Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Berberine as Source of Antiproliferative Hybrid Compounds: In Vitro Antiproliferative Activity and Quantitative Structure-activity Relationship

Author(s): Mario A. Leyva-Peralta, Ramón E. Robles-Zepeda, Rodrigo S. Razo-Hernández, Laura P.Á. Berber, Karen O. Lara, Eduardo Ruiz-Bustos and Juan C. Gálvez-Ruíz*

Volume 19, Issue 15, 2019

Page: [1820 - 1834] Pages: 15

DOI: 10.2174/1871520619666190503121820

Price: $65

Abstract

Background: Despite advances for cancer treatment, it still remains a major worldwide public health problem. Compounds derived from natural sources are important alternatives to combat this mortal disease. Berberine is an isoquinoline alkaloid with a wide variety of pharmacological properties, including antiproliferative activity. Previously, we have found that fatty acids also show antiproliferative activity against cancer cell lines.

Objective: To combine berberine and fatty acids, or carboxylic acids, in order to improve their antiproliferative properties.

Methods: We synthetized six new hybrid derivatives through a simple methylenedioxy group-cleavage method followed by the reaction with fatty acids, or carboxylic acids. The structure of the compounds was elucidated by IR, NMR and HRMS. The in vitro antiproliferative activity against four human cancer cell lines (HeLa, A-549, PC-3 and LS-180) and one normal cell line (ARPE-19), was evaluated by the MTT method. Chemical structures were drawn using SPARTAN '08 software and the conformational analysis was carried out with a molecular mechanic level of theory and the SYBIL force field. All molecular structures were subjected to geometrical optimization at the semi-empirical method PM3. Molecular descriptors were calculated using DRAGON 5.4 and SPARTAN ´08 programs.

Results: The geranic acid and berberine hybrid compound (6) improved the antiproliferative activity shown by natural berberine, even more than the 16- to 18-carbon atoms fatty acids. Compound 6 showed IC50 values of 2.40 ± 0.60, 1.5 ± 0.24, 5.85 ± 1.07 and 5.44 ± 0.24 μM, against HeLa, A-549, PC-3 and LS-180 human cancer cell lines, respectively. Using this information, we performed a quantitative structure-activity relationship (QSAR) of the hybrid molecules and found that the molecular descriptors associated with the antiproliferative activity are: hydrophobic constant associated with substituents (π(A) = 6.5), molecular volume descriptor (CPKvolume≈ 700 Å3), EHOMO, number of rotatable bonds (RBN) and number of 6-membered rings (nR06).

Conclusion: The methylendioxy and methoxyl groups in berberine are important for the antiproliferative activity shown by its derivatives. Better results in antiproliferative activity were obtained in compound 6 with the prenyl moiety. The QSAR indicates that the molecular descriptors which associated positively with the antiproliferative activity are: hydrophobic constant associated with substituents (π(A) = 6.5), molecular volume descriptor (CPKvolume≈ 700 Å3) and EHOMO. This research gave the basis for the design and preparation of new, easily afforded molecules derived from berberine and carboxylic acids, with improved antiproliferative activity.

Keywords: Berberine, antiproliferative activity, QSAR, hybrid compounds, alkaloids, molecular descriptors.

