Geiparvarin analogues. 4. Synthesis and cytostatic activity of geiparvarin analogues bearing a carbamate moiety or a furocoumarin fragment on the alkenyl side chain.
As a continuation of previous studies on the synthesis and antitumor activity of geiparvarin analogues bearing a carbamate moiety in the alkyl side chain, a series of N-substituted [(E)-3-(4,5-dihydro-5,5-dimethyl-4-oxo-2-furanyl)-2- butenyl]carbamates (15a-f) were synthesized and tested with the objective to investigate the reason for the marked difference of cytostatic activity found between alkyl and phenyl derivatives. A series of compounds, characterized by different physicochemical properties, were designed in order to study this hypothesis. Moreover, to further investigate the modification of the alkenyl side chain, (E)- and (Z)-[2-(4,5-dihydro-5,5-dimethyl-4-oxo-2-furanyl)propenyl]-7H-furo[3,2- g][1]benzopyran-7-one (11a,b) were synthesized, the latter compounds being the combination of two units, namely, the 3(2H)-furanone ring system endowed with potent alkylating properties and the furocoumarin portion which binds to DNA resulting in potential DNA-targeted alkylating agents. The compounds were tested for their cytostatic activity against proliferation of murine (L1210) and human (Molt/4, CEM, or MT-4) tumor cells. The highest cytostatic activity found within both series of carbamic derivatives (15a-d,k and 15e,g-j) was associated with the highest global lipophilicity. With regard to compounds 11a,b, the cytostatic activity of (Z)-furocoumarin 11b might be related to a specific interaction with DNA (i.e., intercalation).
Manfredini
S
S
Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Italy.
Baraldi
P G
PG
Bazzanini
R
R
Guarneri
M
M
Simoni
D
D
Balzarini
J
J
De Clercq
E
E
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D002219:Carbamates / Q000032:analysis*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology*; D011564:Furocoumarins / Q000032:analysis*; D006801:Humans; D007939:Leukemia L1210 / Q000473:pathology; D051379:Mice; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D002219:Carbamates; D003374:Coumarins; D011564:Furocoumarins; C058446:geiparvarin