Bimetallic Catalyzed N-arylation Used in Synthesis of Novel β-carbolines Derivatives

Author(s): Rui Cai, Li Zhu, Pengfei Wang, Yu Zhao*

Journal Name: Letters in Drug Design & Discovery

Volume 17 , Issue 5 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


Background: Natural occurring β-Carbolines alkaloids are abundant in the plant kingdom or other organisms, and they were found to possess good antitumor activity through multiple mechanisms. Based on previous summarized SARs of β-carboline derivatives, the modification on pyridine ring would have a great impact on their antitumor activities. Therefore, we plan to synthesized arylated β-carboline-3-amides to find more valuable β-Carbolines derivatives.

Methods: A novel bimetallic Pd(OAc)2/AgOAc catalyst system was developed for the amidation of aryl iodides under acid condition. A series of N-arylated β-carbolines derivatives were synthesized using this method. The structures of these compounds were confirmed by 1H NMR, 13C NMR and HRMS, and their in vitro antiproliferative activity was investigated against HepG2 and Hela tumor cell lines by MTT assay.

Results: Eleven N-arylated β-carboline-3-amides were synthesized using this bimetallic catalyzed method in 58-98% yields. These synthesized N-arylated compounds showed no antiproliferative activity at 20 μM.

Conclusion: We have discovered an efficient and bimetallic catalytic system allowing the Narylation of secondary acyclic amides. This is the first report that N-arylation of aliphatic secondary acyclic amides under acid condition.

Keywords: Bimetallic catalysis, β-carbolines-3-amide, arylation, synthesis, antiproliferative activity, 1H NMR, 13C NMR.

