Login Register Cart 0
Generic placeholder image

Clinical Cancer Drugs

Editor-in-Chief

ISSN (Print): 2212-697X
ISSN (Online): 2212-6988

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Mini-Review Article

Does the Oxazolidinone Derivatives Constitute a Functional Approach for Cancer Therapy?

Author(s): Eduardo Augusto Vasconcelos de Freitas Ramalho*, Marina Galdino da Rocha Pitta, Hernando de Barros Siqueira Neto and Ivan da Rocha Pitta

Volume 7, Issue 2, 2020

Page: [95 - 106] Pages: 12

DOI: 10.2174/2212697X07999200807210936

Price: $65

Abstract

In the last four decades, the emphasis was laid on the research of small organic molecules with potential anti-cancer activity. Linezolid was the first oxazolidinone derivative approved by FDA for MRSA treatment. Despite its major role in antimicrobial activity, these molecules display other properties, also serving as an antitumor agent. The importance of drug repurposing could be highlighted by the use of Oxazolidinone derivatives in pre-clinical studies, which are able to act through different pathways, such as partial agonist of transcription factor PPAR-γ, an inhibitor of key enzymes related to hormone-dependent disorders and even on sphingolipid metabolism as well. The purpose of this short review is to discuss the application of oxazolidinone derivatives as an antitumor agent by highlighting the most promising molecules studied by many research groups worldwide. Main biological activity against several tumor cell lines, including hematopoietic and solid cancer cell lines have been discussed. In addition, this study intends to report how different types of oxazolidinone derivatives can act as antitumor agents describing their distinct mechanisms of action based on their targets.

Keywords: Cancer, ceramide, oxazolidinone, PPAR, therapeutic, 17β-HSD.

