Ww

Paracrystalline aggregates

Equilibria are displaced toward depolymerization FIGURE 8.2 Depoymerization of microtubules following binding of Vinca alkaloids.

2.1.2. Marine natural products binding at the Vinca domain and their analogs

Marine organisms are a rich source of antitumor compounds that have probably evolved as defense mechanisms in the highly competitive marine environment. Many of these compounds are in advanced preclinical or clinical stage of devel-opment.8 Those acting on microtubules by binding at the Vinca domain include the halichondrins, the dolastatins, the hemiasterlins, the cryptophycins, and the spongistatins, among others.

Halichondrin B is a complex polyether macrolide isolated from the marine sponge Halichondria okadai, with an extraordinarily high potency as an antitumor agent and a high therapeutic index. Although its scarcity in natural sources has hampered efforts to develop halichondrin B as a new anticancer drug, the existence of a route allowing its total synthesis9 has paved the way for the preparation of structurally simpler analogs that retain the remarkable potency of the parent compound, specially the closely related E7389 (ER0865) and ER-086526.10 Besides the deletion of a large region of the molecule, the readily biodegradable lactone group in the natural compounds has been replaced with a ketone. Although available evidence points to a mechanism of action involving tubulin binding and microtubule depolymerization, the reasons for the high potency and broad therapeutic indexes of these compounds are unclear. The more active of the synthetic compounds, E-7389, is under clinical trials for breast11 and prostate12 cancers.

R = NH2 E7389 (ER-086526) R = OH ER-076349

Dolastatin 10, a linear peptide, was isolated in 1987 from an Indian Ocean mollusc, the sea hare Dolabella auricularia. Although this compound progressed through to Phase II trials as a single agent, it did not demonstrate significant antitumor activity against prostate cancer13 or metastatic melanoma.14 Many synthetic derivatives of the dolastatins have been prepared, among which TZT-1027 (auristatin PE, soblidotin),15 cemadotin, and synthadotin have entered clinical trials. The latter compound has the advantage of being orally active and seems to be promising for the treatment of non-small lung cell cancer and refractory prostate cancer.16

Dolastatin 10 was shown to bind to a site close to the Vinca domain where other peptidic agents bound.17 In connection with this finding, it has recently been shown that the Vinca domain in tubulin may be composed of a series of overlapping domains rather than being a single entity, as different levels and types of competition were found when selected tubulin interactive agents were used to investigate the binding characteristics of a tritium-labeled dolastatin probe.18

HsAA^pN H

H3C "CH3

HsAA^pN H

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