Urukthapelstatin A, a Novel Cytotoxic Substance from Marine-derived Mechercharimyces asporophorigenens YM11-542

Abstract

The new cyclic peptide antibiotic, urukthapelstatin A, has been isolated from a culture of Thermoactinomycetaceae bacterium Mechercharimyces asporophorigenens YM11-542. The structure of urukthapelstatin A was elucidated by NMR, MS, Marfey analysis, chiral HPLC and X-ray crystal analyses. Keywords urukthapelstatin A, cyclic peptide, cytotoxic, Thermoactinomyces IntroductionUrukthapelstatin A (1) is a thiopeptide antibiotic which contains three oxazoles and two thiazoles in its cyclic structure and is structurally related to mechercharstatin (former name, mechercharmycin) [1,2] and YM-216391 [3, 4]. The fermentation, isolation and biological properties of 1 (Fig. 1) have been reported in the preceding paper [5]. This report describes the physico-chemical properties and structural determination of 1, which was produced by Mechercharimyces asporophorigenens YM11-542. Results Physico-chemical PropertiesThe physico-chemical properties of 1 are summarized in The relationship of the spin networks was established from 1 H-13 C long-range correlations in the HMBC spectrum and yielded three partial structures, which were assigned to a bithiazole-benzyloxazole moiety (C 15 H 7 N 3 OS 2 , partial structure A), one oxazole (C 3 HNO, partial structure B), and an alanine and isoleucinecontaining part (C 16 H 22 N 4 O 4 , partial structure C, Fig. 2). The HMBC correlations when n J CH was set to 2 Hz, were observed from H-34 (d H 8.59) to C-2 (d C 135.50), and from H-6 (d H 8.88) to C-4 (d C 155.11). Consequently, C-1 of partial structure A was connected to C-2 of partial structure B, and C-4 of partial structure B was connected to C-6 of partial structure C. In addition, the ROESY correlation of H-10 (d H 1.82) and N4-H (d H 9.49) revealed that a vinylmethyl part in partial structure C had a Z configuration (Fig. 2).Although there is no signal between partial structure A and C in HMBC spectrum, the C-20/C-21 connection can be brought about by the comparison of the molecular formula C 34 H 30 N 8 O 6 S 2 with a tolal of each partial structures (A; C 15 H 7 N 3 OS 2 , B; C 3 HNO, C; C 16 H 22 N 4 O 4 ), enabling the planer structure of 1 to be obtained.The absolute configuration of the alanine and isoleucine residues was determined by a Marfey analysis [6] and chiral HPLC analysis of the acid hydrolysate of 1. The Marfey analysis clarified the existence of L-Ala in the acid hydrolysate of 1, but D-Ile and D-allo-Ile were indistinguishable from the reversed-phase HPLC analysis of their FDAA derivatives. The chiral HPLC analysis successfully defined the absolute configuration of isoleucine as D-allo-Ile. Finally, the absolute stereochemistry of 1 was determined as shown in Fig. 1.An X-ray crystallographic analysis was also performed to confirm the full structure of 1. An adequate crystal was obtained by crystallization from CH 2 Cl 2 /MeOH (1 : 1). The crystal data and measurement conditions are summarized in the experimental section, and the ORTEP drawing shown in Fig. 3. The absolute configuration of 1 was ascertained ...

Marine natural products

“…The syntheses highlighted that the optical rotation values were originally misreported as being of opposite sign to their actual values and the authors of the isolation paper had noted this also. 462,463 Syntheses of marinacarbolines A-D, antimalarial b-carboline alkaloids originally obtained from Marinactinospora thermotolerans 464 were achieved in four steps from methyl 1-chloro-bcarboline-3-carboxylate 465 and the cyclic peptide urukthapelstatin A, originally isolated from the bacterium Mechercharimyces asporophorigenens 466,467 has been synthesised via a convergent strategy. 468 Trioxacarcin A, a structurally complex glycosidic metabolite of terrestrial 469 and marine 470 Streptomyces species, has been synthesised via a method which utilised latestage stereoselective glycosylation reactions of aglycon substrates.…”

From Seabed to Bedside: A Review on Promising Marine Anticancer Compounds

“…Peptides such as Lucentamycins A from the actinobacteria Nocardiopsis lucentensis and Mixirins A, B, and C from Bacillus sp., with activity against the human colon carcinoma cell line HCT-116 [25,26]; Ohmyungsamycins A and B from actinobacteria Streptomyces sp. [27], which displayed antiproliferative effects in several human cancer cell lines A519 (lung), SNU-638 (stomach), MDA-MB-231 (breast), and SK-HEP-1 (liver); and Urukthapelstatin A from actinobacteria Mechercharimyces asporophorigenens, with observed anticancer activity in the human lung cancer lines A549, DMS114, and NCIH460, human ovarian cancer cell lines OVCAR-3, OVCAR-4, OVCAR-5, OVCAR-8, and SK-OV3, human breast cancer cell line MCF-7 and in the human colon cancer cell line HCT-116 [28,29]. Interestingly, these peptides are not synthesized by ribosomes but other equivalent prokaryotic complexes and contain D-amino acid residues and other structural peculiarities rarely found in nature [24].…”

Thiazole and Oxazole Alkaloids: Isolation and Synthesis

“…A thiopeptide antibiotic, urukthapelstatin A ( 5 ), Figure 2, was isolated from a culture of Thermoactinomycetaceae bacterium Mechercharimyces asporophorigenens YM11-542 [3]. Its structure was determined by spectroscopic methods and chemical degradation, and confirmed by X-ray crystallographic analysis.…”