Graphical Abstract

[1]
Globocan IARC. http://globocan.iarc.fr/Pages/fact_sheets_cancer. aspx2017
[2]
Shewach DS, Kuchta RD. Introduction to cancer chemotherapeutics. Chem Rev 2009; 109(7): 2859-61.
[http://dx.doi.org/10.1021/cr900208x ] [PMID: 19583428]
[3]
Fugitt RB, Luckenbaugh RW. 5-halomethyl-3-phenyl-2 oxazolidinones U.S. Patent, 4,128,654, 1978.
[4]
Fugitt RB, Martinelli LC. Synthesis and anticancer activity of 5-(propargyloxymethyl)-2-oxazolidinones. J Pharm Sci 1973; 62(6): 1013-6.
[http://dx.doi.org/10.1002/jps.2600620637 ] [PMID: 4712606]
[5]
Braun MG, Elliot R, Hanan E, Heald RA, Macleod C, Staben ST. Benzoxazepin oxazolidinone compounds and methods of use U.S. Patent, WO2017001645 A1, 2016.
[6]
Liu Z, Li D, Zhao W, Zheng X, Wang J, Wang E. A potent lead induces apoptosis in pancreatic cancer cells. PLoS One 2012; 7(6): e37841.
[http://dx.doi.org/10.1371/journal.pone.0037841 ] [PMID: 22745658]
[7]
Bajaj S, Asati V, Singh J, Roy PP. 1,3,4-Oxadiazoles: An emerging scaffold to target growth factors, enzymes and kinases as anticancer agents. Eur J Med Chem 2015; 97(97): 124-41.
[http://dx.doi.org/10.1016/j.ejmech.2015.04.051 ] [PMID: 25965776]
[8]
Zhang XM, Qiu M, Sun J, et al. Synthesis, biological evaluation, and molecular docking studies of 1,3,4-oxadiazole derivatives possessing 1,4-benzodioxan moiety as potential anticancer agents. Bioorg Med Chem 2011; 19(21): 6518-24.
[http://dx.doi.org/10.1016/j.bmc.2011.08.013 ] [PMID: 21962523]
[9]
Singh A, Ha HJ, Park J, Kim JH, Lee WK. 3,4-Disubstituted oxazolidin-2-ones as constrained ceramide analogs with anticancer activities. Bioorg Med Chem 2011; 19(21): 6174-81.
[http://dx.doi.org/10.1016/j.bmc.2011.09.022 ] [PMID: 21978949]
[10]
Harada K, Kubo H, Abe J, et al. Discovery of potent and orally bioavailable 17β-hydroxysteroid dehydrogenase type 3 inhibitors. Bioorg Med Chem 2012; 20(10): 3242-54.
[http://dx.doi.org/10.1016/j.bmc.2012.03.052 ] [PMID: 22512907]
[11]
Patenaude A, Deschesnes RG, Rousseau JLC, et al. New soft alkylating agents with enhanced cytotoxicity against cancer cells resistant to chemotherapeutics and hypoxia. Cancer Res 2007; 67(5): 2306-16.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-3824 ] [PMID: 17332362]
[12]
Chan KK, Hong PS, Tutsch K, Trump DL. Clinical pharmacokinetics of cyclophosphamide and metabolites with and without SR-2508. Cancer Res 1994; 54(24): 6421-9.
[PMID: 7987837]
[13]
Scatena C, Roncella M, Di Paolo A, et al. Doxycycline, an inhibitor of mitochondrial biogenesis, effectively reduces cancer stem cells (CSCs) in early breast cancer patients: A clinical pilot study. Front Oncol 2018; 8(8): 452.
[http://dx.doi.org/10.3389/fonc.2018.00452 ] [PMID: 30364293]
[14]
Koeffler HP. Peroxisome proliferator-activated receptor γ and cancers. Clin Cancer Res 2003; 9(1): 1-9.
[PMID: 12538445]
[15]
Li J, Simpson L, Takahashi M, et al. The PTEN/MMAC1 tumor suppressor induces cell death that is rescued by the AKT/protein kinase B oncogene. Cancer Res 1998; 58(24): 5667-72.
[PMID: 9865719]
[16]
Yang FG, Zhang ZW, Xin DQ, et al. Peroxisome proliferator-activated receptor gamma ligands induce cell cycle arrest and apoptosis in human renal carcinoma cell lines. Acta Pharmacol Sin 2005; 26(6): 753-61.
[http://dx.doi.org/10.1111/j.1745-7254.2005.00753.x ] [PMID: 15916743]
[17]
Tontonoz P, Singer S, Forman BM, et al. Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor gamma and the retinoid X receptor. Proc Natl Acad Sci USA 1997; 94(1): 237-41.
[http://dx.doi.org/10.1073/pnas.94.1.237 ] [PMID: 8990192]
