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ARQ-501 (beta lapachone)

   

Description of ARQ-501: ARQ-501 is a naphthoquinone compound derived from bark of Tabebuia sp., with antitumor, antibacterial, antifungal and antitrypanosomal activities. Beta-lapachone exerts its anti-tumor effect by indirect actions of inducing p53-independent apoptosis and cell cycle arrest mediated through altered activities of cell cycle control regulatory proteins; including down-regulating retinoblastoma protein (pRB), a transcriptional repressor target at transcription factor E2F-1, as well as induces expression of cyclin dependent kinase inhibitor 1A (CDKN1A or p21). Both E2F-1 and p21 are required for G1/S-phase transition during cell cycle. This agent also inhibits DNA topoisomerase I by a mechanism distinct from that of camptothecin, and thereby blocks the formation of a cleavable complex leading to enzyme inhibition and prevent DNA repair. Furthermore, beta-lapachone could induce reactive oxygen species in vivo, and result in cytotoxicity. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

 

Current developer:  ArQule, Inc.

  

MedKoo Cat#: 200284

Name: ARQ-501 (beta lapachone)

CAS#:  4707-32-8

 

Synonym: ARQ-501, beta lapachone; 3,4-Dihydro-2,2-dimethyl-2H-naphtho(1,2-b)pyran-5,6-dione.

  

IUPAC/Chemical name:

2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione

Chemical structure

Theoretical analysis

 

 

  

Chemical Formula: C15H14O3

Exact Mass: 242.09429

Molecular Weight: 242.27

Elemental Analysis: C, 74.36; H, 5.82; O, 19.81

   

 

Availability and price:

   

 ARQ-501 is available through custom synthesis.

 

To inquire the quotation and lead time of custom synthesis for this agent, please send email to sales@medkoo.com to describe your needs. A representative will respond your email shortly. We offer big discount for orders of bulk quantities.

 

Quality control data:

Product will be shipped with supporting analytical data.

 

 

Information about this agent

 

References

  1: Bae JH, Kim JW, Kweon GR, Park MG, Jeong KH, Kim JJ, Moon DG. Corpus Cavernosal Smooth Muscle Relaxation Effect of a Novel AMPK Activator, Beta-Lapachone. J Sex Med. 2010 May 11. [Epub ahead of print] PubMed PMID: 20487243.

2: Blanco E, Bey EA, Khemtong C, Yang SG, Setti-Guthi J, Chen H, Kessinger CW, Carnevale KA, Bornmann WG, Boothman DA, Gao J. Beta-lapachone micellar nanotherapeutics for non-small cell lung cancer therapy. Cancer Res. 2010 May 15;70(10):3896-904. Epub 2010 May 11. PubMed PMID: 20460521; PubMed Central PMCID: PMC2873165.

3: Moon DO, Kang CH, Kim MO, Jeon YJ, Lee JD, Choi YH, Kim GY. beta-Lapachone (LAPA) Decreases Cell Viability and Telomerase Activity in Leukemia Cells: Suppression of Telomerase Activity by LAPA. J Med Food. 2010 May 3. [Epub ahead of print] PubMed PMID: 20438329.

4: da Silva EN Jr, Guimarães TT, Menna-Barreto RF, Pinto Mdo C, de Simone CA, Pessoa C, Cavalcanti BC, Sabino JR, Andrade CK, Goulart MO, de Castro SL, Pinto AV. The evaluation of quinonoid compounds against Trypanosoma cruzi: synthesis of imidazolic anthraquinones, nor-beta-lapachone derivatives and beta-lapachone-based 1,2,3-triazoles. Bioorg Med Chem. 2010 May 1;18(9):3224-30. Epub 2010 Mar 16. PubMed PMID: 20378360.

5: da Silva EN Jr, de Deus CF, Cavalcanti BC, Pessoa C, Costa-Lotufo LV, Montenegro RC, de Moraes MO, Pinto Mdo C, de Simone CA, Ferreira VF, Goulart MO, Andrade CK, Pinto AV. 3-arylamino and 3-alkoxy-nor-beta-lapachone derivatives: synthesis and cytotoxicity against cancer cell lines. J Med Chem. 2010 Jan 14;53(1):504-8. PubMed PMID: 19947600.

