(S)-Stereoisomer of telomestatin as a potent G-quadruplex binder and telomerase inhibitor

Abstract

Total synthesis of the (S)-stereoisomer of telomestatin (1) was accomplished. (S)-Telomestatin exhibited potency four times that of the natural product, (R)-telomestatin, which was the most potent telomerase inhibitor previously reported. In the circular dichroism spectral analysis of the complexes possessing randomly structured single-stranded d[TTAGGG](4) oligonucleotide, (S)-telomestatin, like (R)-telomestatin, induced an antiparallel G-quadruplex structure. The melting temperature (T(m)) value of the (S)-isomer complex was greater than that of the (R)-telomestatin complex. Therefore, it is concluded that the stereochemistry of the thiazoline of telomestatin is important to the binding ability of a G-quadruplex binder, and (S)-telomestatin as a G-quadruplex binder is more potent than the natural product.

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

“…7,8 Amidation of cysteine-derived monooxazoles 8a and 8b with serine-derived monooxazole 9 using PyBroP 18 afforded 10a and 10b (Scheme 1). 7 Cyclodehydration of 10a and 10b was performed by treatment with the Burgess reagent, 19 followed by using BrCCl 3 /DBU 20 to provide trisoxazoles 6a and 6b, respectively.…”

“…7 We also synthesized its enantiomer, (S)-1, which was four-fold as potent as (R)-1; this was evaluated by determining the T m values of the complexes with ss-telo24 as observed in the CD melting curves as well as with the results of a telomerase repeat amplification protocol (TRAP) assay. 8 In addition, we discovered that heptaoxazole macrocycle (R)-2, which is a synthetic intermediate in the formation of the thiazoline ring of telomestatin, also has potential inhibitory activity against telomerase such that its activity is one fourth that of the natural product.…”

“…15 Despite many intensive studies focusing on hexaoxazole macrocycles, only a few examples of heptaoxazole macrocycles that have planar structures have been reported. 8,16 This is probably because the construction of the seventh oxazole in a macrocycle will be difficult due to high strain energy. 10a,13 Notably, the Nagasawa group reported that amine-linked heptaoxazole macrocycle L1H1-7OTD is a more favorable binder than the corresponding hexaoxazole macrocycle for strongly inducing a conformational change of ss-telo24 to an antiparallel G-quadruplex structure.…”

A bio-inspired approach to proline-derived 2,4-disubstituted oxazoles

“…Analysis of the literature data published on 'biocores' obtained by a combination of oxazole and common heteroaliphatic amines (pyrrolidine/piperidine) shows that 2-(2-pyrrolidinyl)oxazoles 4 are most often encountered in papers and patents [25]. As in the case of the general structure 1, however, nearly all known compounds 4 are substituted with R 1 = aryl or CO 2 R, or are derived from them [7][8][9][10][11][12][21][22][23].…”

“…It is not surprising, therefore, that 2,4-disubstituted oxazoles of general formula 1 derived from α-amino acids have attracted much attention as promising building blocks for drug discovery [6][7][8][9][10][11][12][13] or total synthesis of natural products including plantazolicins [14,15], telomestatin [16], ulapualides [17,18] and diazonamide A [19,20] and as ligands for enantioselective catalysis [21,22]. In most cases, a 'biomimetic' approach to the synthesis of 1 has been used, including the formation of oxazoline 2 and its subsequent aromatization (Scheme 1) [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. However, this method is effective only when the substituent R 1 in the oxazole ring formed is an electron-withdrawing group (e.g.…”