos PhD grant ref SFRH/BD/119144/2016. J. Calheiro thanks ICETA for her grant ref. ICETA2019-71. M. Monteiro thanks ICETA for her grant ref. ICETA2019-70 We thank (POCH), specifically the BiotechHealth Programme (Doctoral Programme on Cellular and Molecular Biotechnology Applied to Health Sciences; PD/00016/2012).

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Improving colon cancer therapy with a new promising small-molecule activator of the p53-pathway through disruption of p53-MDM2/MDMX interactions
Published: 30 October 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5

Impairment of the tumour suppressor p53 pathway is a major event in human cancers, making p53 activation one of the most attractive therapeutic strategies [1]. This work describes the synthesis and biological evaluation of the (R)-tryptophanol-derived bicyclic lactam SYNAP as a selective p53 activator with potent anticancer activity against colon cancer [2]. The anticancer activity and mechanism of action of SYNAP was studied in both 2D and 3D models of human colon adenocarcinoma HCT116 cells with wild-type p53 (HCT116 p53+/+) and the corresponding p53-null isogenic derivative cells (HCT116 p53-/-), alone and in combination with conventional chemotherapeutic agents. The anti-proliferative activity of SYNAP was analysed by sulforhodamine B assay and by clonogenic assays. The compound presented an anti-proliferative effect in human cancer cells dependent on p53 status. In HCT116 p53+/+cells, SYNAP p53-dependent growth inhibition was associated with cell cycle arrest and apoptosis, analysed by flow cytometry, and with anti-migratory activity. Western blot and RT-PCR analysis also showed an upregulation of several p53 transcriptional targets upon treatment with SYNAP. A yeast-based assay and a co-immunoprecipitation assay in human cancer cells were performed to study the disruption of the p53 interaction with its endogenous inhibitors murine double minute (MDM)2 and MDMX by SYNAP. The obtained results indicated that SYNAP potentially targeted p53 by disruption of the p53-MDM2/MDMX interactions. Moreover, SYNAP sensitized colon cancer cells to the cytotoxic effect of known chemotherapeutic agents. In addition, SYNAP did not induce acquired or cross-resistance and re-sensitized doxorubicin-resistant colon cancer cells to the therapy. Importantly, SYNAP was non-genotoxic and presented low cytotoxic effects against normal cells.

Collectively, this work reports a new selective dual inhibitor of p53-MDM2/MDMX interactions with promising application in colon cancer therapy, both as monotherapy and in combination with known chemotherapeutic agents. Additionally, SYNAP represents a starting point for improved p53 activators, particularly inhibitors of the p53 interaction with MDM2 and MDMX.

1 – Graves B et al. PNAS 2012; 109: 11788-11793; 2 – Raimundo L et al. Br. J. Pharmacol. 2018; 175: 3947-3962.

This work received financial support from PT national funds (FCT/MCTES, Fundação para a Ciência e Tecnologia and Ministério da Ciência, Tecnologia e Ensino Superior) through grant UID/QUI/50006/2019. This work received financial support from the European Union (FEDER funds through the Operational Competitiveness Program (COMPETE) POCI-01-0145-FEDER-006684/POCI-01-0145-FEDER-007440 and (3599-PPCDT) PTDC/DTP-FTO/1981/2014 – POCI-01-0145-FEDER-016581) and the FCT grants PTDC/QUIQOR/29664/2017, UID/DTP/04138/2013 (iMed.ULisboa), IF/00732/2013 (M.M.M. Santos). We thank FCT and ESF (European Social Fund) through POCH (Programa Operacional Capital Humano) for: L. Raimundo PhD grant ref. SFRH/BD/117949/2016; J. Loureiro PhD grant ref SFRH/BD/128673/2017; M. Espadinha PhD grant ref SFRH/BD/117931/2016. J. Calheiro thanks ICETA for her grant ref. ICETA2019-71. We thank (POCH), specifically the BiotechHealth Programme (Doctoral Programme on Cellular and Molecular Biotechnology Applied to Health Sciences; PD/00016/2012).