6: D'Anneo A, Augello G, Santulli A, Giuliano M, di Fiore R, Messina C, Tesoriere G, Vento R. Paclitaxel and beta-lapachone synergistically induce apoptosis in human retinoblastoma Y79 cells by downregulating the levels of phospho-Akt. J Cell Physiol. 2010 Feb;222(2):433-43. PubMed PMID: 19918798.

7: Terai K, Dong GZ, Oh ET, Park MT, Gu Y, Song CW, Park HJ. Cisplatin enhances the anticancer effect of beta-lapachone by upregulating NQO1. Anticancer Drugs. 2009 Nov;20(10):901-9. PubMed PMID: 19738461.

8: Dong GZ, Youn H, Park MT, Oh ET, Park KH, Song CW, Choi EK, Park HJ. Heat shock increases expression of NAD(P)H:quinone oxidoreductase (NQO1), mediator of beta-lapachone cytotoxicity, by increasing NQO1 gene activity and via Hsp70-mediated stabilisation of NQO1 protein. Int J Hyperthermia. 2009;25(6):477-87. PubMed PMID: 19657853.

9: Jeong SY, Park SJ, Yoon SM, Jung J, Woo HN, Yi SL, Song SY, Park HJ, Kim C, Lee JS, Lee JS, Choi EK. Systemic delivery and preclinical evaluation of Au nanoparticle containing beta-lapachone for radiosensitization. J Control Release. 2009 Nov 3;139(3):239-45. Epub 2009 Jul 18. PubMed PMID: 19619590.

10: Salustiano EJ, Netto CD, Fernandes RF, da Silva AJ, Bacelar TS, Castro CP, Buarque CD, Maia RC, Rumjanek VM, Costa PR. Comparison of the cytotoxic effect of lapachol, alpha-lapachone and pentacyclic 1,4-naphthoquinones on human leukemic cells. Invest New Drugs. 2010 Apr;28(2):139-44. Epub 2009 Mar 4. PubMed PMID: 19255723.

11: de Almeida ER, Lucena FR, Silva CV, da Silva Costa-Junior W, Cavalcanti JB, Couto GB, da Silva LL, da Mota DL, da Silveira AB, de Sousa Filho SD, da Silva AC. Toxicological assessment of beta-lapachone on organs from pregnant and non-pregnant rats. Phytother Res. 2009 Sep;23(9):1276-80. PubMed PMID: 19197915.

12: Ferreira DC, Tapsoba I, Arbault S, Bouret Y, Alexandre Moreira MS, Ventura Pinto A, Goulart MO, Amatore C. Ex vivo activities of beta-lapachone and alpha-lapachone on macrophages: a quantitative pharmacological analysis based on amperometric monitoring of oxidative bursts by single cells. Chembiochem. 2009 Feb 13;10(3):528-38. PubMed PMID: 19123194.

13: Dong Y, Chin SF, Blanco E, Bey EA, Kabbani W, Xie XJ, Bornmann WG, Boothman DA, Gao J. Intratumoral delivery of beta-lapachone via polymer implants for prostate cancer therapy. Clin Cancer Res. 2009 Jan 1;15(1):131-9. PubMed PMID: 19118040; PubMed Central PMCID: PMC2845536.

14: Miao XS, Zhong C, Wang Y, Savage RE, Yang RY, Kizer D, Volckova E, Ashwell MA, Chan TC. In vitro metabolism of beta-lapachone (ARQ 501) in mammalian hepatocytes and cultured human cells. Rapid Commun Mass Spectrom. 2009 Jan;23(1):12-22. PubMed PMID: 19051226.

15: Hernández DM, de Moura MA, Valencia DP, González FJ, González I, de Abreu FC, da Silva Júnior EN, Ferreira VF, Pinto AV, Goulart MO, Frontana C. Inner reorganization during the radical-biradical transition in a nor-beta-lapachone derivative possessing two redox centers. Org Biomol Chem. 2008 Sep 21;6(18):3414-20. Epub 2008 Jul 16. PubMed PMID: 18802650.

16: Netto-Ferreira JC, Lhiaubet-Vallet V, de Oliveira Bernardes B, Ferreira AB, Miranda MA. Photosensitizing properties of triplet beta-lapachones in acetonitrile solution. Photochem Photobiol. 2009 Jan-Feb;85(1):153-9. Epub 2008 Jul 30. PubMed PMID: 18673323.

