Geiparvarin Analogs. 4.1. Synthesis and Cytostatic Activity of Geiparvarin Analogs 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-butenyllcarbama(t1e5s a-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 (2)-[2-(4,5-dihydro- 5,5-dimethy1-4-oxo-2-furany1)propeny11-7~-furo[3,2-g][11benzop~an-7-o(nllea ,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/ 4F, 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 lla,b, the cytostatic activity of (Z)-furocoumarin llb might be related to a specific interaction with DNA (Le., intercalation).