Geiparvarin analogues. 3. Synthesis and cytostatic activity of 3(2H)-furanone and 4,5-dihydro-3(2H)-furanone congeners of geiparvarin, containing a geraniol-like fragment in the side chain.
Continuing our study on the structural features of geiparvarin (1), responsible for cytostatic activity, a series of 4,5-dihydro-3(2H)-furanones 10a-f and of 3(2H)-furanones 11a-f as well as 2",3"-dihydrogeiparvarin (14) have been designed and synthesized. Their cytostatic activity was evaluated against proliferation of murine (L1210, FM3A) and human (Raji, Molt/4F, and MT4) tumor cells. Modifications in the region of the olefinic double bond by introduction of the characteristic alkenyl side chain of ascofuranone (compounds 10a-f and 11a-f) markedly decreased the cytostatic activity as compared to geiparvarin itself, but this effect does not seem to be correlated to the presence of the furanone moiety linked to the alkenyl chain or to the ability to afford Michael type adducts. Replacement of the coumarin portion by other aromatic rings did not alter the cytostatic activity. The essential inactivity of 2",3"-dihydrogeiparvarin (14) points to the importance of the 3(2H)-furanone ring system in the cytostatic activity; consequently, this moiety may be considered as the determinant pharmacophore for antitumor activity, while the side chain plays a rather modulatory role.
Baraldi
P G
PG
Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Italy.
Manfredini
S
S
Simoni
D
D
Tabrizi
M A
MA
Balzarini
J
J
De Clercq
E
E
D000080462:Acyclic Monoterpenes; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D003374:Coumarins / Q000138:chemical synthesis* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005663:Furans / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects; D051379:Mice; D013729:Terpenes / Q000737:chemistry*; D014407:Tumor Cells, Cultured
D000080462:Acyclic Monoterpenes; D000972:Antineoplastic Agents, Phytogenic; D003374:Coumarins; D005663:Furans; D013729:Terpenes; C074657:2'',3''-dihydrogeiparvarin; C007836:geraniol; C058446:geiparvarin