New anti-mitotic drugs with distinct anti-calmodulin activity

• Published in: Mini reviews in medicinal chemistry Vol. 6; no. 10; p. 1145
• Main Authors: Orosz, F, Horváth, I, Ovádi, J
• Format: Journal Article
• Language: English
• Published: Netherlands 01.10.2006
• Subjects: Animals; Antineoplastic Agents - adverse effects; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Calmodulin - antagonists & inhibitors; Calmodulin - chemistry; Cell Proliferation - drug effects; Drug Screening Assays, Antitumor; Humans; Indole Alkaloids - adverse effects; Indole Alkaloids - chemistry; Indole Alkaloids - pharmacology; Microtubules - drug effects; Mitosis - drug effects; Molecular Conformation; Structure-Activity Relationship; Tubulin - drug effects
• ISSN: 1389-5575
• DOI: 10.2174/138955706778560094

Bisindole Vinca alkaloids target microtubule system causing anti-mitotic activity. The problem of their clinical application is the lack of selectivity resulting in toxic side effects. In this paper we review the late history of new bisindole derivatives focusing on KARs recognized as potent anti-cancer drugs with low side effect. KARs, just as other bisindoles, impede microtubule assembly of mitotic spindle, however, they display no anti-calmodulin activity. This new drug family appears to be less potent than vinblastine in vitro systems, but it shows high antitumor efficacy with considerably higher doses being well tolerated in the animal tumor models. 3D data of calmodulin complexed with KAR-2 explain the specificity and unique pharmacology of KAR derivatives.