The Preparation and Evaluation of 1-Substituted 1,2,3,4-Tetrahydro- and 3,4-Dihydro-.BETA.-carboline Derivatives as Potential Antitumor Agents

Abstract

Marine natural products which contain a b-carboline skeleton are widely distributed in marine invertebrates. 1-3)The discovery of natural b-carboline metabolites as potent antitumor and antiviral agents has stimulated great interest in the synthetic and pharmacological studies of b-carboline derivatives. [4][5][6] Particularly interesting targets include such compounds as eudistomins 7,8) and manzamines, 9,10) which were isolated from marine tunicates and sponges, respectively. As a class, the oxathiazepine containing eudistomines exhibited potent inhibitory activity toward DNA virus HSV-1. In addition, the antiviral eudistomines C (1) and E (2) were also found active against HSV-2, the Vaccinia virus and RNA viruses.11) The novel structures of manzamines, however, were reported to possess potent antitumor, 12,13) antibacterial, antifungal, and anti-HIV activities.14) The most active was manzamine A (3), a principal metabolite from several species of sponges, which showed cytotoxicity against murine P-388 cells at 0.07 mg/ml. 15) Our previous report has revealed that manzamine A-D and H exhibited potent cytotoxicities against human KB-16, A-549 and HT-29 tumor cell lines. 16)The common b-carboline or 1,2,3,4-tetrahydro-b-carboline moieties appear to be important for the biological activity. In order to investigate the essential structural features for the antitumor activity of manzamine A (3), the synthesis of 1-substituted 1,2,3,4-tetrahydro-and 3,4-dihydro-b-carboline derivatives were initiated. The difficult isolation of manzamine A (3) from sponge and its limited source make this current program more important and significant. A facile synthetic method by the application of Pictet-Spengler reaction [17][18][19][20] and DDQ oxidation 21) allowed the preparation of compounds 4-29. Herein, we wish to report the preparation, characterization and biological evaluation of 1-substituted 1,2,3,4-tetrahydro-and 3,4-dihydro-b-carboline derivatives. Results and DiscussionAs summarized in Chart 1, compounds 4-16 were synthesized from tryptamine (I) and substituted benzaldehydes via Pictet-Spengler cyclization. Subsequent oxidation of 1,2,3,4-tetrahydro-b-carbolines (4-16, A compounds) by DDQ furnished 3,4-dihydro-b-carboline derivatives (17-29, B compounds). The spectral data for 4-29 are illustrated in Experimental. Table 1 shows the biological results for compounds 4-29 and manzamine A (3) as tested against murine P-388 (leukemia) and human tumor cell lines, including KB-16 (nasopharyngeal carcinoma), A-549 (lung adenocarcinoma) and HT-29 (colon adenocarcinoma) in vitro. All of the compounds exhibited promising activity except for 19, which had no activity toward the four tumor cell lines. Among them, compound 29 exhibited the most potent activity against all tested tumor cells. For P-388 inhibitory activity, compounds 8 and 29 were more potent than or comparable to 3. Compounds 4, 12, 14, 15, 25 and 28 showed potent to moderate activity. As for KB-16 cell cytotoxicity, compound 29 was equal in potency to manzamine A ...

New Heterocyclic Systems Based on Substituted 3,4-Dihydro-1H-Spiro[Quinoline-2,1'-Cycloalkanes]*

“…It should be noted that spectra of compounds 5a,b lacked signals due to secondary amino group protons, which is characteristic for the spectra of β-carbolines [16,17].…”

“…The most intense signals (I rel = 100%) were produced by ions due to elimination of a CO molecule from molecular ions (for compounds 3a and 5a), a CO molecule and methyl radical (for compounds 3b, 4b, 5b, and 6b), a methyl radical and two CO molecules (for compounds 4a and 6a) [11,15,17].…”

Synthesis of 1,2,3,4-Tetrahydroeudistomin U Derivatives and PreliminaryIn Vitro. Antitumor Evaluation

“…Recently, a series of 1,2,3,4-tetrahydro-β-carboline derivatives were reported to be CDK4-specific inhibitors (Aubry et al, 2006), which may cause G1 arrest of tumor cells. Several 1-aryl substituted 1,2,3,4-tetrahydro-β-carboline derivatives also showed significant cytotoxicity against murine P-388 and human tumor cell lines, KB-16, A-549, and HT-29 (Shen et al, 2005).…”

Synthesis and antiviral activity of β-carboline derivatives bearing a substituted carbohydrazide at C-3 against poliovirus and herpes simplex virus (HSV-1)

“…Studies on structure-activity relationship have demonstrated the influence of the substituents in positions-1, -3, and -9 of the b-carboline skeleton for a variety of synthetic b-carboline derivatives [10][11][12][13][14][15][16][17][18][19]. Furthermore, antiviral activity has been reported for several compounds possessing the carbohydrazide moiety [20][21][22][23].…”

“…Druglikeness and drug-score values of the most active compounds(6,7,10,11,12) and Acyclovir (ACV) using Osiris program.6.71 (2H, d, J ¼ 7.5 Hz, H-3 0 /H-5 0 ), 7.71-7.58-7.66 (5H, m, Ar-H), 7.80 (2H, d, J ¼ 8.0 Hz, H-2 00 /H-6 00 ), 8.07 (2H, d, J ¼ 7.5 Hz, H-2 0 /H-6 0 ), 8.26 (1H, d, J ¼ 7.8 Hz, H-5), 8.39 (1H, s, N]CH), 9.13 (1H, s, Yield: 83%; mp: 310-312 C; IR (KBr) n max (cm À1 ): 3304 (N-H), 1657 (C]O), 1534-1314 (C]C); 1 H NMR (300 MHz, CDCl 3 /CD 3 OD): d 7.15 (2H, d, J ¼ 7.8 Hz, H-3 0 /H-5 0 ), 7.37 (1H, t, J ¼ 7.8 Hz; H-6), 7.55-7.40 (3H, m, Ar-H), 7.66 (1H, d, J ¼ 7.8 Hz, H-8), 7.84 (2H, d, J ¼ 7.8 Hz, H-2 0 /H-6 0 ), 7.95 (2H, d, J ¼ 8.0 Hz; H-2 00 /H-6 00 ), 8.27 (1H, d, J ¼ 8.0 Hz, H-5), 8.33 (1H, s, N]CH), 8.93 (1H, s, H-4); 13 C NMR (CDCl 3 /CD 3 OD): d 112.Hydroxyphenyl)-N 0 -(4-nitrobenzylidene)-9H-pyrido[3,4-b]indole-3-carbohydrazide (8). Yield: 80%; mp: 342-344 C; IR (KBr) n max (cm À1 ): 3380 (N-H), 1675 (C]O), 1524-1310 (C]C); 1 H NMR (300 MHz, DMSO-d 6 ): d 7.08 (2H, d, J ¼ 7.5 Hz, H-3 0 /H-5 0 ), 7.35 (1H, t, J ¼ 7.5 Hz, H-6), 7.60 (1H, t, J ¼ 7.5 Hz, H-7), 7.73 (1H, d, J ¼ 7.5 Hz, H-8), 8.03 (2H, d, J ¼ 8.0 Hz, H-3 00 /H-5 00 ), 8.13 (2H, d, J ¼ 7.5 Hz, H-2 0 / H-6 0 ), 8.34 (2H, d, J ¼ 8.0 Hz, H-2 00 /H-6 00 ), 8.47 (1H, d, J ¼ 7.…”