Acylshikonin analogues: synthesis and inhibition of DNA topoisomerase-I.
Compounds bearing an acyl group of a various size at 1'-OH of shikonin were synthesized as acyl analogues of shikonin, which was isolated from the root of Lithospermum erythrorhizon, and evaluated for inhibitory effect on topoisomerase-I activity. A selective acylation at 1'-OH of shikonin in the presence of dicyclohexylcarbodiimide and 4-(dimethylamino)pyridine gave rise to a good yield of corresponding acylshikonin derivatives. In general, analogues with an acyl group of shorter chain lengths (C2-C6) exerted a stronger inhibitory action than those with longer chain lengths (C7-C20). While the halogen substitution at C-2 of the acetyl moiety failed to increase the inhibitory potency, the placement of double bonds in the acyl group (C5-C7) augmented the potency remarkably. Of the 32 derivatives evaluated, 15 compounds exhibited a higher inhibitory effect than shikonin. Noteworthy, the inhibitory potency of acetylshikonin, propanoylshikonin, and 4-pentenoylshikonin was approximately 4-fold greater than that of camptothecin. All these data suggest that the size of acyl moiety is important for the enhancement of potency, and the presence of olefinic double bonds is also beneficial.
Ahn
B Z
BZ
College of Pharmacy, Chungnam National University, Korea.
Baik
K U
KU
Kweon
G R
GR
Lim
K
K
Hwang
B D
BD
D000107:Acetylation; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000494:pharmacology*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004278:DNA, Superhelical / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D009285:Naphthoquinones / Q000138:chemical synthesis* / Q000494:pharmacology*; D010936:Plant Extracts / Q000494:pharmacology; D018517:Plant Roots / Q000737:chemistry; D059004:Topoisomerase I Inhibitors
D000972:Antineoplastic Agents, Phytogenic; D004278:DNA, Superhelical; D009285:Naphthoquinones; D010936:Plant Extracts; D059004:Topoisomerase I Inhibitors; C016101:shikonin; D004264:DNA Topoisomerases, Type I