Desoxazoline ascidiacyclamide derivatives

Desoxazoline ascidiacyclamide derivatives (DOASC)

Ascidiacyclamide (ASC), cyclo(-Ile-Oxz-D-Val-Thz-)₂, is a unique cyclic octapeptide1 (Fig.1) containing unusual amino acids (Thz, thiazole and Oxz, oxazoline), and the two major conformations (squared & folded forms) have been demonstrated by NMR and X-ray diffraction methods. A conformational equilibrium has been postulated between two conformers. To control the conformational behavior of ASC in the equilibrium, we have focused on the C₂-symmetry of ASC and a Ile residue was substituted for Gly, Leu or Phe. The NOE parameters and molecular dynamics simulations suggested that the replaced amino acid could be a trigger on shifting the equilibrium toward the folded conformer. However, the folded conformer has not yet been captured in solid state in spite of NMR evidences. Our serious structural studies imply that the Oxz and Thz blocks limit the variation of molecular folding. Therefore, the release of rigid block(s) would make the molecules flexible and it seems to be a noteworthy approach to investigate the structural behaviors of ASC derivatives. We are also interested in such flexible conformers to consider the control of molecular folding. Indeed, the desoxazoline-ascidiacyclamide [(DOASC), 1 = cyclo(-Ile-aThr-D-Val-Thz-)₂], which lacks the Oxz blocks of ASC, resulted in the novel pseudoboat or pseudochair form in solution (aThr, L-allo-threonine). Furthermore, the relationships between DOASC and the accumulation of certain metals in marine organisms have been suggested and the ability of carrying metals was assumed for DOASC. Their metal complexes are also interesting in controlling the conformation.

Fig.1. Synthesis of ascidiacyclamide from desoxazoline-ascidiacyclamide.
Desoxazoline ascidiacyclamide derivatives (DOASC) are the precursers of ascidiacyclamide in the organic synthesis.

We also applied the asymmetric modifications for 1 to pilot the conformer distribution. As shown in folows, the position 1 was replaced with Ala or Val; 2 = cyclo(-Ala-aThr-D-Val-Thz-Ile-aThr-D-Val-Thz-), 3 = cyclo(-Val-aThr-D-Val-Thz-Ile-aThr-D-Val-Thz-), and a epimer of 1 at position 3 was synthesized; 4 = cyclo(-Ile-aThr-Val-Thz-Ile-aThr-D-Val-Thz-). The structures of these compounds were analyzed by X-ray diffraction method.

Paper: Effects of amino acids and chirality for molecular folding of desoxazoline-ascidiacyclamide derivatives: X-ray crystal structures of four cyclic octapeptides including unusual amino acid, cyclo(-Ile-aThr-D-Val-Thz-)₂, cyclo(-Ala-aThr-D-Val-Thz-Ile-aThr-D-Val-Thz-), cyclo(-Val-aThr-D-Val-Thz-Ile-aThr-D-Val-Thz-), and cyclo(-Ile-aThr-Val-Thz-Ile-aThr-D-Val-Thz-).

Akiko Asano, Mitsunobu Doi, Kiyomi Kobayashi, Masao Arimoto, Toshimasa Ishida, Yoshio Katsuya, Yoshihiro Mezaki, Hiroshi Hasegawa, Masamichi Nakai, Masahiro Sasaki, Taizo Taniguchi, and Akira Terashima

Biopolymers, 58, 295-304 (2001).

Summary of X-ray structure

compound           iasco             aasco           vasco           ilvasco
Formula            2(C36H56N8O8S2)   C33H50N8O8S2    2(C35H54N8O8S2) 2(C36H56N8O8S2)
Solvent(s)         H2O               CH3CH2OH        2(CH3CH2OH)     4(C3H8O)ĽH2O
  Mr               1604.0            797.0           704.1           1844.4
Crystal system     monoclinic        orthorhombic    monoclinic      monoclinic
Space group        P2                P212121         P21             P21
  a (A)            17.884(10)        18.6011(3)      13.9298(3)      15.4631(299)
  b (A)            11.225(6)         20.2838(3)      18.7115(3)      16.5630(196)
  c (A)            25.41(2)          10.4905(2)      16.2356(4)      20.8925(454)
  b (Ą)            93.90(6)          90.0            91.0671(7)      109.8615(875)
Volume (A3)        5089(6)           3958.08(11)     4231.03(15)     5033(16)
  Z                4                 4               4               4
Temperature (K)    273(2)            100(2)          100(2)          100(2)
Description        plate             cubic           plate           needle
Size (mm3)         0.40x0.25x0.10    0.12x0.12x0.12  0.30x0.12x0.08  0.30x0.02x0.02
Dx (g cm-1)        1.047             1.337           1.295           1.212
F(000)             1716              1704            1768            1972
m (mm-1)           1.350             0.197           0.187           0.166
Radiation source    CuKa             SPring-8*       SPring-8*       SPring-8*
Wavelength (A)     1.5418            0.834           0.834           0.834
NREF               5981              7969            5590            10097
Resolution (A)     0.97              0.80            0.80            0.80
Structure sol.     SHELXS-97         SHELXS-97       SHELXS-97       LODEM
Refinement         SHELXL-97         SHELXL-97       SHELXL-97       SHELXL-97
Npara              983               498             1031            1127
  R1               0.0989            0.0687          0.0510          0.0574
  wR               0.2768            0.1863          0.1486          0.1545
(shift/d)ma        0.222             0.008           0.115           0.348
Drmax (e A3)       0.507             0.828           0.358           0.615
Drmin (e A3)      -0.422            -0.566          -0.367          -0.413

Get PDB            yes               yes             yes             yes

*Data were measured on a synchrotron, SPring-8/BL24XU-A, with the approval of Hyogo prefecture and Japan Synchrotron Radiation Research Institute (Approval No. C99A24XU-005N).

Trials for X-ray diffraction method

Blanketed structures (linked) were solved now (Dec. 1999).