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  • 36 Reads
Acetoxystachybotrydial acetate, a natural compound isolated from Stachybotrys chartarum is a potent inhibitor of human protein kinase CK2
Published: 30 October 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5

Human protein kinase CK2 is an emerging target for drug design. Overexpression of CK2 is closely related to many types of human cancer. It was shown that elevated levels of CK2 protect tumor cells from apoptosis [1]. Inhibition of CK2 activity can lead tumor cells into apoptosis, whereas viability of healthy cells is not affected [2]. Up till now, one ATP competitive inhibitor of CK2, silmitasertib, is in clinical trials phase II [3]. Here we report on the screening of natural compounds isolated from Stachybotrys chartarum [4]. Twelve phenylspirodrimanes and three triphenylphenols were investigated on inhibitory activity towards CK2 using a CE-based assay [5]. Triphenyl phenolestachybotrychromene C, phenylspirodrimanes stachybotrydial acetate and acetoxystachybotrydial acetate with IC50 ­values of 0.3 µM, 0.7 µM and 1.9 µM, respectively, were identified as potent CK2 inhibitors. Effect of these compounds on the proliferation of breast cancer cells MCF-7 was determined using an EdU assay. For comparison, viability of breast cancer cells MCF-7 as well as lung cancer cells A427 and epidermal cancer cells A 431 was tested using the MTT assay. In particular, acetoxystachybotrydial acetate turned out to be the most active compound. After treatment of MCF-7 cells with 1 µM for 24 h cell proliferation was blocked almost completely (99%), whereas cell viability was decreased only by 63%. Here we describe phenlyspirodrimanes as new class of CK2 inhibitors, among them acetoxystachybotrydial acetate which has proved to be the most potent representative of this series.

References

  1. Faust M, Montenarh M. Cell Tissue Res 2000; 301:329-340.
  2. Ruzzene M, Pinna LA. Biochim Biophys Acta 2010; 1804:499-504.
  3. Gowda C et al. Curr Pharm Des 2017; 23:95-107.
  4. Gratz A et al. Electrophoresis 2010; 31:634–640.
  5. Jagels A et al., Mycotoxin Res. 2018; 34: 179-185.
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  • 69 Reads
Production of high valued medicinal compounds using plant cell tissue and organ culture
Published: 30 October 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5

Today market demand for natural products is high and the conventional practices to get the herbs from wild nature or cultivated fields are not sufficiently efficient to meet the demand. Alternative approaches such as plant tissue organ and cell cultures (PTOC) are believed to be promising and inexpensive methods. The PTOC approach offers the opportunity to sustain the standardized natural products of uniform quality and ensures to be free of agrochemicals, toxins or other environmental pollutants. Number of studies using in vitro tissue culture approaches have extensively been studied and adopted for uniform and continuous supply of natural products. There are companies taking advantages of this technology, which offers the opportunity to produce medicinal compounds continuously and in a imited space rather than cultivating on hectares of land. Despite these advantages the PTOC system needs optimization and there are factors regulating plant cell machinery to process primary metabolites for the secondary metabolites (medicinal compounds) production. These factors are plant growth regulators (PGRs), substrate type and concentration, light condition, elicitors and precursors feeding. Additionally, the bioreactor design also plays important role to ensure the large scale production using plant cells and organs cultures.

