Drugs that inhibit tubulin polymerization: the particular case of podophyllotoxin and analogues.
Tubulin being a major cellular target for antitumor drugs, tubulin-interacting compounds have attracted great attention as antimitotic agents. Two main classes of antimitotic drugs are known and one of them includes podophyllotoxin, a natural product. The clinical use of podophyllotoxin in the treatment of cancer has been limited by severe toxic side effects. In an attempt to find less toxic analogues, many podophyllotoxin derivatives have been prepared. Identification of two types of mechanisms of action has led to the development of two groups of podophyllotoxin analogues: tubulin polymerisation inhibitors and topoisomerase II inhibitors. The present article focuses on the first group of podophyllotoxin analogues i.e. those that retain "podophyllotoxin-like" activity. The review starts with a short summary of the structural characteristics of tubulin and its interactions with drugs that affect the microtubule dynamics and then deals with the particular case of podophyllotoxin. Particular attention is given to the nature and the location of the binding sites compared to those of colchicine. The main purpose of the present review being the search for structure-activity relationships, the structural significant features required for antitubulin activity are described and discussed in details.
Desbène
Stéphanie
S
Laboratoire de Chimie Thérapeutique, UMR CNRS-Université René Descartes N 8638, Faculté des Sciences Pharmaceutiques et Biologiques, 4 avenue de l'Observatoire, 75270 Paris Cedex 06, France.
Giorgi-Renault
Sylviane
S
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D001704:Biopolymers / Q000037:antagonists & inhibitors; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D001704:Biopolymers; D050257:Tubulin Modulators; D011034:Podophyllotoxin