Abstract
From the recent studies, 3,5-dibenzoyl-1,4-dihydropyridone (DHP) derivatives, DP-7, has emerged as a potent multidrug reverting agent that inhibits efflux of drug from cell wall by inhibiting the activity of ATP Binding Cassettes. On the other hand, dihydropyrimidine (DHPM) derivative, (aza analogue) namely, monastrol inhibits the protein Eg5, which is responsible for the separation of daughter chromosomes during cell division and controls the growth of the tumor cells. In the present report, we have reported the hybridize molecules of these two potent molecules to check the dual action in cancer chemotherapy by synthesizing various thio and oxo analogues, bearing substituted aryl groups at 4th position of the DHPM ring. The newly synthesized molecules were screened for antiproliferative effects in mdr1-gene transfected mouse lymphoma cell line (l5178 y). Among these newly synthesized compounds namely, II h, I g, I i, and I j showed a very potent antiproliferative activity.
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Alderighi D, Sgaragli T, Dragoni S, Frosini M, Valoti M, Saponara S, Fusi F, Shah A, Kawasae M, Motohashi N, Molnar J, Sgaragli, G. 33rd National Conference of the Italian Society of Pharmacology, Cagliari, Italy, June 6–9, 2007
Alexander JS, Ardy VH, Gerrit VM, Katalin S, Ervin W, Gergely S, Andras V, Balazs S, Piet B (2000) MDR3 P-glycoprotein, a phosphatidylcholine translocase, transports several cytotoxic drugs and directly interacts with drugs as judged by interference with nucleotide trapping. J Biol Chem 275:23530–23539. doi:10.1074/jbc.M909002199
Biginelli P, Gazz P (1893) Synthesis of 3,4-dihydropyrimidin-2(1H)-ones. Chim Ital 23:360–413
Borst P, Evers R, Kool M, Wijnholds J (2000) A family of drug transporters: the multidrug-resistance associated proteins. J Natl Cancer Inst 92:1295–1302. doi:10.1093/jnci/92.16.1295
Brier S, Lemaire D, DeBonis S, Forest E, Kozielski F (2004) Identification of the protein binding region of S-trityl-l-cysteine, a new potent inhibitor of the mitotic kinesin Eg5. Biochemistry 43:13072–13082. doi:10.1021/bi049264e
Chen CJ, Chin JE, Ueda K, Clark DP, Pastan I, Gottesman MM, Roninson IB (1986) Internal duplication and homology with bacterial transport proteins in the mdr1 (P-glycoprotein) gene from multidrug-resistant human cells. Cell 47:381–389. doi:10.1016/0092-8674(86)90595-7
Cochran JC, Gatial JE, Kapoor TM, Gilbert SP (2005) Monastrol inhibition of the mitotic kinesin Eg5. J Biol Chem 280:12658–12667. doi:10.1074/jbc.M413140200
Cole SP, Bhardwaj G, Gerlach JH, Mackie JE, Grant CE, Almquist KC, Stewart AJ, Kurz EU, Duncan AM, Deeley RG (1992) Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 258:1650–1654. doi:10.1126/science.1360704
Deeley RG, Cole SP (1997) Function, evolution and structure of multidrug-resistance protein (MRP). Semin Cancer Biol 8:193–204. doi:10.1006/scbi.1997.0070
Endicott JA, Ling V (1989) The biochemistry of P-glycoprotein-mediated multidrug-resistance. Annu Rev Biochem 58:137–171. doi:10.1146/annurev.bi.58.070189.001033
Ferry DR, Malkandi PJ, Russell MA, Kerr DJ (1995) Allosteric regulation of [3H] vinblastine binding to P-glycoprotein of MCF-7 ADR cells by dexniguldipine. Biochem Pharmacol 49:1851–1861. doi:10.1016/0006-2952(95)02078-0
