Synthesis of 6-Halo-Substituted Pericosine A and an Evaluation of Their Antitumor and Antiglycosidase Activities.

The enantiomers of 6-fluoro-, 6-bromo-, and 6-iodopericosine A were synthesized. An efficient synthesis of both enantiomers of pericoxide via 6-bromopericosine A was also developed. These 6-halo-substituted pericosine A derivatives were evaluated in terms of their antitumor activity against three types of tumor cells (p388, L1210, and HL-60) and glycosidase inhibitory activity. The bromo- and iodo-congeners exhibited moderate antitumor activity similar to pericosine A against the three types of tumor cell lines studied. The fluorinated compound was less active than the others, including pericosine A. In the antitumor assay, no significant difference in potency between the enantiomers was observed for any of the halogenated compounds. Meanwhile, the (-)-6-fluoro- and (-)-6-bromo-congeners inhibited α-glucosidase to a greater extent than those of their corresponding (+)-enantiomers, whereas (+)-iodopericosine A showed increased activity when compared to its (-)-enantiomer.

Enantiomeric composition of natural pericosine A derived from Periconia byssoides and α-glycosidase inhibitory activity of (-)-enantiomer.

Chiral high-performance liquid chromatography (HPLC) analysis of natural pericosine A, which appeared in literature first in 1977, from Periconia byssoides was conducted using a column CHIRALPAK® AD-H to determine the enantiomeric composition of the original mixture which was found to be 68: 32 mixtures of (+)- and (-)-enantiomer, respectively. Furthermore, two independently isolated samples of pericosine A from the same fungus were also analyzed to show the two peaks in the HPLC charts at approximate 1:1 ratio. These results concluded that pericosine A derived from Periconia byssoides was indeed an enantiomeric mixture. Synthesized enantiomers were subjected to evaluation of antitumor activity against three kinds of tumor cells (p388, L1210, HL-60), indicating moderate cytotoxicity against all three kinds of tumor cell lines, but significant difference in potency between the enantiomers was not observed. In contrast, when both the enantiomers of pericosine A were evaluated against five kinds of glycosidases-inhibitory activities (α- and ß-glucosidases, α- and ß-galactosidases, and α-mannosidase), an apparent difference on anti-glycosidase assay was found between the enantiomers: (-)-pericosine A inhibited α-glucosidase at IC50 : 2.25 mM, and ß-galactosidase at IC50 : 5.38 mM, albeit the (+)-enantiomer showed inactivity against these five enzymes.

Syntheses and Glycosidase Inhibitory Activities, and in Silico Docking Studies of Pericosine E Analogs Methoxy-Substituted at C6.

Inspired by the significant -glucosidase inhibitory activities of (+)- and (-)-pericosine E, we herein designed and synthesized 16 analogs of these marine natural products bearing a methoxy group instead of a chlorine atom at C6. Four of these compounds exhibited moderate -glucosidase inhibitory activities, which were weaker than those of the corresponding chlorine-containing species. The four compounds could be prepared by coupling reactions utilizing the (-)-pericosine B moiety. An additional in silico docking simulation suggested that the reason of reduced activity of the C6-methoxylated analogs might be an absence of hydrogen bonding between a methoxy group with the surrounding amino acid residues in the active site in -glucosidase.

Synthesis of Natural O-Linked Carba-Disaccharides, (+)- and (-)-Pericosine E, and Their Analogues as α-Glucosidase Inhibitors.

Pericosine E (6), a metabolite of Periconia byssoides OUPS-N133 was originally isolated from the sea hare Aplysia kurodai, which exists as an enantiomeric mixture in nature. The enantiospecific syntheses of both enantiomers of Periconia byssoides OUPS-N133 has been achieved, along with six stereoisomers, using a common simple synthetic strategy. For these efficient syntheses, highly regio- and steroselective processes for the preparation of bromohydrin and anti-epoxide intermediates were applied. In order to access the unique O-linked carbadisaccharide structure, coupling of chlorohydrin as a donor and anti-epoxide as an acceptor was achieved using catalytic BF3·Et2O. Most of the synthesized compounds exhibited selectively significant inhibitory activity against α-glycosidase derived from yeast. The strongest analog showed almost 50 times the activity of the positive control, deoxynojirimycin.

Synthesis of marine natural product (-)-pericosine E.

The first synthesis of (-)-pericosine E (6), a metabolite of the Periconia byssoides OUPS-N133 isolated originally from the sea hare Aplysia kurodai, has been achieved. Efficient and regioselective synthetic procedures for the synthesis of key intermediates, anti- and syn-epoxides 9 and 10, were developed using an anti-epoxidation of diene 12 with TFDO and a bromohydrination of 12 with NBS in CH(3)CN/H(2)O (2:3), respectively. In addition, comparison of the specific optical rotations between synthetic 6 and natural 6 elucidated that the naturally preferred enantiomer of pericosine E had the same absolute configuration as (-)-6 synthesized from chlorohydrin (-)-8 and anti-epoxide (+)-9.

Stereostructure reassignment and determination of the absolute configuration of pericosine D(o) by a synthetic approach.

A combination of chemical synthesis and NMR methods was used to reassign the structure of pericosine D(o) (8), a cytotoxic marine natural product produced by the fungus Periconia byssoides OUPS-N133 that was originally derived from the sea hare Aplysia kurodai. Chemical synthesis was used to prepare pericoisne D(o) (8) from a known chlorohydrin that was in turn derived from (-)-quinic acid. The absolute configuration of natural pericosine D(o) (8) was determined to be methyl (3R,4S,5S,6S)-6-chloro-3,4,5-trihydroxy-1-cyclohexene-1-carboxylate. HPLC analyses using a chiral-phase column indicated that pericosine D(o) (8) exists in an enantiomerically pure form in nature.

Facile and efficient synthesis of naturally occurring carbasugars (+)-pericosines A and C.

An efficient synthesis of antitumor marine natural product (+)-pericosine A was achieved from (-)-quinic acid in 11.7% overall yield, which is 20 times better than our previously reported synthesis. The crucial steps of this synthesis include the regio- and stereoselective bromohydrination of an unstable diene and the ring opening of an epoxide. This synthetic route was applicable to a synthesis of (+)-pericosine C and also to a synthesis of (-)-pericosine C.

Synthesis of (-)-pericosine B, the antipode of the cytotoxic marine natural product.

The stereoselective synthesis of (-)-pericosine B, which is the antipode of the cytotoxic metabolite of the fungus Periconia byssoides OUPS-N133 separated from the sea hare, was accomplished in 9 steps in 12% total yield from (-)-quinic acid, together with the synthesis of its epimer. Every crucial step of this total synthesis, including ring opening of a beta-epoxide and NaBH4 reduction of an unstable beta,gamma-unsaturated enone, proceeded with excellent stereoselectivity.