Maytansinol Derivatives: Side Reactions as a Chance for New Tubulin Binders

Abstract

Maytansinol is a valuable precursor for the preparation of maytansine derivatives (known as maytansinoids). Inspired by the intriguing structure of the macrocycle and the success in targeted cancer therapy of the derivatives, we explored the maytansinol acylation reaction. As a result, we were able to obtain a series of derivatives with novel modifications of the maytansine scaffold. We characterized these molecules by docking studies, by a comprehensive biochemical evaluation, and by determination of their crystal structures in complex with tubulin. The results shed further light on the intriguing chemical behavior of maytansinoids and confirm the relevance of this peculiar scaffold in the scenario of tubulin binders.

Synthesis and Biological Evaluation of C(13)/C(13’)-Bis-Desmethyl-Disorazole Z

“…These findings are in line with the exquisite antiproliferative activity of the compound. The binding constants Kb of 1 and 3 for soluble tubulin were 1.59 ± 0.31 x 10 6 M -1 and 0.95 ± 0.19 x 10 6 M -1 , respectively (mean values ± SEM); Kb values of 1.16 x 10 6 M -1 [53] and 9.0 x 10 7 M -1 [54] have been reported for maytansine. [55] Unsurprisingly, the removal of the C(13)/C(13') side chains in analog 32 leads to a drop in cellular potency of several 1000-fold (Table 1); [56] likewise, the compound at 10% super-stoichiometric concentration affects tubulin polymerization in vitro only weakly.…”

Maytansinol Functionalization: Towards Useful Probes for Studying Microtubule Dynamics

“…Previously, it has been shown that the ester at the C‐3 position of ansamitocins, maytansine, and maytansinoids plays an important role in biological activity and cell permeability [3,13,14] . In our recent study, we extensively investigated a series of C‐3 derivatized maytansinoids obtained by acylation of maytansinol [12] . By X‐ray crystallography experiments, we observed that the studied maytansinoids retained a fundamental spatial arrangement with respect to β‐tubulin.…”

“…Conjugate compounds 7-10 can be obtained by a CuAAC reaction between the fragment of an alkyne (11,15,16) and an azide (12)(13)(14) providing the corresponding triazole derivatives (Scheme 3). Both fragments can be prepared as ester starting from maytansinol and guanosine (or acyclovir) by condensation with carboxylic acids.…”

“…[10] However, the high-affinity of maytansine towards β-tubulin (K D = 6.8-14 nM) not only makes it well suited as a cytotoxin, but also derivatives with a similar affinity could be used as molecular probes. [11,12] As of today, effortless generation of maytansine-based molecular probes is hampered by major drawbacks such as the complexity of the natural product scaffold and lack of SAR studies, which could suggest suitable points for attachment of fluorophore tags or radionuclides. Here, we report on both of these aspects: the chemistry of maytansinol (Figure 1, 1) for the creation of maytansinoid conjugates and the suitability of the C3-position to tolerate bulky substituents without affecting the binding mode.…”

“…This success has further prompted their development as targeted cancer therapeutics, for example, in the form of nanoparticles [8,9] or recently reported immune checkpoint‐targeting maytansinoid conjugates [10] . However, the high‐affinity of maytansine towards β‐tubulin ( K D =6.8–14 nM) not only makes it well suited as a cytotoxin, but also derivatives with a similar affinity could be used as molecular probes [11,12] . As of today, effortless generation of maytansine‐based molecular probes is hampered by major drawbacks such as the complexity of the natural product scaffold and lack of SAR studies, which could suggest suitable points for attachment of fluorophore tags or radionuclides.…”