Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

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

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Anticancer Properties of Amino Acid and Peptide Derivatives of Mycophenolic Acid

Author(s): Agnieszka Siebert, Milena Deptuła, Mirosława Cichorek, Anna Ronowska, Grzegorz Cholewiński* and Janusz Rachon

Volume 21, Issue 4, 2021

Published on: 16 May, 2020

Page: [462 - 467] Pages: 6

DOI: 10.2174/1871520620666200516151456

Price: $65

Abstract

Background: Although Mycophenolic Acid (MPA) is applied as prodrugs in clinic as an immunosuppressant, it also possesses anticancer activity. MPA acts as Inosine-5’-Monophosphate Dehydrogenase (IMPDH) inhibitor, where the carboxylic group at the end of the side chain interacts with Ser 276 of the enzyme via hydrogen bonds. Therefore, MPA derivatives with other polar groups indicated high inhibition too. On the other hand, potent anticancer agents like dacarbazine and cisplatin give numerous side-effects.

Objective: Based on the literature data, MPA derivatives should be explored towards anticancer properties. Conversion of the carboxylic group of MPA to amide could maintain antiproliferative activity. Therefore, we decided to investigate several amino acid and peptide derivatives of MPA against chosen cancer cell lines in vitro.

Methods: Amides of MPA hold threonine and arginine amino acid unit. These amino acid derivatives were tested as L and D enantiomers and both in free acid and methyl esters forms. Additionally, MPA was modified with tuftsin or retro-tuftsin as biologically active peptides, which could act as a drug carrier.

Results: Amino acid and peptide derivatives of MPA were investigated in vitro as potential anticancer agents on cell lines: Ab melanoma, A375 melanoma and SHSY5Y neuroblastoma. The activity of the tested compounds was compared to parent MPA and known chemotherapeutics: dacarbazine and cisplatin.

Conclusion: Amino acid moiety and the sequence of amino acids in the peptide part influenced observed activity. The most active amino acid MPA analogues occurred to be D and L-threonine derivatives as methyl esters, probably due to better cell membrane penetration.

Keywords: Mycophenolic acid, amino acid, peptide, anticancer, amides, conjugates.