[18]
Pal T, Joshi H, Ramaa CS. Design and development of oxazol-5-ones as potential partial PPAR-γ agonist against cancer cell lines. Anticancer Agents Med Chem 2014; 14(6): 872-83.
[http://dx.doi.org/10.2174/1871520614666140528155118 ] [PMID: 24875128]
[19]
Krische D. The glitazones: proceed with caution. West J Med 2000; 173(1): 54-7.
[http://dx.doi.org/10.1136/ewjm.173.1.54 ] [PMID: 10903299]
[20]
Williams DA, Lemke TL. Foye’s Principles of Medicinal Chemistry.Ed. B.I. Publication Pvt. Ltd, New Delhi 2005; p. 645.
[21]
Guasch L, Sala E, Castell-Auví A, et al. Identification of PPARgamma partial agonists of natural origin (I): development of a virtual screening procedure and in vitro validation. PLoS One 2012; 7(11): e50816.
[http://dx.doi.org/10.1371/journal.pone.0050816 ] [PMID: 23226391]
[22]
Mesaik MA, Rahat S, Khan KM, et al. Synthesis and immunomodulatory properties of selected oxazolone derivatives. Bioorg Med Chem 2004; 12(9): 2049-57.
[http://dx.doi.org/10.1016/j.bmc.2004.02.034 ] [PMID: 15080909]
[23]
Khan KM, Mughal UR, Khan MT. Zia-Ullah, Perveen S, Choudhary MI. Oxazolones: new tyrosinase inhibitors; synthesis and their structure-activity relationships. Bioorg Med Chem 2006; 14(17): 6027-33.
[http://dx.doi.org/10.1016/j.bmc.2006.05.014 ] [PMID: 16750372]
[24]
Perron-Sierra FM, Pierré A, Burbridge M, Guilbaud N. Novel bicyclic oxazolone derivatives as anti-angiogenic agents. Bioorg Med Chem Lett 2002; 12(11): 1463-6.
[http://dx.doi.org/10.1016/S0960-894X(02)00197-X ] [PMID: 12031320]
[25]
Villacorta L, Schopfer FJ, Zhang J, Freeman BA, Chen YE. PPARgamma and its ligands: therapeutic implications in cardiovascular disease. Clin Sci (Lond) 2009; 116(3): 205-18.
[http://dx.doi.org/10.1042/CS20080195 ] [PMID: 19118492]
[26]
Schwartz AV, Sellmeyer DE, Vittinghoff E, et al. Thiazolidinedione use and bone loss in older diabetic adults. J Clin Endocrinol Metab 2006; 91(9): 3349-54.
[http://dx.doi.org/10.1210/jc.2005-2226 ] [PMID: 16608888]
[27]
Guasch L, Sala E, Valls C, et al. Structural insights for the design of new PPARgamma partial agonists with high binding affinity and low transactivation activity. J Comput Aided Mol Des 2011; 25(8): 717-28.
[http://dx.doi.org/10.1007/s10822-011-9446-9 ] [PMID: 21691811]
[28]
Zou G, Gao Z, Wang J, et al. Deoxyelephantopin inhibits cancer cell proliferation and functions as a selective partial agonist against PPARgamma. Biochem Pharmacol 2008; 75(6): 1381-92.
[http://dx.doi.org/10.1016/j.bcp.2007.11.021 ] [PMID: 18164690]
[29]
Yin Y, Russell RG, Dettin LE, et al. Peroxisome proliferator-activated receptor δ and γ agonists differentially alter tumor differentiation and progression during mammary carcinogenesis. Cancer Res 2005; 65(9): 3950-7.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-3990 ] [PMID: 15867396]
[30]
Campos JF, Pereira MC, de Sena WLB, et al. Synthesis and in vitro anticancer activity of new 2-thioxo-oxazolidin-4-one derivatives. Pharmacol Rep 2017; 69(4): 633-41.
[http://dx.doi.org/10.1016/j.pharep.2017.03.005 ] [PMID: 28511054]
[31]
Fiaux H, Kuntz DA, Hoffman D, et al. Functionalized pyrrolidine inhibitors of human type II alpha-mannosidases as anti-cancer agents: optimizing the fit to the active site. Bioorg Med Chem 2008; 16(15): 7337-46.
[http://dx.doi.org/10.1016/j.bmc.2008.06.021 ] [PMID: 18599296]
[32]
Schug ZT, Gonzalvez F, Houtkooper RH, Vaz FM, Gottlieb E. BID is cleaved by caspase-8 within a native complex on the mitochondrial membrane. Cell Death Differ 2011; 18(3): 538-48.
