Abstract:Five new alkaloids, dictyodendrins A-E (1-5), were isolated from the Japanese marine sponge Dictyodendrilla verongiformis as telomerase inhibitors. Their structures were elucidated by spectroscopic and chemical methods. Dictyodendrins are tyramine-based pyrrolocarbazole derivatives containing three or four p-hydroxybenzene groups. They inhibited telomerase completely at a concentration of 50 microg/mL.
“…1 These alkaloids completely inhibit telomerase at concentration of 50 g/ml and are reported to be the first telomerase-inhibitory marine natural products. They also demonstrated that the sulfate functions of the molecules are essential for the bioactivity as the desulfated compound was completely inactive.…”
Abstract-Formal synthesis of the telomerase inhibitory marine pyrrolocarbazole alkaloid dictyodendrin B is described. The key features are consecutive palladium-catalyzed cross-coupling reactions and intramolecular reductive coupling reaction to construct the pyrrolo[2,3-c]carbazole framework.
“…1 These alkaloids completely inhibit telomerase at concentration of 50 g/ml and are reported to be the first telomerase-inhibitory marine natural products. They also demonstrated that the sulfate functions of the molecules are essential for the bioactivity as the desulfated compound was completely inactive.…”
Abstract-Formal synthesis of the telomerase inhibitory marine pyrrolocarbazole alkaloid dictyodendrin B is described. The key features are consecutive palladium-catalyzed cross-coupling reactions and intramolecular reductive coupling reaction to construct the pyrrolo[2,3-c]carbazole framework.
“…The search for natural products in marine and terrestrial environments has led to the discovery of a number of biologically active indole alkaloids which includes the family of dictyodendrins, isolated from a Japanese marine sponge, Dictyodendrilla verongiformis in 2003 [46] (Fig. 1.6).…”
Section: Dictyodendrin a And Dictyodendrin Bmentioning
“…Owing to specific binding to the telomeric G-quadruplex structure of the 3’-telomere end and strong telomerase inhibitory activity 2 , it is globally used as the standard substance for in vitro assays 3–8 . To date, various telomerase inhibitors have been isolated from natural products 9–11 or developed in organic synthesis studies 12–14 , and their activities have been evaluated. However, no compound showing stronger activity than 1 has been found, except for synthetic ( S )-isomer 15 .Figure 1( A ) The chemical structure of 1 and putative amino acid constitution from the structure.…”
Telomestatin, a strong telomerase inhibitor with G-quadruplex stabilizing activity, is a potential therapeutic agent for treating cancers. Difficulties in isolating telomestatin from microbial cultures and in chemical synthesis are bottlenecks impeding the wider use. Therefore, improvement in telomestatin production and structural diversification are required for further utilization and application. Here, we discovered the gene cluster responsible for telomestatin biosynthesis, and achieved production of telomestatin by heterologous expression of this cluster in the engineered Streptomyces avermitilis SUKA strain. Utilization of an optimal promoter was essential for successful production. Gene disruption studies revealed that the tlsB, tlsC, and tlsO–T genes play key roles in telomestatin biosynthesis. Moreover, exchanging TlsC core peptide sequences resulted in the production of novel telomestatin derivatives. This study sheds light on the expansion of chemical diversity of natural peptide products for drug development.
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