« Previous Next »
Graphical Abstract

[1]
Ardesteni, F.; Fatemi, S.S.; Yakchali, B.; Hosseyni, S.M.; Najafpour, G. Evaluation of mycophenolic acid production by Penicillium bervicompactum MUCL 19011 in batch of continuous submerged cultures. Biochem. Eng. J.,, 2010, 50, 99-103.
[http://dx.doi.org/10.1016/j.bej.2010.03.008]
[2]
Patel, G.; Patil, M.D.; Soni, S.; Khobragade, T.P.; Chisti, Y.; Banerjee, U.C. Production of mycophenolic acid by Penicillium brevicompactum-A comparison of two methods of optimization. Biotechnol. Rep. (Amst.), 2016, 11, 77-85.
[http://dx.doi.org/10.1016/j.btre.2016.07.003] [PMID: 28352543]
[3]
Gillot, G.; Jany, J.L.; Dominguez-Santos, R.; Poirier, E.; Debaets, S.; Hidalgo, P.I.; Ullán, R.V.; Coton, E.; Coton, M. Genetic basis for mycophenolic acid production and strain-dependent production variability in Penicillium roqueforti. Food Microbiol., 2017, 62, 239-250.
[http://dx.doi.org/10.1016/j.fm.2016.10.013] [PMID: 27889155]
[4]
Siebert, A.; Prejs, M.; Cholewiński, G.; Dzierzbicka, K. New Analogues of mycophenolic acid. Mini Rev. Med. Chem., 2017, 17, 734-745.
[http://dx.doi.org/10.2174/1389557516666161129160001] [PMID: 27903231]
[5]
Kaplan, B. Mycophenolic acid trough level monitoring in solid organ transplant recipients treated with mycophenolate mofetil: Association with clinical outcome. Curr. Med. Res. Opin., 2006, 22(12), 2355-2364.
[http://dx.doi.org/10.1185/030079906X148481] [PMID: 17257450]
[6]
Ghio, L.; Ferraresso, M.; Zacchello, G.; Murer, L.; Ginevri, F.; Belingheri, M.; Peruzzi, L.; Zanon, F.; Perfumo, F.; Berardinelli, L.; Tirelli, S.; Dello Strologo, L.; Fontana, I.; Valente, U.; Cardillo, M.; Edefonti, A. Longitudinal evaluation of mycophenolic acid pharmacokinetics in pediatric kidney transplant recipients. The role of post-transplant clinical and therapeutic variables. Clin. Transplant., 2009, 23(2), 264-270.
[http://dx.doi.org/10.1111/j.1399-0012.2008.00932.x] [PMID: 19191807]
[7]
Jablecki, J.; Kaczmarzyk, L.; Patrzałek, D.; Domanasiewicz, A.; Boratyńska, Z. First Polish forearm transplantation: Report after 17 months. Transplant. Proc., 2009, 41(2), 549-553.
[http://dx.doi.org/10.1016/j.transproceed.2009.01.005] [PMID: 19328923]
[8]
Cholewiński, G.; Iwaszkiewicz-Grześ, D.; Prejs, M.; Głowacka, A.; Dzierzbicka, K. Synthesis of the inosine 5′-monophosphate dehydrogenase (IMPDH) inhibitors. J. Enzyme Inhib. Med. Chem., 2015, 30(4), 550-563.
[http://dx.doi.org/10.3109/14756366.2014.951349] [PMID: 25198892]
[9]
Hedstrom, L. IMP dehydrogenase: Structure, mechanism, and inhibition. Chem. Rev., 2009, 109(7), 2903-2928.
[http://dx.doi.org/10.1021/cr900021w] [PMID: 19480389]
[10]
Ratcliffe, A.J. Inosine 5′-monophosphate dehydrogenase inhibitors for the treatment of autoimmune diseases. Curr. Opin. Drug Discov. Devel., 2006, 9(5), 595-605.
[PMID: 17002220]
[11]
Chen, L.; Pankiewicz, K.W. Recent development of IMP dehydrogenase inhibitors for the treatment of cancer. Curr. Opin. Drug Discov. Devel., 2007, 10(4), 403-412.
[PMID: 17659481]
[12]
Sunohara, K.; Mitsuhashi, S.; Shigetomi, K.; Ubukata, M. Discovery of N-(2,3,5-triazoyl)mycophenolic amide and mycophenolic epoxyketone as novel inhibitors of human IMPDH. Bioorg. Med. Chem. Lett., 2013, 23(18), 5140-5144.
[http://dx.doi.org/10.1016/j.bmcl.2013.07.016] [PMID: 23937979]
[13]
Felczak, K.; Vince, R.; Pankiewicz, K.W. NAD-based inhibitors with anticancer potential. Bioorg. Med. Chem. Lett., 2014, 24(1), 332-336.
[http://dx.doi.org/10.1016/j.bmcl.2013.11.005] [PMID: 24269162]
[14]
Yalowitz, J.A.; Pankiewicz, K.; Patterson, S.E.; Jayaram, H.N. Cytotoxicity and cellular differentiation activity of methylenebis(phosphonate) analogs of tiazofurin and mycophenolic acid adenine dinucleotide in human cancer cell lines. Cancer Lett., 2002, 181(1), 31-38.
[http://dx.doi.org/10.1016/S0304-3835(02)00045-9] [PMID: 12430176]
[15]
Feichtiger, H.; Wieland, E.; Armstrong, V.W.; Shipkova, M. The acyl glucuronide metabolite of mycophenolic acid induces tubulin polymerization in vitro. Clin. Biochem., 2010, 43(1-2), 208-213.
[http://dx.doi.org/10.1016/j.clinbiochem.2009.08.023] [PMID: 19744471]
