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Medicinal Chemistry Research

, Volume 21, Issue 12, pp 4002–4009 | Cite as

Synthesis, characterization and anticancer activity of 3-aza-analogues of DP-7

  • Jalpa J. Bariwal
  • Manav Malhotra
  • Joseph Molnar
  • Kishor S. Jain
  • Anamik K. Shah
  • Jitender B. Bariwal
Original Research

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.

Keywords

Dihydropyrimidines DP-7 Anticancer MDR reverting agents 

References

  1. 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, 2007Google Scholar
  2. 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 CrossRefGoogle Scholar
  3. Biginelli P, Gazz P (1893) Synthesis of 3,4-dihydropyrimidin-2(1H)-ones. Chim Ital 23:360–413Google Scholar
  4. 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 PubMedCrossRefGoogle Scholar
  5. 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 PubMedCrossRefGoogle Scholar
  6. 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 PubMedCrossRefGoogle Scholar
  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 PubMedCrossRefGoogle Scholar
  8. 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 PubMedCrossRefGoogle Scholar
  9. 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 PubMedCrossRefGoogle Scholar
  10. 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 PubMedCrossRefGoogle Scholar
  11. 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 PubMedCrossRefGoogle Scholar
  12. 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 634–635Google Scholar
  13. 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 7:949–959PubMedCrossRefGoogle Scholar
  14. 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 PubMedCrossRefGoogle Scholar
  15. 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 PubMedCrossRefGoogle Scholar
  16. Heald R (2000) Motor function in the mitotic spindle. Cell 102:399–402. doi: 10.1016/S0092-8674(00)00044-1 PubMedCrossRefGoogle Scholar
  17. Higgins CF (1992) ABC transporters: from microorganisms to man. Annu Rev Cell Biol 8:67–113. doi: 10.1146/annurev.cb.08.110192.000435 PubMedCrossRefGoogle Scholar
  18. 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 PubMedCrossRefGoogle Scholar
  19. 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 PubMedCrossRefGoogle Scholar
  20. Jauk B, Pernat T, Kappe CO (2000) Design and synthesis of a conformationally rigid mimic of the dihydropyrimidine calcium channel modulator SQ32, 926. Molecules 5:227–239CrossRefGoogle Scholar
  21. Juliano RL, Ling VA (1976) Surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 455:152–162PubMedCrossRefGoogle Scholar
  22. Kappe CO (1993) 100 Years of the Biginelli dihydropyrimidine synthesis. Tetrahedron 49:6937–6963. doi: 10.1016/S0040-4020(01)87971-0 CrossRefGoogle Scholar
  23. Kappe CO (1998) 4-Aryldihydropyrimidines via the Biginelli condensation: aza-analogs of nifedipine-type calcium channel nodulators. Molecules 3:1–9CrossRefGoogle Scholar
  24. 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 PubMedCrossRefGoogle Scholar
  25. 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 PubMedCrossRefGoogle Scholar
  26. Kappe CO (2003) The generation of dihydropyrimidine libraries utilizing Biginelli multicomponent chemistry. QSAR Comb Sci 22:630–645CrossRefGoogle Scholar
  27. 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 57:3537–3547PubMedGoogle Scholar
  28. 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 PubMedCrossRefGoogle Scholar
  29. 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 58:931–959PubMedCrossRefGoogle Scholar
  30. 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 288:105–114CrossRefGoogle Scholar
  31. 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 CrossRefGoogle Scholar
  32. 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 12:287–311CrossRefGoogle Scholar
  33. 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 PubMedCrossRefGoogle Scholar
  34. 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 PubMedCrossRefGoogle Scholar
  35. Peters T, Lindenmaier H, Haefeli WE, Weiss J (2006) Interaction of the mitotic kinesin Eg5 inhibitor monastrol with P-glycoprotein. Arch Pharmacol 372:291–299CrossRefGoogle Scholar
  36. Rampe D, Triggle DJ (1993) New synthetic ligands for L-type voltage-gated calcium channels. Prog Drug Res 40:191–238PubMedGoogle Scholar
  37. 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 PubMedCrossRefGoogle Scholar
  38. 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 PubMedCrossRefGoogle Scholar
  39. 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 PubMedCrossRefGoogle Scholar
  40. Szabo D, Molnar J (2006) The role of stereoselectivity of chemosensitizers in the reversal of multidrug- resistance of mouse lymphoma cells. Anticancer Res 18:3039–3044Google Scholar
  41. 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 PubMedCrossRefGoogle Scholar
  42. 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 43:2267–2272PubMedGoogle Scholar
  43. 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 84:3004–3008PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Jalpa J. Bariwal
    • 1
    • 4
  • Manav Malhotra
    • 1
  • Joseph Molnar
    • 2
  • Kishor S. Jain
    • 3
  • Anamik K. Shah
    • 4
  • Jitender B. Bariwal
    • 1
    • 4
    • 5
  1. 1.Department of Pharmaceutical ChemistryISF College of PharmacyMogaIndia
  2. 2.Department of Medical Microbiology and Immunobiology, Faculty of MedicineUniversity of SzegedSzegedHungary
  3. 3.Sinhgad College of PharmacyPuneIndia
  4. 4.Department of ChemistrySaurashtra UniversityRajkotIndia
  5. 5.Department of Medicinal ChemistryISF College of PharmacyMogaIndia

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