Streptomyces anulatus

Shin-ya K et al. (2001) Telomestatin, a novel telomerase inhibitor from Streptomyces anulatus. J Am Chem Soc 123(6) 1262-1263... 

In 1993, Oki et al. isolated the novel carbazole antibiotics epocarbazolin A (258) and B (259) from the culture broth of Streptomyces anulatus T688-8 (230). They represent the first carbazole alkaloids with an epoxide moiety in a side chain, and are the epoxides corresponding to carbazomadurin A (256) and B (257). Epocarbazolin A (258) [oC + 75.0 (c 0.5, MeOH) and B (259) Mg -b 78.0 (c 0.5, MeOH) were obtained from Nature in optically active form. However, their absolute configuration is not known. These alkaloids showed potent 5-lipoxygenase inhibitory activity and weak antibacterial activity (230) (Scheme 2.63). 

A potent specific telomerase inhibitor designated as telomestatin, 363, was isolated from Streptomyces anulatus 3533-SV4 <2001JA1262>. Although telomerase consists of several components with DNA polymerase or reverse transcriptase activity in addition to its intrinsic telomerase component, telomestatin specifically inhibited telomerase without affecting DNA polymerase and human immunodeficiency virus-reverse transcriptase (HIV-RT). 

Last but not least, the most potent natural product known to act as a selective telomerase inhibitor is telomestatin (13), isolated from Streptomyces anulatus. This novel macrocycle has been shown to bind quadruplex structures with high specificity and indeed influence the type of G-quadruplex fold formed in solution (see below).We now examine some of these systems in more detail. 

Macrocyclic torands (telomestatin and derivatives) as natural products of Streptomyces anulatus emerge as agents targeting the G-quadruplexes such a hexazole-designated oxazole (HXDV) is inhibitory to human leukemia lymphoblasts [432]. Telomestatin derivatives of macrocyclic stmctures (with 6 oxazole rings) and porphyrin-based ligands stabilize telomerase-driven cell divisions [433 35], but so far have not reached the clinics. 

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