Antiviral and antitumor structure-activity relationship studies on tetracyclic eudistomines

Abstract

The in vitro antiviral and antitumor activities of (-)-debromoeudistomin K (1a) and 10 structural analogues (1b-1j and 11) were evaluated. The synthesis was accomplished with an intramolecular Pictet-Spengler condensation reaction as the key step. This examination revealed some structural and stereochemical features that are important for both the antiviral and antitumor activities. The most striking points for activity are the necessity to have the correct natural stereochemistry at both C(1) and C(13b) and the presence of the C(1)-NH2 substituent. As was revealed before with naturally isolated eudistomins a substituent in the indole ring greatly influences the biological activity. The 5-OMe derivative 1h shows high potency in both antiviral and antitumor models.

β-Carboline Alkaloids: Biochemical and Pharmacological Functions

“…Eudistalbin A was shown to possess cytotoxic activity with ED50 3.2ug/ml, whereas eudistalbin B was inactive [161]. Moreover, Maarseveen et al [162] found that (-)-debromoeudistomin K (59) Kobayashi et al [166] reported that 6-hydroxymanzamine A (33) and 3,4-dihydromanzamine A (34) were cytotoxic against L1210 (IC 50 1.5 and 4.8 g/ml, respectively) and KB cells (IC 50 Appropriate substituent at C-3 is benefical for antitumor activity in vitro and in vivo, but amino,alkoxycarbonylamino and hydroxymethyl are unfavorable Fig. (5).…”

“…Exhibition cytotoxicities against murine P-388 [158] 2. Exhibition antitumor activities in vivo against L1210, A549 and HCT-8 cell lines [158] Eudistomidins B, C and D Exhibition cytotoxicities against murine leukemia L1210 L5178Y cell lines [159] Eudistomin U and its derivatives Exhibition cytotoxicities against murine P-388 [160] (-)-Debromoeudistomin K and its analogues Exhibition cytotoxicities against murine leukemiaL1210, Molt/4F, MT-4 and leukemia P-388 cells [162] Hyrtioerectines A Exhibition cytotoxicity against HeLa cell lines [163] Plakortamines A, B, C and D Exhibition cytotoxicities against HCT-116 human colon tumor cell line [164] N-methyl -carbolinium derivatives Exhibition cytotoxicities against four human tumor cell lines LOX, OVCAR-3, COLO-205 and MOLT-4 [165] 6-Hydroxymanzamine A, 3,4-dihydromanzamine Exhibition cytotoxicities against L1210 and KB cell lines [166] Manzamine A…”

“…Antiviral activities against HSV-II [167] (-)-Debromoeudistomin K and its 10 analogues Inhibition replication of a number of viruses [162] Manzamine A 8-Hydroxymanzamine A 6-Deoxymanzamine X Anti-HIV activities against human peripheral blood mononuclear (PBM) cells [169] Ichiba et al [167] reported that manzamine A (27), 8-hydroxymanzamine A (31) and 8-methoxymanzamine A (32) displayed significant antiviral activities against HSV-II with MIC 0.05, 0.1 and 0.1 g/ml, repectively. Afterwards, (-)-debromoeudistomin K and its 10 structural analogues [162] were also evaluated for their inhibitory effects on the replication of a number of viruses.…”

Synthesis and Evaluation of Acyl Protein Thioesterase 1 (APT1) Inhibitors

“…To this end, thioest-er 55, which was accessible following a literature procedure, [33] was treated with sodium methylate, and subsequently the free thiol group was protected as a tert-butyl disulfide using the methodology of Wünsch et al (Scheme 10). [34] The methoxy tetrahydropyran group in 57 was cleaved and the resulting alcohol was then transformed into the desired mesylate 58.…”

Thermal Isomerization of 1,3-Dipolar Cycloadducts of 3,4-Dihydro-β-carboline 2-Oxide

“…[10] [11] Particularly, in β-carboline compounds, the stereochemical relationship between 1-H in the β-carboline ring and 1Ј-H in the 1,2-fused ring (D ring) or in the substitution group in 1-position has a great influence on the biological activity ( Figure 1). For example, in eudistomins C, E, F, K, and L, cis configuration between the protons 1-H and 1Ј-H is an indispensable factor for antiviral and antitumor activity, [12] while in eudistomidine B [11] and woodinine, [13] trans configuration between them is essential. It is thus probable that chemical requirements.…”