17: Yang RY, Kizer D, Wu H, Volckova E, Miao XS, Ali SM, Tandon M, Savage RE, Chan TC, Ashwell MA. Synthetic methods for the preparation of ARQ 501 (beta-Lapachone) human blood metabolites. Bioorg Med Chem. 2008 May 15;16(10):5635-43. Epub 2008 Apr 1. PubMed PMID: 18424157.

18: Cunha-Filho MS, Martínez-Pacheco R, Landín M. Dissolution rate enhancement of the novel antitumoral beta-lapachone by solvent change precipitation of microparticles. Eur J Pharm Biopharm. 2008 Aug;69(3):871-7. Epub 2008 Feb 23. PubMed PMID: 18395431.

19: Savage RE, Tyler AN, Miao XS, Chan TC. Identification of a novel glucosylsulfate conjugate as a metabolite of 3,4-dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione (ARQ 501, beta-lapachone) in mammals. Drug Metab Dispos. 2008 Apr;36(4):753-8. Epub 2008 Jan 28. PubMed PMID: 18227145.

20: Miao XS, Song P, Savage RE, Zhong C, Yang RY, Kizer D, Wu H, Volckova E, Ashwell MA, Supko JG, He X, Chan TC. Identification of the in vitro metabolites of 3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione (ARQ 501; beta-lapachone) in whole blood. Drug Metab Dispos. 2008 Apr;36(4):641-8. Epub 2008 Jan 7. PubMed PMID: 18180274.

21: Salas C, Tapia RA, Ciudad K, Armstrong V, Orellana M, Kemmerling U, Ferreira J, Maya JD, Morello A. Trypanosoma cruzi: activities of lapachol and alpha- and beta-lapachone derivatives against epimastigote and trypomastigote forms. Bioorg Med Chem. 2008 Jan 15;16(2):668-74. Epub 2007 Oct 18. PubMed PMID: 18029184.

22: Cunha-Filho MS, Martínez-Pacheco R, Landín M. Compatibility of the antitumoral beta-lapachone with different solid dosage forms excipients. J Pharm Biomed Anal. 2007 Nov 30;45(4):590-8. Epub 2007 Aug 19. PubMed PMID: 17890039.

23: da Silva Júnior EN, de Souza MC, Pinto AV, Pinto Mdo C, Goulart MO, Barros FW, Pessoa C, Costa-Lotufo LV, Montenegro RC, de Moraes MO, Ferreira VF. Synthesis and potent antitumor activity of new arylamino derivatives of nor-beta-lapachone and nor-alpha-lapachone. Bioorg Med Chem. 2007 Nov 15;15(22):7035-41. Epub 2007 Aug 22. PubMed PMID: 17827021.

24: Bentle MS, Reinicke KE, Dong Y, Bey EA, Boothman DA. Nonhomologous end joining is essential for cellular resistance to the novel antitumor agent, beta-lapachone. Cancer Res. 2007 Jul 15;67(14):6936-45. PubMed PMID: 17638905.

25: Bey EA, Bentle MS, Reinicke KE, Dong Y, Yang CR, Girard L, Minna JD, Bornmann WG, Gao J, Boothman DA. An NQO1- and PARP-1-mediated cell death pathway induced in non-small-cell lung cancer cells by beta-lapachone. Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11832-7. Epub 2007 Jul 3. PubMed PMID: 17609380; PubMed Central PMCID: PMC1913860.

26: Blanco E, Bey EA, Dong Y, Weinberg BD, Sutton DM, Boothman DA, Gao J. Beta-lapachone-containing PEG-PLA polymer micelles as novel nanotherapeutics against NQO1-overexpressing tumor cells. J Control Release. 2007 Oct 8;122(3):365-74. Epub 2007 Apr 29. PubMed PMID: 17574288; PubMed Central PMCID: PMC2064869.

27: Moon DO, Choi YH, Kim ND, Park YM, Kim GY. Anti-inflammatory effects of beta-lapachone in lipopolysaccharide-stimulated BV2 microglia. Int Immunopharmacol. 2007 Apr;7(4):506-14. Epub 2007 Jan 16. PubMed PMID: 17321474.

28: Kung HN, Chien CL, Chau GY, Don MJ, Lu KS, Chau YP. Involvement of NO/cGMP signaling in the apoptotic and anti-angiogenic effects of beta-lapachone on endothelial cells in vitro. J Cell Physiol. 2007 May;211(2):522-32. PubMed PMID: 17192848.

