Synthesis and antitumor activity of structural analogues of the epipodophyllotoxins.
Several ring-contracted analogues of the antitumor agent etoposide have been prepared. The synthesis of the simple indanyl system 3 is described along with two bicyclic systems of general structure 4 prepared through a stereoselective allylation of the keto-ester 6. A cis-fused lactone analogue 5, which is isomeric with the etoposide aglycone, has been synthesized via a dialkylation of the indene-2-carboxylate anion. Regiochemical and stereochemical results of these alkylations are described. The cytotoxicity of these derivatives toward several tumor cell lines is described and generally follows the structure-activity relationships known for the agent podophyllotoxin (2).
Klein
L L
LL
Anti-Infective Division, Abbott Laboratories, Abbott Park, Illinois 60064.
Yeung
C M
CM
Chu
D T
DT
McDonald
E J
EJ
Clement
J J
JJ
Plattner
J J
JJ
D000230:Adenocarcinoma / Q000188:drug therapy; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D002277:Carcinoma / Q000188:drug therapy; D055598:Chemical Phenomena; D002621:Chemistry; D003110:Colonic Neoplasms / Q000188:drug therapy; D005047:Etoposide / Q000031:analogs & derivatives / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D007189:Indans / Q000737:chemistry / Q000627:therapeutic use; D007941:Leukemia P388 / Q000188:drug therapy; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D015394:Molecular Structure; D011034:Podophyllotoxin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D007189:Indans; D005047:Etoposide; D011034:Podophyllotoxin