Furniss BS, Hannaford AJ, Smith PWG, Tatchell AR (1998) In Vogel’s text book of practical organic chemistry, 5th edn. Addison-Wesley Longman, Harlow, pp 634–635
Fusi F, Saponara S, Valoti M, Dragoni SD, Ela P, Sgaragli T, Alderighi D, Kawase M, Shah A, Motohashi N, Sgaragli G (2006) Cancer cell permeability-glycoprotein as a target of MDR reverters: possible role of novel dihydropyridine derivatives. Curr Drug Targets 7:949–959
Gottesman MM, Pastan I (1993) Biochemistry of multidrug-resistance mediated by the multidrug transporter. Annu Rev Biochem 62:385–427. doi:10.1146/annurev.bi.62.070193.002125
Gottesman MM, Fojo T, Bates SE (2002) Multidrug-resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2:48–58. doi:10.1038/nrc706
Heald R (2000) Motor function in the mitotic spindle. Cell 102:399–402. doi:10.1016/S0092-8674(00)00044-1
Higgins CF (1992) ABC transporters: from microorganisms to man. Annu Rev Cell Biol 8:67–113. doi:10.1146/annurev.cb.08.110192.000435
Hofmann J, Wolf A, Spitaler M, Bock G, Drach J, Ludescher C, Grunicke HH (1992) Reversal of multidrug- resistance by B859–35, a metabolite of B859–35, niguldipine, verapamil and nitrendipine. J Cancer Res Clin Oncol 118:361–366. doi:10.1007/BF01294440
Hollt V, Kouba M, Dietel M, Vogt G (1992) Stereoisomers of calcium antagonists which differ markedly in their potencies as calcium blockers are equally effective in modulating drug transport by P-glycoprotein. Biochem Pharmacol 43:2601–2608. doi:10.1016/0006-2952(92)90149-D
Jauk B, Pernat T, Kappe CO (2000) Design and synthesis of a conformationally rigid mimic of the dihydropyrimidine calcium channel modulator SQ32, 926. Molecules 5:227–239
Juliano RL, Ling VA (1976) Surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 455:152–162
Kappe CO (1993) 100 Years of the Biginelli dihydropyrimidine synthesis. Tetrahedron 49:6937–6963. doi:10.1016/S0040-4020(01)87971-0
Kappe CO (1998) 4-Aryldihydropyrimidines via the Biginelli condensation: aza-analogs of nifedipine-type calcium channel nodulators. Molecules 3:1–9
Kappe CO (2000a) Recent advances in the Biginelli dihydropyrimidine synthesis. New tricks from an old dog. Acc Chem Res 33:879–888. doi:10.1021/ar000048h
Kappe CO (2000b) Biologically active dihydripyrimidones of the Bignelli-type. A literature survey. Eur J Med Chem 35:1043–1052. doi:10.1016/S0223-5234(00)01189-2
Kappe CO (2003) The generation of dihydropyrimidine libraries utilizing Biginelli multicomponent chemistry. QSAR Comb Sci 22:630–645
Kool M, Haas M, Scheffer GL, Scheper RJ, Vaneijk MJ, Juijn JA, Baas F, Borst P (1997) Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug-resistance associated protein gene (MRP1), in human cancer cell lines. Cancer Res 57:3537–3547
Lecureur V, Courtois A, Payen L, Verhnet L, Guillouzo A, Fardel O (2000) Expression and regulation of hepatic drug and bile acid transporters. Toxicology 153:203–219. doi:10.1016/S0300-483X(00)00315-2
Litman T, Druley TE, Stein WD, Bates SE (2001) From MDR to MXR: new understanding of multidrug- resistance systems, their properties and clinical significance. Cell Mol Life Sci 58:931–959
Malkandi PJ, Ferry DR, Boer R, Gekeler V, Ise W, Kerr DJ (1994) Dexniguldipine-Hcl is a potent allosteric inhibitor of [3H] vinblastine binding to P-glycoprotein of CCRF ADR 500 cells. Eur J Pharmacol Mol Pharmacol 288:105–114
