Methylenedioxy-benzopyran analogs of podophyllotoxin, a new synthetic class of antimitotic agents that inhibit tubulin polymerization.
A new class of compounds was synthesized and, based on structural analogy to podophyllotoxin, examined as potential microtubule inhibitors and evaluated for in vivo antineoplastic activity. These agents are derivatives of methylenedioxy-benzopyran bearing a phenyl substituent at position 8. The hydrogen atoms at positions 7 and 8 are in a trans configuration, in contrast to the cis configuration of analogous hydrogen atoms at positions 1 and 2 in podophyllotoxin. Compounds with a variety of substituents at positions 6 and 7 were examined, as well as compounds with varying methoxy substituent patterns on the phenyl ring attached at position 8. The most active compounds inhibited tubulin polymerization at concentrations approximately stoichiometric with tubulin, competitively inhibited the binding of colchicine to tubulin, and caused mitotic arrest at cytotoxic drug concentrations. No structure-activity correlations were obvious for the substituents at positions 6 and 7, but optimal activity was only observed when the phenyl substituent at position 8 was a trimethoxybenzene ring identical to the analogous ring in podophyllotoxin (i.e. methoxy groups at positions 3', 4' and 5'). Despite their structural and functional similarities to podophyllotoxin, however, the methylenedioxy-benzopyran derivatives subtly differ from the natural product in their interaction with tubulin, for they stimulated rather than inhibited tubulin-dependent GTP hydrolysis.
Batra
J K
JK
Laboratory of Pharmacology and Experimental Therapeutics, National Cancer Institute, Bethesda, MD 20892.
Kang
G J
GJ
Jurd
L
L
Hamel
E
E
D000818:Animals; D000970:Antineoplastic Agents; D001578:Benzopyrans / Q000378:metabolism; D001667:Binding, Competitive; D002417:Cattle; D003078:Colchicine / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D066298:In Vitro Techniques; D008870:Microtubules / Q000187:drug effects*; D008938:Mitosis / Q000187:drug effects*; D011034:Podophyllotoxin / Q000378:metabolism; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*
D000970:Antineoplastic Agents; D001578:Benzopyrans; D014404:Tubulin; D006160:Guanosine Triphosphate; D011034:Podophyllotoxin; D003078:Colchicine