[http://dx.doi.org/10.1038/cdd.2010.135 ] [PMID: 21072056]
[33]
Garcia-Perez C, Roy SS, Naghdi S, Lin X, Davies E, Hajnóczky G. Bid-induced mitochondrial membrane permeabilization waves propagated by local reactive oxygen species (ROS) signaling. Proc Natl Acad Sci USA 2012; 109(12): 4497-502.
[http://dx.doi.org/10.1073/pnas.1118244109 ] [PMID: 22393005]
[34]
Naresh A, Venkateswara Rao M, Kotapalli SS, Ummanni R, Venkateswara Rao B. Oxazolidinone derivatives: cytoxazone-linezolid hybrids induces apoptosis and senescence in DU145 prostate cancer cells. Eur J Med Chem 2014; 80: 295-307.
[http://dx.doi.org/10.1016/j.ejmech.2014.04.062 ] [PMID: 24793880]
[35]
Palumbo Piccionello A, Musumeci R, Cocuzza C, et al. Synthesis and preliminary antibacterial evaluation of Linezolid-like 1,2,4-oxadiazole derivatives. Eur J Med Chem 2012; 50: 441-8.
[http://dx.doi.org/10.1016/j.ejmech.2012.02.002 ] [PMID: 22365410]
[36]
Kakeya H, Morishita M, Koshino H, Morita Ti T, Kobayashi K, Osada H. Cytoxazone: A Novel Cytokine Modulator Containing a 2-Oxazolidinone Ring Produced by Streptomyces sp. J Org Chem 1999; 64(3): 1052-3.
[http://dx.doi.org/10.1021/jo981922b ] [PMID: 11674189]
[37]
Carter PH, LaPorte JR, Scherle PA, Decicco CP. A new synthesis of cytoxazone and its diastereomers provides key initial SAR information. Bioorg Med Chem Lett 2003; 13(7): 1237-9.
[http://dx.doi.org/10.1016/S0960-894X(03)00131-8 ] [PMID: 12657253]
[38]
Ummanni R, Jost E, Braig M, et al. Ubiquitin carboxyl-terminal hydrolase 1 (UCHL1) is a potential tumour suppressor in prostate cancer and is frequently silenced by promoter methylation. Mol Cancer 2011; 10: 129.
[http://dx.doi.org/10.1186/1476-4598-10-129 ] [PMID: 21999842]
[39]
Pyne NJ, Pyne S. Sphingosine 1-phosphate and cancer. Nat Rev Cancer 2010; 10(7): 489-503.
[http://dx.doi.org/10.1038/nrc2875 ] [PMID: 20555359]
[40]
Schiffmann S, Sandner J, Birod K, et al. Ceramide synthases and ceramide levels are increased in breast cancer tissue. Carcinogenesis 2009; 30(5): 745-52.
[http://dx.doi.org/10.1093/carcin/bgp061 ] [PMID: 19279183]
[41]
Kinloch RA, Treherne JM, Furness LM, Hajimohamadreza I. The pharmacology of apoptosis. Trends Pharmacol Sci 1999; 20(1): 35-42.
[http://dx.doi.org/10.1016/S0165-6147(98)01277-2 ] [PMID: 10101960]
[42]
Sawai H, Hannun YA. Ceramide and sphingomyelinases in the regulation of stress responses. Chem Phys Lipids 1999; 102(1-2): 141-7.
[http://dx.doi.org/10.1016/S0009-3084(99)00082-1 ] [PMID: 11001568]
[43]
Burow ME, Weldon CB, Tang Y, et al. Differences in susceptibility to tumor necrosis factor alpha-induced apoptosis among MCF-7 breast cancer cell variants. Cancer Res 1998; 58(21): 4940-6.
[PMID: 9810003]
[44]
Webb LM, Arnholt AT, Venable ME. Phospholipase D modulation by ceramide in senescence. Mol Cell Biochem 2010; 337(1-2): 153-8.
[http://dx.doi.org/10.1007/s11010-009-0294-z ] [PMID: 19856145]
[45]
Bourbon NA, Sandirasegarane L, Kester M. Ceramide-induced inhibition of Akt is mediated through protein kinase Czeta: implications for growth arrest. J Biol Chem 2002; 277(5): 3286-92.
[http://dx.doi.org/10.1074/jbc.M110541200 ] [PMID: 11723139]
[46]
Fillet M, Bentires-Alj M, Deregowski V, et al. Mechanisms involved in exogenous C2- and C6-ceramide-induced cancer cell toxicity. Biochem Pharmacol 2003; 65(10): 1633-42.
[http://dx.doi.org/10.1016/S0006-2952(03)00125-4 ] [PMID: 12754099]
[47]
Ha H-J, Hong MC, Ko SW, Kim YW, Lee WK, Park J. Synthesis of constrained ceramide analogs and their potent antileukemic activities. Bioorg Med Chem Lett 2006; 16(7): 1880-3.