[16]
Shipkova, M.; Armstrong, V.W.; Wieland, E.; Niedmann, P.D.; Schütz, E.; Brenner-Weiss, G.; Voihsel, M.; Braun, F.; Oellerich, M. Identification of glucoside and carboxyl-linked glucuronide conjugates of mycophenolic acid in plasma of transplant recipients treated with mycophenolate mofetil. Br. J. Pharmacol., 1999, 126(5), 1075-1082.
[http://dx.doi.org/10.1038/sj.bjp.0702399] [PMID: 10204993]
[17]
Mitsuhashi, S.; Takenaka, J.; Iwamori, K.; Nakajima, N.; Ubukata, M. Structure-activity relationships for inhibition of inosine monophosphate dehydrogenase and differentiation induction of K562 cells among the mycophenolic acid derivatives. Bioorg. Med. Chem., 2010, 18(22), 8106-8111.
[http://dx.doi.org/10.1016/j.bmc.2010.09.004] [PMID: 20934342]
[18]
Siebert, A.; Cholewiński, G.; Garwolińska, D.; Olejnik, A.; Rachoń, J.; Chojnacki, J. The synthesis and structure of a potential immunosupressant: N-mycophenoyl malonic acid dimethyl ester. J. Mol. Struct.,, 2018, 1151, 218-222.
[http://dx.doi.org/10.1016/j.molstruc.2017.09.041]
[19]
Cholewinski, G.; Malachowska-Ugarte, M.; Dzierzbicka, K. The chemistry of mycophenolic acid--synthesis and modifications towards desired biological activity. Curr. Med. Chem., 2010, 17(18), 1926-1941.
[http://dx.doi.org/10.2174/092986710791163920] [PMID: 20377512]
[20]
Peng, Y.; Dong, Y.; Mahato, R.I. Synthesis and characterization of a novel mycophenolic acid-quinic acid conjugate serving as immunosuppressant with decreased toxicity. Mol. Pharm., 2015, 12(12), 4445-4453.
[http://dx.doi.org/10.1021/acs.molpharmaceut.5b00639] [PMID: 26529468]
[21]
Siebert, A.; Cholewiński, G.; Trzonkowski, P.; Rachon, J. Immunosuppressive properties of amino acid and peptide derivatives of mycophenolic acid. Eur. J. Med. Chem., 2020, 189112091
[http://dx.doi.org/10.1016/j.ejmech.2020.112091] [PMID: 32007665]
[22]
Siebert, A.; Wysocka, M.; Krawczyk, B.; Cholewiński, G.; Rachoń, J. Synthesis and antimicrobial activity of amino acid and peptide derivatives of mycophenolic acid. Eur. J. Med. Chem., 2018, 143, 646-655.
[http://dx.doi.org/10.1016/j.ejmech.2017.11.094] [PMID: 29216563]
[23]
Bomirski, A.; Słominski, A.; Bigda, J. The natural history of a family of transplantable melanomas in hamsters. Cancer Metastasis Rev., 1988, 7(2), 95-118.
[http://dx.doi.org/10.1007/BF00046481] [PMID: 3293837]
[24]
Cichorek, M.; Kozłowska, K.; Bryl, E. The activity of caspases in spontaneous and camptothecin-induced death of melanotic and amelanotic melanoma cell. Cancer Biol. Ther., 2007, 6(3), 346-353.
[http://dx.doi.org/10.4161/cbt.6.3.3701] [PMID: 17312383]
[25]
Siebert, A.; Gensicka-Kowalewska, M.; Cholewiński, G.; Dzierzbicka, K. Tuftsin - Properties and Analogs. Curr. Med. Chem., 2017, 24(34), 3711-3727.
[http://dx.doi.org/10.2174/0929867324666170725140826] [PMID: 28745220]
[26]
Gupta, C.M.; Haq, W. Tuftsin-bearing liposomes as antibiotic carriers in treatment of macrophage infections. Methods Enzymol., 2005, 391, 291-304.
[http://dx.doi.org/10.1016/S0076-6879(05)91016-1] [PMID: 15721387]
[27]
Dzierzbicka, K. Synthesis of conjugates of muramyl dipeptyde and nor-muramyl dipeptide with retro-tuftsin (Arg-Pro-Lys-ThrOMe) as potential immunostimulants. Pol. J. Chem., 2004, 78, 409-416.
[28]
Dzierzbicka, K.; Sowiński, P.; Kołodziejczyk, A.M. Synthesis of analogues of anthraquinones linked to tuftsin or retro-tuftsin residues as potential topoisomerase inhibitors. J. Pept. Sci., 2006, 12(10), 670-678.
[http://dx.doi.org/10.1002/psc.777] [PMID: 16953492]
[29]
Dzierzbicka, K.; Wardowska, A.; Rogalska, M.; Trzonkowski, P. New conjugates of muramyl dipeptide and nor-muramyl dipeptide linked to tuftsin and retro-tuftsin derivatives significantly influence their biological activity. Pharmacol. Rep., 2012, 64(1), 217-223.
[http://dx.doi.org/10.1016/S1734-1140(12)70749-1] [PMID: 22580539]
[30]
Brandao, J. Blair, R.; Kelly, A.; Fowlkes, N.; Shiomitsu, K.; Ghomes F.E.; Rich, G.; Tully, T.N. Amelanotic Melanoma in the Rabbit: A Case Report With an Overview of Immunohistochemical Characterization. J. Exot. Pet Med., 2015, 24, 193-200..
