Total Synthesis and Conformational Analysis of Apratoxin C

Abstract

Total synthesis of apratoxin C, a cyanobacterial cyclodepsipeptide with highly potent cytotoxicity against some cancer cell lines, was achieved using the apratoxin A synthetic strategy developed by us. To elucidate the relationship between conformation and activity, the tertiary structure of apratoxin C was analyzed by NMR spectroscopy. We obtained 37 ROEs and five (3)JH,H values, which were translated into distance and dihedral angle constraints, respectively. Molecular modeling was performed with a restrained conformational search by a distance geometry method. The lowest energy structure indicated that the methyl group at C37 and the isopropyl group at C39 play critical roles in maintaining the conformation, whereas the methyl group at C34 does not. Moreover, we confirmed that apratoxin A and C possess similar conformations, providing a likely explanation for their nearly equivalent cytotoxicities.

Potent oxazoline analog of apratoxin C: Synthesis, biological evaluation, and conformational analysis

“…The spectral data for 9 were identical with the data previously reported. Additionally, the total yield for alcohol 9 was notably improved to 52%, which was significantly higher than the 34% yield in our previous synthetic method (Scheme ) …”

“…Further modification of 9 was then performed using our previously reported procedure to produce Pro‐Dtrina 8 . The detailed synthesis of apratoxin C oxazoline analog ( 3 ) is illustrated in Scheme .…”

“…Our recent report on the total synthesis of apratoxin C ( 1 ) exhibited their potent cytotoxicities against HCT‐116 cells with IC 50 values of 4.1 n M for 1 and 3.2 n M for 2 , respectively (Table ). The tertiary structures of apratoxins C ( 1 ) and A ( 2 ) were also analyzed through NMR experiments . The distance geometry method was used along with J ‐coupling and ROE data to propose structural models for these molecules.…”

“…After the alkylation of the resulting acid 11 produced ketone 10 , a stereoselective reduction of the ketone and a reduction of the ester moiety furnished intermediate 9 . Conversion of the intermediate into Pro‐Dtrina 8 was performed in the same manner as our previously reported synthesis of apratoxin C ( 1 ) …”

The apratoxin marine natural products: isolation, structure determination, and asymmetric total synthesis

“…The synthesis of apratoxin F was undertaken as part of a SAR study with multiple apratoxin analogs. Like the previous syntheses, 7a,b,d, [11][12][13]39,40 Luesch chose the retrosynthetic pathway in which the macrocycle was disconnected into tripeptide 12b and thiazoline polyketide 130, with the latter having an N-methyl alanine residue where proline previously was (Scheme 28). The synthesis of apratoxin F began with formation of olefin 68 according to Takahashi, Doi and co-workers' second generation synthesis of apratoxin A.…”