[http://dx.doi.org/10.1016/j.bmcl.2005.12.091 ] [PMID: 16455244]
[48]
Reynolds CP, Maurer BJ, Kolesnick RN. Ceramide synthesis and metabolism as a target for cancer therapy. Cancer Lett 2004; 206(2): 169-80.
[http://dx.doi.org/10.1016/j.canlet.2003.08.034 ] [PMID: 15013522]
[49]
Jarvis WD, Fornari FA Jr, Traylor RS, et al. Induction of apoptosis and potentiation of ceramide-mediated cytotoxicity by sphingoid bases in human myeloid leukemia cells. J Biol Chem 1996; 271(14): 8275-84.
[http://dx.doi.org/10.1074/jbc.271.14.8275 ] [PMID: 8626522]
[50]
Singh A, Kim B, Lee WK, Ha H-J. Asymmetric synthesis of 1-deoxyazasugars from chiral aziridines. Org Biomol Chem 2011; 9(5): 1372-80.
[http://dx.doi.org/10.1039/c0ob00730g ] [PMID: 21206946]
[51]
van Bokhoven A, Varella-Garcia M, Korch C, et al. Molecular characterization of human prostate carcinoma cell lines. Prostate 2003; 57(3): 205-25.
[http://dx.doi.org/10.1002/pros.10290 ] [PMID: 14518029]
[52]
Poirier D. Inhibitors of 17 beta-hydroxysteroid dehydrogenases. Curr Med Chem 2003; 10(6): 453-77.
[http://dx.doi.org/10.2174/0929867033368222 ] [PMID: 12570693]
[53]
Adamski J, Jakob FJ. A guide to 17beta-hydroxysteroid dehydrogenases. Mol Cell Endocrinol 2001; 171(1-2): 1-4.
[http://dx.doi.org/10.1016/S0303-7207(00)00383-X ] [PMID: 11165003]
[54]
Koh E, Noda T, Kanaya J, Namiki M. Differential expression of 17beta-hydroxysteroid dehydrogenase isozyme genes in prostate cancer and noncancer tissues. Prostate 2002; 53(2): 154-9.
[http://dx.doi.org/10.1002/pros.10139 ] [PMID: 12242730]
[55]
Vicker N, Sharland CM, Heaton WB, et al. The design of novel 17β-hydroxysteroid dehydrogenase type 3 inhibitors. Mol Cell Endocrinol 2009; 301(1-2): 259-65.
[http://dx.doi.org/10.1016/j.mce.2008.08.005 ] [PMID: 18775469]
[56]
Radi M, Botta L, Casaluce G, Bernardini M, Botta M. Practical one-pot two-step protocol for the microwave-assisted synthesis of highly functionalized rhodanine derivatives. J Comb Chem 2010; 12(1): 200-5.
[http://dx.doi.org/10.1021/cc9001789 ] [PMID: 20028090]
[57]
Jones G. The Knoevenagel condensation. Org React 1967; 15: 204-599.
[58]
Harada K, Kubo H, Tanaka A, Nishioka K. Identification of oxazolidinediones and thiazolidinediones as potent 17β-hydroxysteroid dehydrogenase type 3 inhibitors. Bioorg Med Chem Lett 2012; 22(1): 504-7.
[http://dx.doi.org/10.1016/j.bmcl.2011.10.095 ] [PMID: 22137341]
[59]
Bechard P, Lacroix J, Poyet P, Gaudreault RC. Synthesis and cytotoxic activity of new alkyl-[3-(chloroethyl)ureido] benzene derivatives. Eur J Med Chem 1994; 29(12): 963-6.
[http://dx.doi.org/10.1016/0223-5234(94)90196-1]
[60]
Lacroix J, Gaudreault RC, Pagé M, Joly LP. In vitro and in vivo activity of 1-aryl-3-(2-chloroethyl) urea derivatives as new antineoplastic agents. Anticancer Res 1988; 8(4): 595-8.
[PMID: 3052247]
[61]
Gaudreault RC, Lacroix J, Pagé M, Joly LP. 1-Aryl-3-(2-chloroethyl) ureas: synthesis and in vitro assay as potential anticancer agents. J Pharm Sci 1988; 77(2): 185-7.
[http://dx.doi.org/10.1002/jps.2600770218 ] [PMID: 3361435]
[62]
Petitclerc E, Deschesnes RG, Côté MF, et al. Antiangiogenic and antitumoral activity of phenyl-3-(2-chloroethyl)ureas: a class of soft alkylating agents disrupting microtubules that are unaffected by cell adhesion-mediated drug resistance. Cancer Res 2004; 64(13): 4654-63.
[http://dx.doi.org/10.1158/0008-5472.CAN-03-3715 ] [PMID: 15231678]
[63]
Gaudreault RC, Alaui-Jamali MA, Batist G, Béchard P, Lacroix J, Poyet P. Lack of cross-resistance to a new cytotoxic arylchloroethyl urea in various drug-resistant tumor cells. Cancer Chemother Pharmacol 1994; 33(6): 489-92.