Sankar, R.; Babu, S.A. Construction of tertiary amides: NiII-catalyzed n-arylation of secondary acyclic amides (2-picolinamides) with aryl halides. Asian J. Org. Chem., 2017, 6, 269-273. [].
Shakespeare, W.C. Palladium-catalyzed coupling of lactams with bromobenzenes. Tetrahedron Lett., 1999, 40, 2035-2038. [].
Castillo, P.R.; Buchwald, S.L. Applications of palladium-catalyzed C-N Cross-coupling reactions. Chem. Rev., 2016, 116, 12564-12649. []. [PMID: 27689804].
Hicks, J.D.; Hyde, A.M.; Cuezva, A.M.; Buchwald, S.L. Pd-catalyzed N-arylation of secondary acyclic amides: catalyst development, scope, and computational study. J. Am. Chem. Soc., 2009, 131(46), 16720-16734. []. [PMID: 19886610].
Chen, Y-J.; Chen, H-H. 1,1,1-tris(hydroxymethyl)ethane as a new, efficient, and versatile tripod ligand for copper-catalyzed cross-coupling reactions of aryl iodides with amides, thiols, and phenols. Org. Lett., 2006, 8(24), 5609-5612. []. [PMID: 17107084].
De, S.; Yin, J.; Ma, D. copper-catalyzed coupling reaction of (hetero)aryl chlorides and amides. Org. Lett., 2017, 19(18), 4864-4867. []. [PMID: 28858514].
Deng, W.; Wang, Y-F.; Zou, Y.; Liu, L.; Guo, Q-X. Amino acid-mediated Goldberg reactions between amides and aryl iodides. Tetrahedron Lett., 2004, 45, 2311-2315. [].
Kathiravan, S.; Ghosh, S.; Hogarth, G.; Nicholls, I.A. Copper catalysed amidation of aryl halides through chelation assistance. Chem. Commun., 2015, 51, 4834-4837. [].
Klapars, A.; Huang, X.; Buchwald, S.L. A general and efficient copper catalyst for the amidation of aryl halides. J. Am. Chem. Soc., 2002, 124(25), 7421-7428. []. [PMID: 12071751].
Racine, E.; Monnier, F.; Vors, J.P.; Taillefer, M. A simple copper-catalyzed synthesis of tertiary acyclic amides. Org. Lett., 2011, 13(11), 2818-2821. []. [PMID: 21548643].
Tinnis, F.; Stridfeldt, E.; Lundberg, H.; Adolfsson, H.; Olofsson, B. Metal-free N-arylation of secondary amides at room temperature. Org. Lett., 2015, 17(11), 2688-2691. []. [PMID: 25966029].
Ishida, J.; Wang, H.K.; Bastow, K.F.; Hu, C.Q.; Lee, K.H. Antitumor agents 201. Cytotoxicity of harmine and beta-carboline analogs. Bioorg. Med. Chem. Lett., 1999, 9(23), 3319-3324. []. [PMID: 10612592].
Rashid, M.A.; Gustafson, K.R.; Boyd, M.R. New cytotoxic N-methylated beta-carboline alkaloids from the marine ascidian Eudistoma gilboverde. J. Nat. Prod., 2001, 64(11), 1454-1456. []. [PMID: 11720532].
Kuo, P.C.; Shi, L.S.; Damu, A.G.; Su, C.R.; Huang, C.H.; Ke, C.H.; Wu, J.B.; Lin, A.J.; Bastow, K.F.; Lee, K.H.; Wu, T-S. Cytotoxic and antimalarial beta-carboline alkaloids from the roots of Eurycoma longifolia. J. Nat. Prod., 2003, 66(10), 1324-1327. []. [PMID: 14575431].
Michael, C.; Robert, W.W.; Fil, G.; James, M.C.; Steven, A.B.; Kenner, C.R.; Jacqueline, N.C.; Steven, M.P.; Phil, S. Beta-carbolines: Synthesis and neurochemical and pharmacological actions on brain benzodiazepine receptors. J. Med. Chem., 1982, 25, 1081. []. [PMID: 6127411].
Wang, P.; Luo, L.; Shen, Q.; Shi, G.; Mohammed, A.; Ni, S.; Wu, X. Rosuvastatin improves myocardial hypertrophy after hemodynamic pressure overload via regulating the crosstalk of Nrf2/ARE and TGF-β/ smads pathways in rat heart. Eur. J. Pharmacol., 2018, 820, 173-182. []. [PMID: 29225188].
Luo, L.; Xu, T.; Wang, P.; Mao, L.; Xi, C.; Huang, J.; Zhang, W. Expression of muscarinic acetylcholine receptors in hepatocytes from rat fibrotic liver. Exp. Toxicol. Pathol., 2017, 69(2), 73-81. []. [PMID: 27899232].
Rivas, P.; Cassels, B.K. Morello, Effects of some β-carboline alkaloids on intact Trypanosoma cruzi epimastigotes. Comp. Biochem. Physiol. Part C, 1999, 122(1), 27-33.
Srivastava, S.K.; Agarwal, A.; Chauhan, P.M.S.; Agarwal, S.K.; Bhaduri, A.P.; Singh, S.N.; Fatima, N.; Chatterjee, R.K. Potent 1,3-disubstituted-9H-pyrido[3,4-b]indoles as new lead compounds in antifilarial chemotherapy. Bioorg. Med. Chem., 1999, 7(6), 1223-1236. []. [PMID: 10428395].
Ling, Y.; Guo, J.; Yang, Q.; Zhu, P.; Miao, J.; Gao, W.; Peng, Y.; Yang, J.; Xu, K.; Xiong, B.; Liu, G.; Tao, J.; Luo, L.; Zhu, Q.; Zhang, Y. Development of novel β-carboline-based hydroxamate derivatives as HDAC inhibitors with antiproliferative and antimetastatic activities in human cancer cells. Eur. J. Med. Chem., 2018, 144, 398-409. []. [PMID: 29288941].
Khorasani, A.; Heydari, B.N.; Shalchyan, V.; Daliri, M.R. Continuous force decoding from local field potentials of the primary motor cortex in freely moving rats. Sci. Rep., 2016, 6, 35238. []. [PMID: HYPERLINK “”27767063].
Ling, Y.; Xu, C.; Luo, L.; Cao, J.; Feng, J.; Xue, Y.; Zhu, Q.; Ju, C.; Li, F.; Zhang, Y.; Zhang, Y.; Ling, X. novel β-carboline/hydroxamic acid hybrids targeting both histone deacetylase and dna display high anticancer activity via regulation of the p53 signaling pathway. J. Med. Chem., 2015, 58(23), 9214-9227. []. [PMID: 26555243].
Cox, E.D.; Cook, J.M. The Pictet-Spengler condensation: A new direction for an old reaction. Chem. Rev., 1995, 95, 1797-1842. [].
Ling, Y.; Wang, X.; Zhu, H.; Wang, Z.; Xu, C.; Wang, X.; Chen, L.; Zhang, W. Synthesis and biological evaluation of novel farnesylthiosalicylic acid derivatives for cancer treatment. Arch. Pharm. (Weinheim), 2014, 347(5), 327-333. []. [PMID: 24435839].
Ling, Y.; Wang, X.; Wang, C.; Xu, C.; Zhang, W.; Zhang, Y.; Zhang, Y. Hybrids from farnesylthiosalicylic acid and hydroxamic acid as dual ras-related signaling and histone deacetylase (HDAC) inhibitors: Design, synthesis and biological evaluation. ChemMedChem, 2015, 10(6), 971-976. []. [PMID: 25882299].
Li, X.H.; Wang, X.M.; Xu, C.J.; Huang, J.K.; Wang, C.N.; Wang, X.Y.; He, L.Q.; Ling, Y. Synthesis and biological evaluation of nitric oxide-releasing hybrids from gemcitabine and phenylsulfonyl furoxans as anti-tumor agents. MedChemComm, 2015, 6, 1130-1136. [].
Ling, Y.; Feng, J.; Luo, L.; Guo, J.; Peng, Y.; Wang, T.; Ge, X.; Xu, Q.; Wang, X.; Dai, H.; Zhang, Y. Design and synthesis of c3-substituted β-carboline-based histone deacetylase inhibitors with potent antitumor activities. ChemMedChem, 2017, 12(9), 646-651. []. [PMID: 28425177].
Yin, J.; Buchwald, S.L. Palladium-catalyzed intermolecular coupling of aryl halides and amides. Org. Lett., 2000, 2(8), 1101-1104. []. [PMID: 10804564].
Horino, H.; Inoue, N.J. Ortho vinylation of aromatic amides via cyclopalladation complexes Org. Chem, 1981, 46, 4416-4422. [].

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Page: [520 - 525]
Pages: 6
DOI: 10.2174/1570180815666181025124615
Price: $65

Article Metrics

PDF: 15