Microtubule-Stabilizing Marine Metabolite Laulimalide and Its Derivatives:  Synthetic Approaches and Antitumor Activity

Mulzer, Johann; Öhler, Elisabeth

doi:10.1021/cr940368c

Cited by 83 publications

(32 citation statements)

References 170 publications

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“…The first total synthesis of 36 was reported by Ghosh and co-workers. 154 Several other synthetic approaches, reviewed by Mulzer and Ohler, 155 have been developed. Notably, scientists at the Eisai Research Institute were able to synthesize sufficient quantities of laulimalide to enable in vivo efficacy studies.…”

Section: Mt-stabilizing Natural Products and Analogues Thereofmentioning

confidence: 99%

Microtubule Stabilizing Agents as Potential Treatment for Alzheimer’s Disease and Related Neurodegenerative Tauopathies

et al. 2012

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The microtubule (MT)-associated protein tau, which is highly expressed in the axons of neurons, is an endogenous MT-stabilizing agent that plays an important role in the axonal transport. Loss of MT-stabilizing tau function, caused by misfolding, hyperphosphorylation and sequestration of tau into insoluble aggregates, leads to axonal transport deficits with neuropathological consequences. Several in vitro and preclinical in vivo studies have shown that MT-stabilizing drugs can be utilized to compensate for the loss of tau function and to maintain/restore an effective axonal transport. These findings indicate that MT-stabilizing compounds hold considerable promise for the treatment of Alzheimer disease and related tauopathies. The present article provides a synopsis of the key findings demonstrating the therapeutic potential of MT-stabilizing drugs in the context of neurodegenerative tauopathies, as well as an overview of the different classes of MT-stabilizing compounds.

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Section: Mt-stabilizing Natural Products and Analogues Thereofmentioning

confidence: 99%

Microtubule Stabilizing Agents as Potential Treatment for Alzheimer’s Disease and Related Neurodegenerative Tauopathies

et al. 2012

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“…[6] In addition, d-lactones are very useful building blocks for the synthesis of bioactive compounds. [7] Many approaches, most often multistep procedures, have been elaborated for the preparation of d-lactones. [8] The most direct route to a,b-unsaturated d-lactones is based on hetero-Diels-Alder (HDA) reactions.…”

mentioning

confidence: 99%

Catalytic Asymmetric Formation of δ‐Lactones by [4+2] Cycloaddition of Zwitterionic Dienolates Generated from α,β‐Unsaturated Acid Chlorides

Tiseni

Peters

2007

Angew Chem Int Ed

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d-Lactones are subunits of numerous natural and unnatural products that display a wide range of biological activity. In many cases they show high efficacy as antibacterial, [1] antiviral (HIV protease inhibitors), [2] anticancer, [3] immunosuppressive, [4] or cholesterol-lowering agents (HMGR inhibitors). [5] For example, the majority of statin drugs such as Lipitor and Zocor, the worlds best-selling drugs in 2004, contain a bhydroxy-d-lactone moiety or the corresponding open-chain dhydroxy carboxylate form. [6] In addition, d-lactones are very useful building blocks for the synthesis of bioactive compounds. [7] Many approaches, most often multistep procedures, have been elaborated for the preparation of d-lactones. [8] The most direct route to a,b-unsaturated d-lactones is based on hetero-Diels-Alder (HDA) reactions. [9] In order to generate directly the desired oxidation state, a vinylketene equivalent such as a vinylketene acetal is required as the diene component. It has been reasoned though that twofold substitution at the butadiene terminus has a deleterious effect upon the enantioselectivity of HDA reactions, thus explaining why these dienes have been less frequently used in asymmetric HDA reactions than Danishefsky-type dienes. [10] Up to now, only three highly enantioselective, catalytic HDA-based methodologies using a vinylketene acetal have been reported, [11][12][13] which are all restricted to the use of Brassard-type dienes (1,3dialkoxy-1-(trimethylsiloxy)butadienes) [14] and aromatic aldehydes [15] and which all require long reaction times (48-72 h) to provide useful yields.We present herein a new concept for the synthesis of a,bunsaturated d-lactones 6 which circumvents the preformation, isolation, and purification of moisture-and acid-sensitive vinylketene acetals. Our work was based on the hypothesis that substituted vinylketenes 2 should be formed in situ by dehydrohalogenation of a,b-unsaturated acid chlorides 1 (Scheme 1). [16] Vinylketenes are known to be inherently unstable species, [17] but they might be trapped and at the same time activated as a diene component of a Diels-Alder reaction by an enantiopure tertiary amine, thus forming an enantiomerically pure zwitterionic dienolate 4. This type of species was supposed to be reactive enough, in an s-cis conformation, to undergo [4+2] cycloadditions with aldehydes, by either a stepwise or a concerted mechanism. Our investigations were inspired by the tertiary-amine-catalyzed asymmetric synthesis of b-lactones from ketene via zwitterionic enolate intermediates. [18] Because of the considerable homology of 4 to vinylketene acetals, the intermediate formation of these dienolates was anticipated to overcome the pronounced tendency of vinylketenes to preferentially undergo [2+2] cycloaddition reactions. [19] 3,4-Dimethylpent-2-enoyl chloride (1 a; R 1 = iPr) and trichloroacetaldehyde (chloral, 5 a; R 2 = CCl 3 ) were chosen as model substrates for the development of this process. Initial experiments in acetonitrile at À15 8C using stoichiometric ...

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“…The extremely exciting biology and potential of laulimalide as a therapeutic agent has led to a substantial amount of synthetic efforts [87,88]. The first total synthesis of the natural product was completed by Ghosh [89,90].…”

Section: Laulimalidementioning

confidence: 99%

Microtubule-Stabilizing Natural Products as Promising Cancer Therapeutics

Gallagher¹

2007

CMC

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Paclitaxel and related taxanes exhibit their anticancer activity by promoting tubulin polymerization and stabilizing microtubules, which results in mitotic G2/M arrest and apoptosis. The clinical success of paclitaxel in treating a wide array of tumor types has led to numerous efforts to identify novel natural products with paclitaxel-like mechanisms of action, but which may overcome some of the liabilities of the taxanes. Although the list of natural products that share the paclitaxel-like mechanism is relatively small, it continues to expand and currently includes a number of structurally distinct classes. Despite the mechanistic similarities between these classes, differences exist which may translate into their differential efficacy in the clinic. The past several years have seen a considerable amount of pre-clinical and clinical progress in developing these novel microtubule-stabilizing natural products as cancer therapeutics. This review focuses primarily on recent advances published since 2002.

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Microtubule-Stabilizing Marine Metabolite Laulimalide and Its Derivatives: Synthetic Approaches and Antitumor Activity

Cited by 83 publications

References 170 publications

Microtubule Stabilizing Agents as Potential Treatment for Alzheimer’s Disease and Related Neurodegenerative Tauopathies

Microtubule Stabilizing Agents as Potential Treatment for Alzheimer’s Disease and Related Neurodegenerative Tauopathies

Catalytic Asymmetric Formation of δ‐Lactones by [4+2] Cycloaddition of Zwitterionic Dienolates Generated from α,β‐Unsaturated Acid Chlorides

Microtubule-Stabilizing Natural Products as Promising Cancer Therapeutics

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