Inhibitors of Microtubule Assembly

7.04.2.1 Inhibitors Targeting the Vinca Alkaloid Binding Domain

In this well-known class, tubulin binding agents can be divided broadly into two categories, peptidic and nonpeptidic.1 The nonpeptide compounds bind within the vinca domain and can be either competitive or noncompetitive inhibitors of vinca alkaloid binding to tubulin.2 The peptides and depsipeptides, however, are exclusively noncompetitive inhibitors of vinca-tubulin binding, and recent evidence suggests that these compounds bind tubulin at the so-called peptide binding site, which is distinct from and yet proximal to the vinca site.3 Rather than simply destabilizing microtubules, the vinca alkaloids alter the dynamic equilibrium of tubulin addition and loss at mitotoic spindles.4-6

Many of these compounds have generated clinical interest, and currently three vinca alkaloids are in clinical use. A number of vinca domain inhibitors, including analogs of halichondrin, dolastatin, and hemiasterlin, are currently under clinical evaluation, and several excellent reviews covering their clinical progress have recently been published.7-10

7.04.2.1.1 Nonpeptide vinca site inhibitors

7.04.2.1.1.1 Vinca alkaloids

The vinca bis-indole alkaloids, isolated from Catharanthus roseus, include naturally occurring vinblastine 1 and vincristine 2. These compounds have demonstrated clinical utility against leukemias and lymphomas since the early 1960s.11'12 Vinblastine, primarily used in the treatment of Hodgkin's disease,13 and vincristine, part of combination therapy for non-Hodgkin's lymphoma, are currently the subjects of several human clinical trials.14 The mode of action of the vinca alkaloids involves inhibition of tubulin dynamics by binding at the vinca site.15 More recently, it has been suggested that antiangiogenesis may play a role in the antiproliferative activity of these compounds.16

In addition to the naturally occurring vinca alkaloids (Figure 2), a semisynthetic analog, vinorelbine 4,17,18 has been approved by the US Food and Drug Administration for treatment of nonsmall-cell lung cancer either as a single agent or in combination with cisplatin.19 Further evaluation of the vinca structure-activity relationship (SAR)20-23 has led to the identification of several analogs, including vinflunine 5 and KAR-2 6, that have progressed to advanced preclinical and clinical trials.24-26

7.04.2.1.1.2 Maytansines

The isolation and structure of maytansine 7 from the East African shrubs Maytenus serrata and M. buchananii was reported by Kupchan et al. in 1972.27 This compound inhibits tubulin polymerization by binding within the vinca domain adjacent to the vinca site. Thus, binding of maytansine at this site inhibits vinblastine binding and prevents association of GTP with tubulin. This binding site is shared by rhizoxin 8.28,29 In addition to several naturally occurring maytansinoids, a number of semisynthetic analogs have been prepared to aid in establishing an SAR, and the resulting data are summarized in Figure 3.30-33 Although the presence of a C-3 ester is required for activity, structural variability of the side chain is allowed; furthermore, the presence of the C-9 carbinolamide is essential for antiproliferative activity. Although no maytansinoids are currently in clinical use, an immunoconjugate of DM1, a C-3 side-chain analog of maytansine, was recently evaluated in phase I human clinical trials as part of an antibody-directed therapy.34 The immunoconjugate was delivered intravenously over 30 min at doses ranging from 22 to 296 mg m - 2. The most common toxicity involved elevation of hematologic transaminases. Nausea, vomiting, fatigue, and diarrhea were observed.35

7.04.2.1.1.3 Rhizoxin

Rhizoxin 8, a 16-membered macrocyclic lactone isolated in 1984 from the fermentation broth of Rhizopus chinensis, was originally identified as the fungal phytotoxin responsible for rice seedling blight.36,37 It is biosynthesized by an

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