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Antimicrobial activity of extract of strawberry of different quality against antibiotic-resistant Staphylococcus aureus
Published: 30 October 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session Posters

Inflammation of the mammary gland in cattle is known as mastitis, and Staphylococcus aureus is the most common causative agent, it has the ability to develop resistance to most of the antibiotics used to combat this disease, which, added to its indiscriminate use, It results in a very difficult infection to control that causes significant economic losses. That is why research for the development of new drugs that fight this condition is of great relevance. The secondary metabolites present in fruits and plants are an important source of naturally occurring antimicrobials. Strawberry is a berry with an important amount of metabolites, mainly anthocyanins, phenolic compounds and flavonoids; The beneficial potential that these compounds have on human, animal and plant health has been demonstrated. However, it is a non-climacteric fruit, with a short shelf life, so much of what is harvested that does not meet the characteristics of export quality (Extra quality), goes to the national fresh market (first quality), to industrialization (first and / or second quality) or to waste. In this sense, the objective of this work was to evaluate the antimicrobial activity of strawberry fruits of these three qualities, as an alternative proposal to add value to the strawberry that does not reach export quality (first and second quality). The Minimum Inhibitory and Bactericidal Concentration (CMI and CMB) of strawberry anthocyanin extracts (extra, first and second), was determined against S. aureus causative of antibiotic multidrug bovine mastitis (AMC 9, AMC 23 and ATCC 27543). The results indicated that all strawberry extracts presented antimicrobial potential. However, there were differences between the different qualities evaluated. Both the MICs and the CMBs presented by the extract of strawberry anthocyanins of second quality were significantly lower (MIC of 6.3 to 12.5 μg / ml; CMB 25 μg / ml) than those presented by extracts of Extra quality (MIC 25 μg / ml; CMB 50 μg / ml) and first quality (MIC from 12.5 to 25 μg / ml; CMB from 50 to 100 μg / ml) for all strains. These results indicate that the multiresistant strains of S. aureus that cause bovine mastitis are susceptible to strawberry anthocyanin extracts, in addition to a quality-dependent effect of the fruit evaluated, being the extract of waste fruits the one that has greater antimicrobial potential against all the strains, which can be a viable alternative for the use of discarded strawberry fruits, as well as for use as a treatment against bovine mastitis.

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  • 19 Reads
In the search of new xanthine oxidase inhibitors: 3-Phenylcoumarins versus 2-phenylbenzofurans
Published: 30 October 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5

Xanthine oxidase (XO) is an enzyme that catalyzes the oxidation of hypoxanthine to xanthine, and this one to uric acid. This process reduces molecular oxygen to O2. Hydroxyl free radicals and hydrogen peroxide, both of which are byproducts of XO activity, can caused oxidative stress in human cells. Overproduction of uric acid in the body leads to hyperuricemia, which is also linked with gout. Uric production in the body can be lowered by XO inhibitors. Inhibition of XO has also been proposed as a mechanism for improving cardiovascular health. Therefore, the search for new efficient XO inhibitors is an interesting topic in drug discovery.

3-Phenylcoumarins and 2-phenylbenzofurans are privileged scaffolds in Medicinal Chemistry. Their structural similarity makes them interesting molecules for a comparative work. Methoxy and nitro substituents were introduced in both scaffolds. A preliminary study gives some insights into the synthesis and biological activity of these molecules against this important target. In general, the studied 3-phenylcoumarins proved to be better XO inhibitors than the similarly substituted 2-phenylbenzofurans. Further studies are still needed to optimize the structure and increase the potential of these molecules as XO inhibitors for the treatment of gout.

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New chalcone derivatives with suitable drug-like lipophilicity targeting mitosis
Published: 30 October 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5

Chalcones are natural flavonoid precursors that have been reported for their wide range of biological activities, namely antitumor [1-2]. In addition, the presence of an α,β-unsaturated ketone moiety makes these compounds a valuable chemical substrate for the synthesis of bioactive derivatives, such as pyrazoles [3]. Our research group has reported two synthetic chalcone derivatives with antimitotic effect [4-5]. Hence, in continuation of our efforts to obtain new chalcone derivatives with improved antitumor and antimitotic activity, a small library of chalcone derivatives, including pyrazole and α,b-epoxide, was synthesized and evaluated for their cell growth inhibitory activity in three human tumor cell lines. Additionally, their lipophilicity using liposomes as a biomimetic membrane model was determined. From this work, nine chalcones showing suitable drug-like lipophilicity with antimitotic effect were identified. Moreover, one of the compounds was able to enhance chemosensitivity of tumor cells to paclitaxel in NCI-H460 cells.