Mayer TU, Kapoor TM, Haggarty SJ, King RW, Schreiber SI, Mitchison TJ (1999) Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science 268:971–974. doi:10.1126/science.286.5441.971
Molnar J, Gyemant N, Tanaka M, Hohmann J, Bergmann-Leitner E, Molnar P, Deli J, Diziapetris R, Ferreira MJU (2006) Inhibition of multidrug-resistance of cancer cells by natural diterpenes, triterpenes and carotenoids. Curr Pharm Design 12:287–311
Paulusma CC, Bosma PJ, Zaman GJR, Bakker CTM, Otter M, Scheffer GL, Scheper RJ, Borst P, Elferink RPJO (1996) Congenital jaundice in rats with a mutation in a multidrug-resistance associated protein gene. Science 271:1126–1128. doi:10.1126/science.271.5252.1126
Paulusma CC, Kool M, Bosma PJ, Scheffer GL, Terborg F, Scheper RJ, Tytgat GNJ, Borst P, Baas F, OudeElferink RPJ (1997) A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin–Johnson syndrome. Hepatology 25:1539–1542. doi:10.1002/hep.510250635
Peters T, Lindenmaier H, Haefeli WE, Weiss J (2006) Interaction of the mitotic kinesin Eg5 inhibitor monastrol with P-glycoprotein. Arch Pharmacol 372:291–299
Rampe D, Triggle DJ (1993) New synthetic ligands for L-type voltage-gated calcium channels. Prog Drug Res 40:191–238
Russowsky D, Canto RFS, Sanches SAA, Doca MGM, Fatima AN, Pilli RA, Kohn LK, Antonio MA, Carvalho JE (2006) Synthesis and differential antiproliferative activity of Bignelli compounds against cancer cell lines: monastrol, oxo monastrol and oxygenated analogues. Bioorg Chem 34:173–182. doi:10.1016/j.bioorg.2006.04.003
Sakowicz R, Finer JT, Beraud C, Crompton A, Lewis E, Fritsch A, Lee Y, Mak J, Moody R, Turincio R, Chabal JC, Gonzales P, Roth S, Weitman S, Wood KW (2004) Potentiation of Antitumor activity of a kinesin inhibitor. Cancer Res 64:3276–3280. doi:10.1158/0008-5472
Saponara S, Ferrara A, Gorelli B, Shah A, Kawase M, Motohashi N, Molnar J, Sgaragli G, Fusi F (2007) 3,5-dibenzoyl-4-(3-phenoxyphenyl)-1,4-dihydro-2,6-dimethylpyridine (DP7): a new multidrug-resistance inhibitor devoid of effects on Langendorff-perfused rat heart. Eur J Pharmacol 563:160–163. doi:10.1016/j.ejphar.2007.02.001
Szabo D, Molnar J (2006) The role of stereoselectivity of chemosensitizers in the reversal of multidrug- resistance of mouse lymphoma cells. Anticancer Res 18:3039–3044
Triggle DJ (2003) Drug targets in the voltage-gated calcium channel family: why some are and some are not. Assay Drug Dev Technol 1:719–733. doi:10.1089/154065803770381075
Tsuruo T, Iida H, Tsukagoshi S, Sakura Y (1983) Circumvention of vincristine and adriamycin resistance in vitro and in vivo by calcium influx blocker. Cancer Res 43:2267–2272
Ueda K, Cardarelli C, Gottesman MM, Pastan I (1987) Expression of a full-length cDNA for the human “MDR1” gene confers resistance to colchicine, doxorubicin, and vinblastine. Proc Natl Acad Sci 84:3004–3008
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Bariwal, J.J., Malhotra, M., Molnar, J. et al. Synthesis, characterization and anticancer activity of 3-aza-analogues of DP-7. Med Chem Res 21, 4002–4009 (2012). https://doi.org/10.1007/s00044-011-9925-5
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DOI: https://doi.org/10.1007/s00044-011-9925-5