Abstract
α‐Carboline (pyrido[2,3‐b]indole) was selected as the basic scaffold for development of antileukemic agents by structural modification. From the structure‐activity study, it was found that sequential introduction of 6‐acetyl and 9‐substituted benzyl groups onto an α‐Carboline scaffold resulted in 6‐acetyl‐9‐(3,5‐dimethoxybenzyl)‐9H‐pyrido[2,3‐b]indole and 6‐acetyl‐9‐(3,4,5‐trimethoxybenzyl)‐9H‐pyrido[2,3‐b]indole with potent cytotoxicity against the HL‐60 cell line. These two compounds will be used as new lead compounds for further investigation.
Keywords: antileukemic agents, α‐Carboline, HL‐60 cells, structure‐activity relationships
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References
- 1. Garcia M, Jemal A, Ward EM, et al. Global Cancer Facts & Figures 2007. Atlanta: American Cancer Society. 2007, 2–3. [Google Scholar]
- 2. Zhou TS, Ye WC, Xu LS, et al. β‐Carboline alkaloids from Hypodematium squamuloso‐pilosum . Phytochem. 1998; 49: 1807–1809. [DOI] [PubMed] [Google Scholar]
- 3. Carbriela MC, Alicia MS. A β‐carboline alkaloid from the soft coral Lignopsis spongiosum . J Nat Prod. 1999; 62: 759–760. [DOI] [PubMed] [Google Scholar]
- 4. Kotanen S, Huybrechts J, Schoofs L, et al. Identification of tryptophan and β‐carboline as paralysins in larvae of the yellow mealworm, Tenebrio molitor . Biochem Biophys Res Commun. 2003; 310: 64–71. [DOI] [PubMed] [Google Scholar]
- 5. Manabe S, Yuan J, Urban JRRC, et al. Age‐related accumulation of 1‐methyl‐1,2,3,4‐tetrahydro‐β‐carboline‐3‐carboxylic acid in human lens. Exp Eye Res. 1996; 63: 179–186. [DOI] [PubMed] [Google Scholar]
- 6. Adachi J, Mizoi Y, Ninomiya I, et al. Identification of tetrahydro‐β‐carboline‐3‐carboxylic acid in foodstuffs, human urine and human milks. J Nutr. 1991; 121: 646–652. [DOI] [PubMed] [Google Scholar]
- 7. Cao R, Chen Q, Xu A, et al. Synthesis, acute toxicities, and antitumor effects of novel 9‐substituted β‐carboline derivatives. Bioorg Med Chem. 2004; 12: 4613–4623. [DOI] [PubMed] [Google Scholar]
- 8. Ishida J, Wang HK, Lee KH, et al. Antitumor agents 201. Cytotoxicity of harmine and β‐carboline analogs. Bioorg Med Chem Lett. 1999; 23: 3319–3324. [DOI] [PubMed] [Google Scholar]
- 9. Xiao S, Lin W, Yang M, et al. Synthesis and biological evaluation of DNA targeting flexible side‐chain substituted β‐carboline derivatives. Bioorg Med Chem Lett. 2001; 11: 437–441. [DOI] [PubMed] [Google Scholar]
- 10. Jenkins PR, Wilson J, Chaudhuri B, et al. Design, synthesis and biological evaluation of new tryptamine and tetrahydro‐β‐carboline‐based selective inhibitors of CDK 4. Bioorg Med Chem. 2008; 16: 7728–7739. [DOI] [PubMed] [Google Scholar]
- 11. Cao R, Chen H, Xu A, et al. Design, synthesis and in vitro and in vivo antitumor activities of novel β‐carboline derivatives. Eur J Med Chem. 2005; 40: 991–1001. [DOI] [PubMed] [Google Scholar]
- 12. Rao KV, Santarsiero BD, Hamann MT, et al. New manzamine alkaloids with activity against infectious and tropical parasitic disease from an indonesian sponge. J Nat Prod. 2003; 66: 823–828. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Charan RD, McKee TC, Boyd MR, et al. Thorectandramine, a novel β‐carboline alkaloid from the marine sponge Thorectandra sp . Tetrahedron Lett. 2002; 43: 5201–5204. [Google Scholar]
- 14. Liger F, Popowycz F, Joseph B, et al. Synthesis and antiproliferative activity of clausine E, mukonine, and koenoline biosteres. Bioorg Med Chem. 2007; 15: 5615–5619. [DOI] [PubMed] [Google Scholar]
- 15. Pawel NH, Lukasz K. Cancerostatica II. Synthesis and preliminary cytostatic screening of some a‐carboline derivatives. Pol J Pharmacol Pharm. 1978; 30: 569–572. [PubMed] [Google Scholar]
- 16. Lucia FM, Marian M. Antineoplastic activity of azacarbazoles II. Effect of a‐carboline and its derivatives on transplantable animal neoplasms. Arch Immunol Ther Exp. 1987; 35: 221–224. [PubMed] [Google Scholar]
- 17. Patricia VL, Ramón A, Juan JV, et al. An improved synthesis of a‐carbolines under microwave irradiation. Org Lett. 2006; 8: 415–418. [DOI] [PubMed] [Google Scholar]
- 18. Murtedza BM, John P. Preparation of all the monochloro‐a‐carbolines and assignment of the 13, C n.m.r. spectrum of a‐carboline. J Chem Research (S). 1980; 43: 0577–0593. [Google Scholar]
- 19. Cédric S, David G, Peter GG, et al. Synthesis of 6‐substituted pyrido[2,3‐b]indoles by electrophilic substitution. Synlett. 2007; 14: 2237–2241. [Google Scholar]