Acknowledgments

This research was partially supported by the Strategic Funding UID/Multi/04423/2019 and under the project PTDC/SAU-PUB/28736/2017 (reference POCI-01-0145-FEDER-028736), co-financed by COMPETE 2020, Portugal 2020 and the European Union through the ERDF and by FCT through national funds. This work was also supported through funds provided by CESPU, Crl under the project ComeTarget_CESPU_2017. Ana Henriques, Joana Moreira and José Soares acknowledge for their FCT grants (SFRH/BD/111365/2015 and SFRH/BD/135852/2018, and SFRH/BD/98105/2013, respectively).

References

[1] Singh P., Anand A., Kumar V., Recent developments in biological activities of chalcones: A mini review, Eur. J. Med. Chem., 85 (2014) 758-777. [2] Ducki S., Antimitotic chalcones and related compounds as inhibitors of tubulin assembly, Anti-cancer Agent Me., 9(3) (2009) 336. [3] MT Albuquerque H., MM Santos C., AS Cavaleiro J., MS Silva A., Chalcones as Versatile Synthons for the Synthesis of 5-and 6-membered Nitrogen Heterocycles, Curr. Org. Chem., 18(21) (2014) 2750-2775. [4] Masawang K., Pedro M., Cidade H., Reis R.M., Neves M. P., Corrêa A. G., Sudprasert W., Bousbaa H., Pinto M.M., Evaluation of 2′, 4′-dihydroxy-3, 4, 5-trimethoxychalcone as antimitotic agent that induces mitotic catastrophe in MCF-7 breast cancer cells, Toxicol. Lett., 229(2) (2014) 393-401. [5] Fonseca J., Marques S., SilvaP., Brandão P., Cidade H., Pinto M., Bousbaa H., Prenylated chalcone 2 acts as an antimitotic agent and enhances the chemosensitivity of tumor cells to paclitaxel, Molecules, 21(8) (2016) 982.

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Antiproliferative and antibacterial activity of 3-arylbenzo[g]indazoles functionalized with nitro and amino groups at position 6
Published: 30 October 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session Posters

Indazoles are benzo-fused pyrazoles for which a broad range of biological properties have been described, including antiproliferative and antibacterial activities. These fused tricyclic pyrazole derivatives are characterized by their conformational restriction. As part of our ongoing project on conformationally restricted ligands interacting at the colchicine binding site in tubulin [1], we have here designed and synthesized a novel series of tricyclic pyrazoline derivatives incorporating a nitro or an amino group at position 6 on the benzo[g]indazol ring and different aryl groups at position 3. The expected (3R,3aS)-rel- and (3R,3aR)-rel-isomers were obtained by reaction of the 5-nitro benzylidene tetralones with hydrazine in acetic acid. The 3D geometries of both isomers were optimized showing that in the (3R,3aR)-rel-isomer one of the hydrogens at position 4 is facing the phenyl ring, and thus this proton is shielded and appears in the 1H NMR spectra around at δ=0.7-0.8 ppm in the whole series. These conformationally constrained compounds were evaluated for their antiproliferative activity against selected cancer cell lines. Some nitro-based indazoles have shown IC50 values between 5-10 μM against the lung carcinoma cell line NCI-H460. Moreover, two of the here synthesized compounds have shown MIC values of 250 and 62.5 μg/mL against N. gonorrhoeae with no hemolytic activity in human red blood cells (RBC).