Graphical Abstract
[1]
Yaacob, N.; Hamzah, N.; Nursyazni, N.; Mohamed, N.; Amalina, S.; Abidin, Z. Anticancer activity of a sub-fraction of dichloromethane extract of Strobilanthes crispus on human breast and prostate cancer cells in vitro. BMC Complement. Altern. Med., 2010, 10, 42.
[2]
Jemal, A.; Bray, F.; Ferlay, J. Global cancer statistics. CA Cancer J. Clin., 2011, 61, 69-90.
[3]
Solowey, E.; Lichtenstein, M.; Sallon, S.; Paavilainen, H.; Solowey, E.; Lorberboum-Galski, H. Evaluating medicinal plants for anticancer activity. ScientificWorldJournal, 2014, 2014721402
[4]
Papo, N.; Shai, Y. New lytic peptides based on the D, L-amphipathic helix motif preferentially kill tumor cells compared to normal cells. J. Biol. Chem., 2003, 42(31), 9346-9354.
[5]
Papo, N.; Shai, Y. Host defense peptides as new weapons in cancer treatment. Cell. Mol. Life Sci. Vis. Ref., 2005, 62, 784-790.
[6]
Pierpaoli, E.; Damiani, E.; Orlando, F.; Lucarini, G.; Bartozzi, B.; Lombardi, P.; Salvatore, C.; Geroni, C.; Provinciali, M. Antiangiogenic and antitumor activities of berberine derivative NAX014 compound in a transgenic murine model of HER2/neu-positive mammary carcinoma. Carcinogenesis, 2015, 36, 1169-1179.
[7]
Chen, X.; Zhang, M.; Fan, P.; Qin, Y.; Zhao, H. Chelerythrine chloride induces apoptosis in renal cancer HEK-293 and SW-839 cell lines. Oncol. Lett., 2016, 42(31), 3917-3924.
[8]
Lu, S.; Nishimura, S.; Ito, M.; Tsuchida, T.; Kakeya, H. Isolation and structure elucidation of cytotoxic saccharothriolides D to F from a rare actinomycete Saccharothrix sp. and their structure-activity relationship. J. Nat. Prod., 2016, 79(7), 1891-1895.
[9]
Schweizer, F. Cationic amphiphilic peptides with cancer-selective toxicity. Eur. J. Pharmacol., 2009, 625, 190-194.
[10]
Romero, M.; Renard, P.; Caignard, D.; Atassi, G.; Solans, X.; Constans, P.; Bailly, C.; Pujol, M. Synthesis and structure-activity relationships of new benzodioxinic lactones as potential anticancer drugs. J. Med. Chem., 2007, 50, 294-307.
[11]
Newman, D.; Cragg, G. Natural products as sources of new drugs over the last 25 years. J. Nat. Prod., 2007, 70, 461-477.
[12]
Tillhon, M.; Guamán, L.; Lombardi, P.; Scovassi, A. Berberine: New perspectives for old remedies. Biochem. Pharmacol., 2012, 84, 1260-1267.
[13]
Lahlou, M. The success of natural products in drug discovery. J. Pharm. Pharmacol., 2013, 4, 17-31.
[14]
Tan, Y.; Sun, X.; Dong, F.; Tian, H.; Jiang, R. Enhancing the structural diversity and bioactivity of natural products by combinatorial modification exemplified by total tanshinones. Chin. J. Chem., 2015, 33, 1084-1088.
[15]
Mônica, S.; De Almeida, V.; Lafayette, E.; De Oliveira, T.; Lucia, A.; Gois, T.; De Carvalho, J. Synthesis, DNA binding, and antiproliferative activity of novel acridine-thiosemicarbazone derivatives. Int. J. Mol. Sci., 2015, 16, 13023-13042.
[16]
Hai-ning, Y.; Zun-chen, W.; Sheng-rong, S.; Wei-guang, S. Effects of capsaicin and its analogs on the growth of gastric cancer cells and their structure-activity relationships in vitro. ‎. Food Sci. Technol. Int., 2013, 19, 865-873.
[17]
Grycová, L.; Dostál, J.; Marek, R. Quaternary protoberberine alkaloids. Phytochemistry, 2007, 68, 150-175.
[18]
Martínez-Martínez, F.; Razo-Hernádez, R.; Pereza-Campos, A.; Villanueva-García, M.; Sumaya-Martínez, M.; Jaramillo-Cano, D.; Gómez-Sandoval, Z. Synthesis and in vitro antioixidant activity evaluation of 3-carboxycoumarin derivatives and QSAR study of their DPPH radical scavenging activity. Molecules, 2012, 17, 14882-14898.
