Novel polyoxazole-based cyclopeptides from Streptomyces sp. Total synthesis of the cyclopeptide YM-216391 and synthetic studies towards telomestatin

Abstract

A convergent, complementary, synthetic approach to the contiguously linked tris-oxazole units 10, 11 and 12 in telomestatin (1) and YM-216391 (2) is described. The route involves coupling reactions between oxazole 4-carboxylic acids, viz 16a, 16c, 16d and oxazole 2-substituted methylamines, viz 16b, 16e, 17, leading to the amides 18 and 21, followed by cyclodehydrations to the corresponding bis-oxazole oxazolines, e.g. 19, and oxidations of the latter using well-established protocols. The tris-oxazoles 11 and 12 were next converted stepwise into the hexa-oxazole bis-macrolactams 33. Although the bis-macrolactams 33 (cf. 28) could be converted into the corresponding oxazoline-hexa-oxazoles 34 and to the enamides 35, neither of these intermediates could be elaborated to the hepta-oxazole 30en route to telomestatin 1. Likewise, neither the hexa-oxazole 47 or application of an intramolecular Hantzsch oxazole ring-forming reaction from 44b allowed access to the advanced polyoxazole-macrolactam intermediates 48 and 30a, respectively, towards telomestatin. Combination of the tris-oxazole based methylamine 70 with the dipeptide carboxylic acid 71 derived from D-valine and L-isoleucine, leads to the corresponding amide which, in two straightforward steps, is converted into the -amino acid 78. Macrolactamisation of 78, using HATU, next produces the cyclopeptide 79 which is then elaborated to the thiazole and oxazole based cyclopeptide YM-216391 (2). The synthetic cyclopeptide 2 is shown to be the enantiomer of the natural product isolated from Streptomyces nobilis.

Synthesis of Heptaoxazole Macrocyclic Analogues of Telomestatin and Evaluation of Their Telomerase Inhibitory Activities

“…The combined organic layer was washed with brine, dried over MgSO 4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (0% to 4% MeOH in CHCl 3 ) to give carboxylic acid 8a (4.31 g, 12.5 mmol, 90% 13 C NMR (100 MHz, CDCl 3 ): ¤ 165. 1, 164.2, 155.2, 145.0, 133.2, 80.5, 49.3, 42.9, 32.5, 30.9, 28.3.…”

“…13 C NMR (100 MHz, CDCl 3 ): ¤ 164.0, 162. 9, 162.0, 161.9, 155.1, 144.2, 141.5, 135.3, 133.2, 80.2, 62.7, 52.5, 50.7, 49.4, 42.9, 31.0, 30.8, 28.5 13 C NMR (100 MHz, CDCl 3 ): ¤ 163. 5,162.2,161.5,159.7,155.0,153.8,144.3,133.0,128.5,80.0,62.9,52.2,49.5,49.1,42.7,31.6,30.8,28.3,cm ¹1 ): 3405,3286,2974,1712,1656,1584,1517,1367,1166,1114,757 13 C NMR (100 MHz, DMSO-d 6 , 80°C): ¤ 162.…”

“…9, 162.0, 161.9, 155.1, 144.2, 141.5, 135.3, 133.2, 80.2, 62.7, 52.5, 50.7, 49.4, 42.9, 31.0, 30.8, 28.5 13 C NMR (100 MHz, CDCl 3 ): ¤ 163. 5,162.2,161.5,159.7,155.0,153.8,144.3,133.0,128.5,80.0,62.9,52.2,49.5,49.1,42.7,31.6,30.8,28.3,cm ¹1 ): 3405,3286,2974,1712,1656,1584,1517,1367,1166,1114,757 13 C NMR (100 MHz, DMSO-d 6 , 80°C): ¤ 162. 9, 162.7, 160.1, 159.5, 145.1, 141.7, 135.5, 135.0, 132.1, 128.0, 127.7, 127.6, 93.8, 78.7, 66.4, 66.3, 65.5, 54.2, 52.5, 27.5, 19.5 ) was added Burgess reagent (1.2 equiv) at room temperature under argon.…”

“…After removal of the solvent, the residue was purified by column chromatography on silica gel to give bisoxazole amide. 13 C NMR (100 MHz, CDCl 3 ): ¤ 164.0, 162. 9, 162.0, 161.9, 155.1, 144.2, 141.5, 135.3, 133.2, 80.2, 62.7, 52.5, 50.7, 49.4, 42.9, 31.0, 30.8, 28.5 13 C NMR (100 MHz, CDCl 3 ): ¤ 163.…”

Targeting G-Quadruplex DNA with Small Molecules

“…No SARs have been reported for telomestatin, due, in part, to the extreme difficulties associated with the synthesis of its highly constrained macrocyclic core. [114] Synthetic analogs of telomestatin containing six or seven oxazole units have recently been prepared and show good G-quadruplex affinity and specificity. [115,116] …”