Acknowledgements: V.C., M.P.C. and B.I. thank the Universidad del Valle (CIAM-2017), COLCIENCIAS and the Science, Technology and Innovation Fund-General Royalties System (FCTeI-SGR) under contract BPIN 2013000100007, Colombia. M.-J. P.-P., E.-M. P. and M.-J. C. acknowledge the financial support of SAF2015-64629-C2-1-R and CSIC-PIE-201680E079

Reference

[1] Bueno, O.; Tobajas, G.; Quesada, E.; Estévez-Gallego, J.; Noppen, S.; Camarasa, M. J.; Díaz, J. F.; Liekens, S.; Priego, E. M.; Pérez-Pérez, M. J. Conformational Mimetics of the α-Methyl Chalcone TUB091 Binding Tubulin: Design, Synthesis and Antiproliferative Activity. Eur. J. Med. Chem. 2018, 148, 337–348. https://doi.org/10.1016/j.ejmech.2018.02.019.

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Acetylcholinesterase and antioxidant evaluation of C18-functionalized ferruginol analogues
Published: 30 October 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5

Nearly 200 years ago, the study of the chemistry of terpenoids started with the analysis of turpentine oil, investigating the first resin acid, abietic acid from pine oleoresin.[1] Abietic acid occurs in plants of the genus Abies and is the first member of a class of plant metabolites, the abietane-type diterpenoids. They are characterized by a tricyclic ring system and have shown a wide range of chemical diversity and biological activity. [2,3] Medicinal chemists have studied derivatives of two readily available materials such as dehydroabietic acid and dehydroabietylamine. [3] To date, there is only one commercial drug, Ecabet® [ecabet sodium], based on abietanes, which is used for the treatment of reflux esophagitis and peptic ulcer disease. The simplest phenolic abietane, ferruginol, exhibits anticancer effects in human ovarian cancer and inhibition of cancer cell migration. It also has shown interesting properties in different models of Alzheimer’s disease, in particular, Zolezzi et al. reported neuroprotective effects of ferruginol against amyloid-b (Ab) oligomers-induced neurodegenerative alterations and Topçu et al. reported butyrylcholinesterase inhibition by ferruginol.[4]

During the last 10 years, we have synthesized several naturally occurring abietanes and derivatives, including ferruginol and other analogues for further biological study. Recently, the simultaneous isolation (in 2014) by Hua and co-workers of the new abietane liquiditerpenoic acid A, a sugiol analogue (7-oxoferruginol derivative), from the resin of Liquidambar formosana, [5] and from Pinus massoniana [6] by Kuo and co-workers named independently as abietopinoic acid prompted us to synthesize it and study its antitumor, GABAA modulation and antileishmanial properties along with some analogues.[7]

Further investigation of those synthesized ferruginol analogues in collaboration with Prof. Rijo at Universidade Lusofona has led to a study on anti-acetylcholinesterase activity, which we present in this communication including the most recent achievements of those molecules as potential antioxidant agents.

References:

[1] Bhat, S. V.; Terpenoids. In: Chemistry of Natural Products. Berlin: Springer; 2005, 131.

[2] For a review on this topic, see: González, M. A. Nat. Prod. Rep. 2015, 32, 684-704.

[3] For a review on this topic, see: González, M. A. Eur. J. Med. Chem. 2014, 87, 834-842.

[4] a) Zolezzi, J. M.; Schmeda-Hirschmann, G.; Inestrosa, N. C. et al. J. Alzheimers Dis., 2018, 63, 705-723; b) Topçu, G.; Öztürk, M.; Boga, M. et al. The Natural Products Journal, 2013, 3, 3-9.

[5] Shang, H.-J.; Li, D.-Y.; Wang, W.-J.; Li, Z.-L.; Hua, H.-M. Nat. Prod. Res. 2014, 28, 1-6.

[6] Mohamed, H. A.; Hsieh, C.-L.; Hsu, C.; Kuo, C.-C.; Kuo, Y.-H. Helv. Chim. Acta 2014, 97, 1146-1151.

[7] Hamulic, D.; Stadler, M.; González-Cardenete, M. A. et al. J. Nat.. Prod. 2019, 82, 823-831.

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