[19]
Leyva-Peralta, M.; Robles-Zepeda, R.; Garibay-Escobar, A.; Ruiz-Bustos, E.; Alvarez-Berber, L.; Gálvez-Ruiz, J. In vitro anti-proliferative activity of Argemone gracilenta and identification of some active components. BMC Complement. Altern. Med., 2015, 15, 1-7.
[20]
Pierpaoli, E.; Arcamone, A.; Buzzetti, F.; Lombardi, P.; Salvatore, C.; Provinciali, M. Antitumor effect of novel berberine derivatives in breast cancer cells. Biofactors, 2013, 39, 672-679.
[21]
Miguel, L.; Ortiz, G.; Tillhon, M.; Parks, M.; Dutto, I.; Prosperi, E.; Savio, M.; Arcamone, A.; Buzzetti, F.; Lombardi, P.; Scovassi, A. Multiple effects of berberine derivatives on colon cancer cells. BioMed Res. Int., 2014, 2014924585
[22]
Bengtsson, C.; Nelander, H.; Almqvist, F. Asymmetric synthesis of 2,4,5-trisubstituted Δ 2-thiazolines. Chem. Eur. J., 2013, 19, 9916-9922.
[23]
Zhang, Y.; Zimmerman, S. Azobenzene dye-coupled quadruply hydrogenbonding modules as colorimetric indicators for supramolecular interactions. Beilstein J. Org. Chem., 2012, 8, 486-495.
[24]
Bhupendra, M.; Young-Soo, K.; Doo Hwan, K. Synthesis, antioxidant and anticancer screenings of berberine-indole conjugates. Res. Chem. Intermed., 2015, 42, 3241-3256.
[25]
Bhupendra, M.; Rahul, V.; Young-Soo, K.; Doo Hwan, K. Evaluation of the biological potencies of newly synthesized berberine derivatives bearing benzothiazole moieties with substituted functionalities. J. Saudi Chem. Soc., 2017, 21, 210-219.
[26]
Bhupendra, M.; Rahul, V.; Young-Soo, K.; Doo Hwan, K. Synthesis of N-Mannich bases of berberine linking piperazine moieties revealing anticancer and antioxidant effects. Saudi J. Biol. Sci., 2017, 24, 36-44.
[27]
Simic, M.; Damjanovic, A.; Kalinic, M.; Tasic, G.; Slavica, M.; Antic-Stankovic, J.; Savic, V. Synthesis, cytotoxicity and computational study of novel protoberberine derivatives. J. Serb. Chem. Soc., 2016, 81, 103-123.
[28]
Viswanadhan, V.; Ghose, A.; Revankar, G.; Robins, R. Atomic physicochemical parameter for three dimensional structure directed quantitative structure-activity relationships, 4. Additional parameters for hydrophobic and dispersive interactions and their application for an automated superposition of certain naturally occurring nucleoside antibiotics. J. Chem. Inf. Model., 1989, 29, 163-172.
[29]
Todeschina, R.; Consonni, V.; Mauri, A.; Pavan, M. Detecting “bad” regression model: Multicriteria fitness functions in regression analysis. Anal. Chim. Acta, 2004, 515, 199-208.
[30]
Roy, K.; Narayan, R. Statiscal methods in QSAR/QPSR. A primer on QSAR/QPSR modeling; Springer: Berlin, 2015. Chapter 2.
[31]
Noolvi, M.; Patel, H. A comparative QSAR analysis and molecular docking studies of quinazoline derivatives as tyrosine kinase (EGFR) inhibitors: A rational approach to anticancer drug desing. J. Saudi Chem. Soc., 2013, 17, 361-379.
[32]
Zydek, G.; Brzezinska, E. Development and validation of quantitative structure-activity relationship models for compound acting on serotoninergic receptors. ScientificWorldJournal, 2012, 2012, 157950
[33]
Pal, K.; Pore, S.; Sinha, S.; Janardhanan, R.; Mukhopadhyay, D.; Banerjee, R. Structure-activity study to develop cationic lipid-conjugated haloperidol derivatives as a new class of anticancer therapeutics. J. Med. Chem., 2011, 54(7), 2378-2390.