[http://dx.doi.org/10.1007/BF00686506 ] [PMID: 8137459]
[64]
Miot-Noirault E, Legault J, Cachin F, et al. Antineoplastic potency of arylchloroethylurea derivatives in murine colon carcinoma. Invest New Drugs 2004; 22(4): 369-78.
[http://dx.doi.org/10.1023/B:DRUG.0000036679.12112.4c ] [PMID: 15292707]
[65]
Mounetou E, Legault J, Lacroix J. C-Gaudreault R. Antimitotic antitumor agents: synthesis, structure-activity relationships, and biological characterization of N-aryl-N'-(2-chloroethyl)ureas as new selective alkylating agents. J Med Chem 2001; 44(5): 694-702.
[http://dx.doi.org/10.1021/jm0010264 ] [PMID: 11262080]
[66]
Legault J, Gaulin JF, Mounetou E, et al. Microtubule disruption induced in vivo by alkylation of beta-tubulin by 1-aryl-3-(2-chloroethyl)ureas, a novel class of soft alkylating agents. Cancer Res 2000; 60(4): 985-92.
[PMID: 10706114]
[67]
Fleury C, Mignotte B, Vayssière JL. Mitochondrial reactive oxygen species in cell death signaling. Biochimie 2002; 84(2-3): 131-41.
[http://dx.doi.org/10.1016/S0300-9084(02)01369-X ] [PMID: 12022944]
[68]
Singh KK, Russell J, Sigala B, Zhang Y, Williams J, Keshav KF. Mitochondrial DNA determines the cellular response to cancer therapeutic agents. Oncogene 1999; 18(48): 6641-6.
[http://dx.doi.org/10.1038/sj.onc.1203056 ] [PMID: 10597269]
[69]
Lee HC, Yin PH, Lin JC, et al. Mitochondrial genome instability and mtDNA depletion in human cancers. Ann N Y Acad Sci 2005; 1042: 109-22.
[http://dx.doi.org/10.1196/annals.1338.011 ] [PMID: 15965052]
[70]
Lemasters JJ, Holmuhamedov E. Voltage-dependent anion channel (VDAC) as mitochondrial governator--thinking outside the box. Biochim Biophys Acta 2006; 1762(2): 181-90.
[http://dx.doi.org/10.1016/j.bbadis.2005.10.006 ] [PMID: 16307870]
[71]
Tsujimoto Y, Shimizu S. The voltage-dependent anion channel: an essential player in apoptosis. Biochimie 2002; 84(2-3): 187-93.
[http://dx.doi.org/10.1016/S0300-9084(02)01370-6 ] [PMID: 12022949]
[72]
Nukui Y, Hatakeyama S, Okamoto K, et al. High plasma linezolid concentration and impaired renal function affect development of linezolid-induced thrombocytopenia. J Antimicrob Chemother 2013; 68(9): 2128-33.
[http://dx.doi.org/10.1093/jac/dkt133 ] [PMID: 23625638]
[73]
Lopez-Garcia B, Luque S, Roberts JA, Grau S. Pharmacokinetics and preliminary safety of high dose linezolid for the treatment of Gram-positive bacterial infections. J Infect 2015; 71(5): 604-7.
[http://dx.doi.org/10.1016/j.jinf.2015.06.007 ] [PMID: 26099449]
[74]
Macherla VRR, Nicholson B, Lam KS. U.S. Patent 7,879,892, 2008.
[75]
Michalska K, Karpiuk I, Król M, Tyski S. Recent development of potent analogues of oxazolidinone antibacterial agents. Bioorg Med Chem 2013; 21(3): 577-91.
[http://dx.doi.org/10.1016/j.bmc.2012.11.036 ] [PMID: 23273607]
[76]
Ali A, Reddy GS, Nalam MN, et al. Structure-based design, synthesis, and structure-activity relationship studies of HIV-1 protease inhibitors incorporating phenyloxazolidinones. J Med Chem 2010; 53(21): 7699-708.
[http://dx.doi.org/10.1021/jm1008743 ] [PMID: 20958050]
[77]
Kloss P, Xiong L, Shinabarger DL, Mankin AS. Resistance mutations in 23 S rRNA identify the site of action of the protein synthesis inhibitor linezolid in the ribosomal peptidyl transferase center. J Mol Biol 1999; 294(1): 93-101.
[http://dx.doi.org/10.1006/jmbi.1999.3247 ] [PMID: 10556031]

Rights & Permissions Print Cite
Article Metrics
43
© 2024 Bentham Science Publishers | Privacy Policy