29: Menacho-Márquez M, Murguía JR. Beta-lapachone activates a Mre11p-Tel1p G1/S checkpoint in budding yeast. Cell Cycle. 2006 Nov 1;5(21):2509-16. Epub 2006 Sep 12. PubMed PMID: 17106258.

30: Sun X, Li Y, Li W, Zhang B, Wang AJ, Sun J, Mikule K, Jiang Z, Li CJ. Selective induction of necrotic cell death in cancer cells by beta-lapachone through activation of DNA damage response pathway. Cell Cycle. 2006 Sep;5(17):2029-35. Epub 2006 Sep 1. PubMed PMID: 16969131.

31: Wang F, Blanco E, Ai H, Boothman DA, Gao J. Modulating beta-lapachone release from polymer millirods through cyclodextrin complexation. J Pharm Sci. 2006 Oct;95(10):2309-19. PubMed PMID: 16883563.

32: Woo HJ, Park KY, Rhu CH, Lee WH, Choi BT, Kim GY, Park YM, Choi YH. Beta-lapachone, a quinone isolated from Tabebuia avellanedae, induces apoptosis in HepG2 hepatoma cell line through induction of Bax and activation of caspase. J Med Food. 2006 Summer;9(2):161-8. PubMed PMID: 16822200.

33: Lee JI, Choi DY, Chung HS, Seo HG, Woo HJ, Choi BT, Choi YH. beta-lapachone induces growth inhibition and apoptosis in bladder cancer cells by modulation of Bcl-2 family and activation of caspases. Exp Oncol. 2006 Mar;28(1):30-5. PubMed PMID: 16614704.

34: Park HJ, Choi EK, Choi J, Ahn KJ, Kim EJ, Ji IM, Kook YH, Ahn SD, Williams B, Griffin R, Boothman DA, Lee CK, Song CW. Heat-induced up-regulation of NAD(P)H:quinone oxidoreductase potentiates anticancer effects of beta-lapachone. Clin Cancer Res. 2005 Dec 15;11(24 Pt 1):8866-71. PubMed PMID: 16361576.

35: Menna-Barreto RF, Henriques-Pons A, Pinto AV, Morgado-Diaz JA, Soares MJ, De Castro SL. Effect of a beta-lapachone-derived naphthoimidazole on Trypanosoma cruzi: identification of target organelles. J Antimicrob Chemother. 2005 Dec;56(6):1034-41. Epub 2005 Nov 3. PubMed PMID: 16269551.

36: Kim EJ, Ji IM, Ahn KJ, Choi EK, Park HJ, Lim BU, Song CW, Park HJ. Synergistic Effect of Ionizing Radiation and beta-lapachone against RKO Human Colon Adenocarcinoma Cells. Cancer Res Treat. 2005 Jun;37(3):183-90. Epub 2005 Jun 30. PubMed PMID: 19956501; PubMed Central PMCID: PMC2785409.

37: Reinicke KE, Bey EA, Bentle MS, Pink JJ, Ingalls ST, Hoppel CL, Misico RI, Arzac GM, Burton G, Bornmann WG, Sutton D, Gao J, Boothman DA. Development of beta-lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels. Clin Cancer Res. 2005 Apr 15;11(8):3055-64. PubMed PMID: 15837761.

38: Lee JH, Cheong J, Park YM, Choi YH. Down-regulation of cyclooxygenase-2 and telomerase activity by beta-lapachone in human prostate carcinoma cells. Pharmacol Res. 2005 Jun;51(6):553-60. PubMed PMID: 15829436.

39: Woo HJ, Choi YH. Growth inhibition of A549 human lung carcinoma cells by beta-lapachone through induction of apoptosis and inhibition of telomerase activity. Int J Oncol. 2005 Apr;26(4):1017-23. PubMed PMID: 15753997.

40: Ough M, Lewis A, Bey EA, Gao J, Ritchie JM, Bornmann W, Boothman DA, Oberley LW, Cullen JJ. Efficacy of beta-lapachone in pancreatic cancer treatment: exploiting the novel, therapeutic target NQO1. Cancer Biol Ther. 2005 Jan;4(1):95-102. Epub 2005 Jan 15. PubMed PMID: 15662131.

41: Kumi-Diaka J, Saddler-Shawnette S, Aller A, Brown J. Potential mechanism of phytochemical-induced apoptosis in human prostate adenocarcinoma cells: Therapeutic synergy in genistein and beta-lapachone combination treatment. Cancer Cell Int. 2004 Aug 17;4(1):5. PubMed PMID: 15315711; PubMed Central PMCID: PMC516040.

