Microtubule-modulating Agents in the Fight Against Neurodegeneration: Will it ever Work?

The microtubule skeleton plays an essential role in nerve cells as the most important structural determinant of morphology and as a highway for axonal transport processes. Many neurodegenerative diseases are characterized by changes in the structure and organization of microtubules and microtubule-regulating proteins such as the microtubule-associated protein tau, which exhibits characteristic changes in a whole class of diseases collectively referred to as tauopathies. Changes in the dynamics of microtubules appear to occur early under neurodegenerative conditions and are also likely to contribute to age-related dysfunction of neurons. Thus, modulating microtubule dynamics and correcting impaired microtubule stability can be a useful neuroprotective strategy to counteract the disruption of the microtubule system in disease and aging. In this article, we review current microtubule-directed approaches for the treatment of neurodegenerative diseases with microtubules as a drug target, tau as a drug target, and post-translational modifications as potential modifiers of the microtubule system. We discuss limitations of the approaches that can be traced back to the rather unspecific mechanism of action, which causes undesirable side effects in non-neuronal cell types or which are due to the disruption of non-microtubule-related interactions. We also develop some
thoughts on how the specificity of the approaches can be improved and what further targets could be used for modulating substances.


Maytansinol derivatives: side reactions as a chance for new tubulin binders

Maytansinol is a valuable precursor for the preparation of maytansine derivatives (known as maytansinoids). Inspired by its intriguing structure and their success in targeted cancer therapy, we explored the maytansinol acylation reaction. As a result, we were able to obtain a series of derivatives, bearing 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 obtained 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.


1,3-Benzodioxole-Modified Noscapine Analogues: Synthesis, Antiproliferative Activity, and Tubulin-Bound Structure

Since the revelation of noscapine’s weak anti-mitotic activity, extensive research has been conducted over the past two decades, with the goal of discovering noscapine derivatives with improved potency. To date, noscapine has been explored at the 1, 7, 6’, and 9’-positions, though the 1,3-benzodioxole motif in the noscapine scaffold that remains unexplored. The present investigation describes the design, synthesis and pharmacological evaluation of noscapine analogues consisting of modifications to the 1,3-benzodioxole moiety. This includes expansion of the dioxolane ring and inclusion of metabolically
robust deuterium and fluorine atoms. Favourable structural modifications were subsequently incorporated into multifunctionalised noscapine derivatives that also possessed modifications previously shown to promote anti-proliferative activity in the 1-, 6’- and 9’-positions. Our research efforts afforded the deuterated noscapine derivative 14e and the dioxino-containing analogue 20 as potent cytotoxic agents with EC50 values of 1.50 and 0.73 μM, respectively, against breast cancer (MCF-7) cells. Compound 20 also exhibited EC50 values of <2 μM against melanoma, non-small cell lung carcinoma, and cancers of the
brain, kidney and breast in an NCI screen. Furthermore, compounds 14e and 20 inhibit tubulin polymerisation and are not vulnerable to the overexpression of resistance conferring Pgp efflux pumps in drug-resistant breast cancer cells (NCIADR/RES). We also conducted X-ray crystallography studies that yielded
the high-resolution structure of 14e bound to tubulin. Our structural analysis revealed the key interactions between this noscapinoid and tubulin and will assist with the future design of noscapine derivatives with improved properties.


Microtubule-targeting agents and neurodegeneration

The association of microtubule (MT) breakdown with neurodegeneration and neurotoxicity has provided an emerging therapeutic approach for neurodegenerative diseases. Tubulin binders are able to modulate MT dynamics and, as a result, are of particular interest both as potential therapeutics and experimental tools used to validate this strategy. Here, we provide a comprehensive overview of current knowledge and recent advancements regarding MT-targeting approaches for neurodegeneration and evaluate the potential application of MT-targeting agents (MTAs) based on available preclinical and clinical data.