Modifications in the upper or Velbenamine Part of the Vinca Alkaloids have Major Implications for Tubulin Interacting Activities

Abstract

Vinca alkaloids represent a chemical class of major interest in cancer chemotherapy. The lead compounds vinblastine and vincristine have been employed in clinical practice for more than thirty years and remain widely used to this day. Several hundred derivatives have been synthesised and evaluated for their pharmacological activities, the majority being modified in the vindoline moiety, bearing several reactive centers. These efforts led to the identification of the amido derivative vindesine, registered in Europe in 1980 and now available in several countries. Then novel chemistry permitted the semisynthesis of derivatives modified in the velbenamine "upper" part of the molecule, creating a new potential in the Vinca alkaloids medicinal chemistry: as a result, vinorelbine, obtained by C' ring contraction of anhydrovinblastine, and is now marketed worldwide. Several strategies aimed at the total synthesis of vinblastine derivatives have been investigated, giving the opportunity to design rationally certain compounds. Modifications in the D' ring appeared to induce dramatic changes in the tubulin interactions. These observations have been confirmed recently by the identification of unprecedented pharmacological properties exerted by the novel fluorinated Vinca alkaloid, vinflunine. This review will focus more specifically on derivatives which have been modified in the velbenamine part, with the aim of inducing different chemical and pharmacological properties.

Targeting the Cytoskeleton with Plant-Bioactive Compounds in Cancer Therapy

“…Vincristine, vinblastine, and vindesine are the irst vinca alkaloids used as antitumor drugs. Vinorelbine is the irst new second-generation vinca alkaloid, while vinlunine, a bis-luorinated vinorelbine derivative, was synthesized by superacid chemistry and studied in phase I-III clinical trials [14,15].…”

Antiangiogenic Concentrations of Vinflunine Increase the Interphase Microtubule Dynamics and Decrease the Motility of Endothelial Cells

“…Microtubule-targeting drugs (MTD), e.g., Vinca alkaloids and taxanes, are major cancer chemotherapeutic drugs largely used in many human tumoral diseases. Vinflunine, the newest Vinca alkaloid, currently in phase III clinical trials (2), is a fluorinated compound obtained by superacid chemistry (3). Similar to other MTDs, vinflunine suppresses microtubule dynamics both in vitro (4,5) and in living cancer cells (4,6).…”

Vinflunine in platinum‐pretreated patients with locally advanced or metastatic urothelial carcinoma

“…7,8 Preclinical studies demonstrated that it has more activity than vinblastine or vinorelbine. 9,10 For example, in an orthotopic model of bladder cancer in mice, vinflunine was found to be more effective than vinorelbine.…”