42: De Moura KC, Salomão K, Menna-Barreto RF, Emery FS, Pinto Mdo C, Pinto AV, de Castro SL. Studies on the trypanocidal activity of semi-synthetic pyran[b-4,3]naphtho[1,2-d]imidazoles from beta-lapachone. Eur J Med Chem. 2004 Jul;39(7):639-45. PubMed PMID: 15236845.

43: Fernández Villamil S, Stoppani AO, Dubin M. Redox cycling of beta-lapachone and structural analogues in microsomal and cytosol liver preparations. Methods Enzymol. 2004;378:67-87. Review. PubMed PMID: 15038958.

44: de Andrade-Neto VF, Goulart MO, da Silva Filho JF, da Silva MJ, Pinto Mdo C, Pinto AV, Zalis MG, Carvalho LH, Krettli AU. Antimalarial activity of phenazines from lapachol, beta-lapachone and its derivatives against Plasmodium falciparum in vitro and Plasmodium berghei in vivo. Bioorg Med Chem Lett. 2004 Mar 8;14(5):1145-9. PubMed PMID: 14980653.

45: Nasongkla N, Wiedmann AF, Bruening A, Beman M, Ray D, Bornmann WG, Boothman DA, Gao J. Enhancement of solubility and bioavailability of beta-lapachone using cyclodextrin inclusion complexes. Pharm Res. 2003 Oct;20(10):1626-33. PubMed PMID: 14620518.

46: Choi BT, Cheong J, Choi YH. beta-Lapachone-induced apoptosis is associated with activation of caspase-3 and inactivation of NF-kappaB in human colon cancer HCT-116 cells. Anticancer Drugs. 2003 Nov;14(10):845-50. PubMed PMID: 14597880.

47: Choi YH, Kim MJ, Lee SY, Lee YN, Chi GY, Eom HS, Kim ND, Choi BT. Phosphorylation of p53, induction of Bax and activation of caspases during beta-lapachone-mediated apoptosis in human prostate epithelial cells. Int J Oncol. 2002 Dec;21(6):1293-9. PubMed PMID: 12429980.

48: Pardee AB, Li YZ, Li CJ. Cancer therapy with beta-lapachone. Curr Cancer Drug Targets. 2002 Sep;2(3):227-42. Review. PubMed PMID: 12188909.

49: Li Y, Li CJ, Yu D, Pardee AB. Potent induction of apoptosis by beta-lapachone in human multiple myeloma cell lines and patient cells. Mol Med. 2000 Dec;6(12):1008-15. PubMed PMID: 11474117; PubMed Central PMCID: PMC1949930.

50: Di Chenna PH, Benedetti-Doctorovich V, Baggio RF, Garland MT, Burton G. Preparation and cytotoxicity toward cancer cells of mono(arylimino) derivatives of beta-lapachone. J Med Chem. 2001 Jul 19;44(15):2486-9. PubMed PMID: 11448231.

51: Planchon SM, Pink JJ, Tagliarino C, Bornmann WG, Varnes ME, Boothman DA. beta-Lapachone-induced apoptosis in human prostate cancer cells: involvement of NQO1/xip3. Exp Cell Res. 2001 Jul 1;267(1):95-106. PubMed PMID: 11412042.

52: Krishnan P, Bastow KF. Novel mechanism of cellular DNA topoisomerase II inhibition by the pyranonaphthoquinone derivatives alpha-lapachone and beta-lapachone. Cancer Chemother Pharmacol. 2001 Mar;47(3):187-98. PubMed PMID: 11320661.

53: Li CJ, Li YZ, Pinto AV, Pardee AB. Potent inhibition of tumor survival in vivo by beta-lapachone plus taxol: combining drugs imposes different artificial checkpoints. Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13369-74. PubMed PMID: 10557327; PubMed Central PMCID: PMC23954.

54: Manna SK, Gad YP, Mukhopadhyay A, Aggarwal BB. Suppression of tumor necrosis factor-activated nuclear transcription factor-kappaB, activator protein-1, c-Jun N-terminal kinase, and apoptosis by beta-lapachone. Biochem Pharmacol. 1999 Apr 1;57(7):763-74. PubMed PMID: 10075082.

 

 

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