[http://dx.doi.org/10.1053/j.jepm.2015.04.009]
[31]
Thomas, N.E.; Kricker, A.; Waxweiler, W.T.; Dillon, P.M.; Busman, K.J.; From, L.; Groben, P.A.; Armstrong, B.K.; Anton-Culver, H.; Gruber, S.B.; Marrett, L.D.; Gallagher, R.P.; Zanetti, R.; Rosso, S.; Dwyer, T.; Venn, A.; Kanetsky, P.A.; Orlow, I.; Paine, S.; Ollila, D.W.; Reiner, A.S.; Luo, L.; Hao, H.; Frank, J.S.; Begg, C.B.; Berwick, M. Genes, Environment, and Melanoma (GEM) Study Group. Comparison of clinicopathologic features and survival of histopathologically amelanotic and pigmented melanomas: a population-based study. JAMA Dermatol., 2014, 150(12), 1306-1314.
[http://dx.doi.org/10.1001/jamadermatol.2014.1348] [PMID: 25162299]
[32]
Chen, K.G.; Valencia, J.C.; Gillet, J.P.; Hearing, V.J.; Gottesman, M.M. Involvement of ABC transporters in melanogenesis and the development of multidrug resistance of melanoma. Pigment Cell Melanoma Res., 2009, 22(6), 740-749.
[http://dx.doi.org/10.1111/j.1755-148X.2009.00630.x] [PMID: 19725928]
[33]
Hecht, M.; Meier, F.; Zimmer, L.; Polat, B.; Loquai, C.; Weishaupt, C.; Forschner, A.; Gutzmer, R.; Utikal, J.S.; Goldinger, S.M.; Geier, M.; Hassel, J.C.; Balermpas, P.; Kiecker, F.; Rauschenberg, R.; Dietrich, U.; Clemens, P.; Berking, C.; Grabenbauer, G.; Schadendorf, D.; Grabbe, S.; Schuler, G.; Fietkau, R.; Distel, L.V.; Heinzerling, L. Clinical outcome of concomitant vs. interrupted BRAF inhibitor therapy during radiotherapy in melanoma patients. Br. J. Cancer, 2018, 118(6), 785-792.
[http://dx.doi.org/10.1038/bjc.2017.489] [PMID: 29438368]
[34]
Silva, I.P.; Long, G.V. Systemic therapy in advanced melanoma: Integrating targeted therapy and immunotherapy into clinical practice. Curr. Opin. Oncol., 2017, 29(6), 484-492.
[http://dx.doi.org/10.1097/CCO.0000000000000405] [PMID: 28914644]
[35]
Deutsch, G.B.; Flaherty, D.C.; Kirchoff, D.D.; Bailey, M.; Vitug, S.; Foshag, L.J.; Faries, M.B.; Bilchik, A.J. Association of surgical treatment, systemic therapy, and survival in patients with abdominal visceral melanoma metastases, 1965-2014: Relevance of surgical cure in the era of modern systemic therapy. JAMA Surg., 2017, 152(7), 672-678.
[http://dx.doi.org/10.1001/jamasurg.2017.0459] [PMID: 28384791]
[36]
Djougarian, A.; Kodsi, S. Hypertensive retinopathy as the initial presentation of neuroblastoma. Am. J. Ophthalmol. Case Rep., 2017, 7, 123-125.
[http://dx.doi.org/10.1016/j.ajoc.2017.06.008] [PMID: 29260095]
[37]
Mullassery, D.; Losty, P.D. Neuroblastoma. Paediatr. Child Health, 2016, 26, 68-72.,
[http://dx.doi.org/10.1016/j.paed.2015.11.005]
[38]
Serrone, L.; Zeuli, M.; Sega, F.M.; Cognetti, F. Dacarbazine-based chemotherapy for metastatic melanoma: Thirty-year experience overview. J. Exp. Clin. Cancer Res., 2000, 19(1), 21-34.
[PMID: 10840932]
[39]
Bhatia, S.; Tykodi, S.S.; Thompson, J.A. Treatment of metastatic melanoma: An overview. Oncology (Williston Park), 2009, 23(6), 488-496.
[PMID: 19544689]
[40]
Rueda Domínguez, A.; Márquez, A.; Gumá, J.; Llanos, M.; Herrero, J.; de Las Nieves, M.A.; Miramón, J.; Alba, E. Treatment of stage I and II Hodgkin’s lymphoma with ABVD chemotherapy: Results after 7 years of a prospective study. Ann. Oncol., 2004, 15(12), 1798-1804.
[http://dx.doi.org/10.1093/annonc/mdh465] [PMID: 15550585]
[41]
Elias, A.; Ryan, L.; Aisner, J.; Antman, K.H. Mesna, doxorubicin, ifosfamide, dacarbazine (MAID) regimen for adults with advanced sarcoma. Semin. Oncol., 1990, 17(2)(Suppl. 4), 41-49.
[PMID: 2110385]
[42]
Pearl, M.L.; Inagami, M.; McCauley, D.L.; Valea, F.A.; Chalas, E.; Fischer, M. Mesna, doxorubicin, ifosfamide, and dacarbazine (MAID) chemotherapy for gynecological sarcomas. Int. J. Gynecol. Cancer, 2002, 12(6), 745-748.
[http://dx.doi.org/10.1136/ijgc-00009577-200211000-00010] [PMID: 12445253]
[43]
Oun, R.; Rowan, E. Cisplatin induced arrhythmia; electrolyte imbalance or disturbance of the SA node? Eur. J. Pharmacol., 2017, 811, 125-128.
[http://dx.doi.org/10.1016/j.ejphar.2017.05.063] [PMID: 28599874]

Rights & Permissions Print Cite
Article Metrics
57
1
© 2024 Bentham Science Publishers | Privacy Policy