Synthesis and structure-activity relationship study of aldose reductase inhibiting marine alkaloid lukianol A and its derivatives

• Published in: Bioscience, biotechnology, and biochemistry Vol. 87; no. 2; pp. 148 - 157
• Main Authors: Ishibashi, Fumito, Zha, Shijiao, Kondo, Taiyo, Sakamoto, Mayu, Ueno, Mikinori, Fukuda, Tsutomu
• Format: Journal Article
• Language: English
• Published: England 24.01.2023
• Subjects: Aldehyde Reductase - metabolism; Alkaloids; Antineoplastic Agents - pharmacology; Enzyme Inhibitors - pharmacology; Humans; Structure-Activity Relationship; aldose reductase inhibitor; lukianol; total synthesis; SAR; marine alkaloid
• ISSN: 1347-6947; 1347-6947
• DOI: 10.1093/bbb/zbac193

Lukianol A (1a) and its six derivatives 1b-1g, in which each hydroxyl groups of 1a was individually modified, were synthesized via the common intermediate 7a, which was obtained by condensation of the styryl carbazate 10 with p-hydroxyphenylpyruvic acid and subsequent [3,3]-sigmatropic rearrangement. The synthesized lukianol derivatives were evaluated for their ability to inhibit human aldose reductase. 4′-O-methyl (1b) and 4′-dehydroxy (1g) derivatives showed the same level of inhibitory activity as 1a (IC50 2.2 µm), indicating that the 4′-OH is irrelevant for the activity. In contrast, methylation of the hydroxyl group at the 4″′-position (1d) resulted in the loss of activity at a concentration of 10 µm, and masking the hydroxyl group at the 4″-position (1e) caused a 9-fold decrease in activity compared with that of 1b, suggesting that the 4″-OH is an essential group, and the 4″′-OH is required for higher activity.