[34]
Chhikara, B.; Mandal, D.; Parang, K. Synthesis, anticancer activities, and cellular uptake studies of lipophilic derivatives of doxorubicin succinate. J. Med. Chem., 2012, 55(4), 1500-1510.
[35]
Wang, M.; Wang, F.; Xu, F.; Ding, L-Q.; Qiu, F. Two pairs of farnesyl phenolic enantiomers as natural nitric oxide inhibitors from Ganoderma sinense. Bioorg. Med. Chem. Lett., 2016, 26, 3342-3345.
[36]
Liu, J-Q.; Lian, Ch-L.; Hu, T-Y.; Wang, C-F.; Cheng, B-H. Two new farnesyl phenolic compounds with anti-inflammatory activities from Ganoderma duripora. Food Chem., 2018, 263, 155-162.
[37]
Islam, M.T.; Ali, E.S.; Uddin, S.J.; Shaw, S.; Atanasov, A.G. Phytol: A review of biomedical activities. Food Chem. Toxicol., 2018, 121, 82-94.
[38]
Raju, R.; Singh, A.; Reddell, P.; Münch, G. Anti-inflammatory activity of prenyl and geranyloxy furanocoumarins from Citrus garrawayi (Rutaceae). Phytochem. Lett., 2018, 27, 197-202.
[39]
Mo, H.; Tatman, D.; Jung, M.; Elson, C.E. Farnesyl anthranilate suppresses the growth, in vitro and in vivo, of murine B16 melanomas. Cancer Lett., 2000, 157, 145-153.
[40]
Suparji, N.S.; Chan, G.; Sapili, H.; Arshad, N.M. In, L.L.; Awang, K.; Nagoor, N.H. Geranylated 4-Phenylcoumarins exhibit anticancer effects against human prostate cancer cells through caspase-independent mechanism. PLoS One, 2016, 11(3)e0151472
[41]
Hosseinymehr, M.; Matin, M.M.; Sadeghian, H.; Bahrami, A.R.; Kaseb-Mojaver, N. 8-Farnesyloxycoumarin induces apoptosis in PC-3 prostate cancer cells by inhibition of 15-lipoxygenase-1 enzymatic activity. Anticancer Drugs, 2016, 9, 854-862.
[42]
Bartmańska, A.; Tronina, T.; Popłoński, J.; Milczarek, M.; Filip-Psurska, B.; Wietrzyk, J. Highly cancer selective antiproliferative activity of natural prenylated flavonoids. Molecules, 2018, 23(11)E2922
[43]
Wätjen, W.; Weber, N.; Lou, Y.J.; Wang, Z.Q.; Chovolou, Y.; Kampkötter, A.; Kahl, R.; Proksch, P. Prenylation enhances cytotoxicity of apigenin and liquiritigenin in rat H4IIE hepatoma and C6 glioma cells. Food Chem. Toxicol., 2007, 45, 119-124.
[44]
Wang, H.M.; Zhang, L.; Liu, J.; Yang, Z.L.; Zhao, H.Y.; Yang, Y.; Shen, D.; Lu, K.; Fan, Z.C.; Yao, Q.W.; Zhang, Y.M.; Teng, Y.O.; Peng, Y. Synthesis and anti-cancer activity evaluation of novel prenylated and geranylated chalcone natural products and their analogs. Eur. J. Med. Chem., 2015, 92, 439-448.
[45]
Offerman, S.C.; Kadirvel, M.; Abusara, O.H.; Bryant, J.L.; Telfer, B.A.; Brown, G.; Freeman, S.; White, A.; Williams, K.J.; Aojula, H.S. N-tert-Prenylation of the indole ring improves the cytotoxicity of a short antagonist G analogue against small cell lung cancer. MedChemComm, 2017, 8, 551-558.
[46]
Shiozawa, M.; Iida, K.; Odagi, M.; Yamanaka, M.; Nagasawa, K. Synthesis of 2,6,7-Trisubstituted prenylated indole. J. Org. Chem., 2018, 83, 7276-7280.
[47]
Johnston, S.R.D. Farnesyl transferase inhibitors: A novel targeted therapy for cancer. Lancet Oncol., 2001, 2, 18-26.
[48]
Schlitzer, M.; Sattler, I. Aromatic carboxylic acids as farnesyl surrogates in farnesyl pyrophosphate-based farnesyltransferase inhibitors. Bioorg. Med. Chem., 1999, 7, 2391-2395.
[49]
Eros, D.; Kovesdi, L.; Orfi, K.; Takacs-Novak, G.; Acsady, G.; Keri, G. Reliability of logP predictions based on calculated molecular descriptors: A critical review. ‎. Curr. Med. Chem., 2002, 9, 1819-1829.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy