Ascidiacyclamides containing oxazoline and thiazole motifs assume square conformations and show high cytotoxicity

Abstract

Four cyclic octapeptides were designed from ascidiacyclamide [cyclo(-Ile-Oxz-D-Val- Thz-) ] (ASC, 1) to investigate the effects of oxazoline (Oxz) and thiazole (Thz) rings on the structures and cytotoxicities of the peptides. cyclo(-Ile-Thz-D-Val-Oxz-) (2) had the same number of Oxz and Thz rings as ASC, but the ring positions were switched. cyclo(-Ile-Oxz-D-Val-Thz-Ile-Thz-D-Val-Thz-) (3) and cyclo(-Ile-Thz-D-Val-Oxz-Ile-Thz-D-Val-Thz-) (4) contained one Oxz and three Thz rings within the molecule. All Oxz rings were substituted with Thz in cyclo(-Ile-Thz-D-Val-Thz-) (5). These analogues had new Oxz and Thz blocks forming the 24-membered ring. Based on CD spectra and X-ray diffraction analyses, the structures of all four analogues were classified as square ASC forms. But the structures of 2 and 5 differed from the original square form of 1, and they showed no cytotoxicity. The structure of 3 was very similar to that of 1, and 3 showed 10 times greater cytotoxicity than 1. Although no definite structure of 4 was obtained, it showed three times greater cytotoxicity than 1. It appears that the position and number of Oxz residues are essential determinants in the structure-cytotoxicity relationship of ASC analogues.

NMR-based quantitative studies of the conformational equilibrium between their square and folded forms of ascidiacyclamide and its analogues

“…We have well established that measuring the CD spectral changes in this solvent system is a useful means of monitoring the conformational equilibrium between the square and folded forms of ascidiacyclamides. [7][8][9]20 Previously recorded CD spectra for 1 are also shown in The spectral changes observed with 11 showed the same features as 1 in this solvent system. The conformation of 11 in CH 3 CN solution was the square form, which was converted to the folded form through TFE titration.…”

“…S43 †), and most T3ASC molecules reportedly retain the square form even in solution. 20 On the other hand, dASC, cyclo(-Ile-alloThr-D-Val-Thz-) 2 , which lacks the Oxz rings of 1, assumes a folded form in both solid and solution states (Fig. S44 †).…”

Thiazole Moiety: An Interesting Scaffold for Developing New Antitumoral Compounds

“…Cyclic thiazole-and oxazoline-containing octapeptides and patellamides, isolated from marine tunicates, have also been an object of modification. It has been shown that changes in the position of thiazoles and oxazolines in ascidiacyclamide can influence their cytotoxic activity, obtaining inactive derivatives and 10 times more active compounds depending on the conformations attained [91].…”

A bis-copper(II)–[D-βVal3,7]ascidiacyclamide complex enveloping two square pyramids and sharing an apex atom from a carbonate anion

“…This coordination leads the Thz-Thr-Oxz unit to be relatively flat and to form four flanking five-membered rings. The chiral modifications or exchange of the azole rings makes the ASC molecule relatively flat (Asano et al, 2001b(Asano et al, , 2002b(Asano et al, , 2018, but the planarity is low in comparison to the metal-coordinated structure. The least-squares planes of the Thz-Ile-Oxz units, calculated using the Cu1, N1, N7 and N37 atoms or the Cu2, N17, N21 and N27 atoms, face one another at an angle of 19.5 ( Fig.…”

“…This restriction arises because the flexibility of their precursor amino acids is lost from Oxz and Thz. The bond rotation is limited to back and forth movement at the planar azole rings (Ishida et al, 1992;Hambley et al, 1992;Asano et al, 2001aAsano et al, , 2018. Consequently, ASC exists in a conformational equilibrium between two major conformers (folded and square) (Doi et al, 1999;Asano et al, 2002aAsano et al, , 2003Asano et al, , 2011Asano et al, , 2014Asano et al, , 2016.…”