Isolation and First Total Synthesis of PM050489 and PM060184, Two New Marine Anticancer Compounds

Martín, María Jesús Sánchez; Coello, Laura; Fernandez, Ritin; Reyes, Fernando; Rodríguez, Alberto; Murcia, Carmen; Garranzo, María; Mateo, C. Reyes; Sánchez-Sancho, Francisco; Bueno, Santiago; Eguilior, Carlos de; Francesch, Andrés; Munt, Simon; Cuevas, Carmen

doi:10.1021/ja404578u

Cited by 101 publications

(73 citation statements)

References 32 publications

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“…It has been previously suggested that the structurally distinct MDAs maytansine (9, 11) and PM060184 (13,14) (Fig. 1A) share a common tubulin-binding site with rhizoxin (9,13,14); however, both drugs were also reported to interfere with the binding of vinblastine (9,(14)(15)(16).…”

Section: Resultsmentioning

confidence: 96%

“…1A) share a common tubulin-binding site with rhizoxin (9,13,14); however, both drugs were also reported to interfere with the binding of vinblastine (9,(14)(15)(16). To clarify the exact binding site of maytansine and PM060184 on tubulin and their mode of interaction with the protein, we solved tubulin structures in complex with either drug at 2.1-and 2.0-Å resolution, respectively, using the same experimental approach as for rhizoxin F (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…17, 18, and 30. The synthesis of 2,3-desepoxy rhizoxin and PM060184 has been described elsewhere (13,19). Maytansine was obtained from the National Institutes of Health Open Chemical Repository Collection.…”

Section: Methodsmentioning

confidence: 99%

“…At the molecular level, it is well established that rhizoxin interferes with the binding of vinblastine to tubulin; however, the exact location of its binding site has been a matter of debate (8)(9)(10). Interestingly, biochemical and mutagenesis data suggest that the structurally unrelated MDA maytansine (9,11), which is part of an ADC that was recently approved by the FDA for the treatment of advanced breast cancer (11,12), and the phase 1 drug PM060184 (13,14) (Fig. 1A) share a common tubulin-binding site with rhizoxin (9,13,14).…”

mentioning

confidence: 99%

“…Interestingly, biochemical and mutagenesis data suggest that the structurally unrelated MDA maytansine (9,11), which is part of an ADC that was recently approved by the FDA for the treatment of advanced breast cancer (11,12), and the phase 1 drug PM060184 (13,14) (Fig. 1A) share a common tubulin-binding site with rhizoxin (9,13,14). These two latter drugs have also been reported to interfere with the binding of vinblastine; however, as for rhizoxin, the exact binding sites and modes of action of maytansine and PM060184 have not been elucidated (9,(14)(15)(16).…”

mentioning

confidence: 99%

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A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs

Prota

Bargsten

Dı́az

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The recent success of antibody-drug conjugates (ADCs) in the treatment of cancer has led to a revived interest in microtubuledestabilizing agents. Here, we determined the high-resolution crystal structure of the complex between tubulin and maytansine, which is part of an ADC that is approved by the US Food and Drug Administration (FDA) for the treatment of advanced breast cancer. We found that the drug binds to a site on β-tubulin that is distinct from the vinca domain and that blocks the formation of longitudinal tubulin interactions in microtubules. We also solved crystal structures of tubulin in complex with both a variant of rhizoxin and the phase 1 drug PM060184. Consistent with biochemical and mutagenesis data, we found that the two compounds bound to the same site as maytansine and that the structures revealed a common pharmacophore for the three ligands. Our results delineate a distinct molecular mechanism of action for the inhibition of microtubule assembly by clinically relevant agents. They further provide a structural basis for the rational design of potent microtubuledestabilizing agents, thus opening opportunities for the development of next-generation ADCs for the treatment of cancer.drug mechanism | microtubule-targeting agents | X-ray crystallography

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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs

Prota

Bargsten

Dı́az

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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236

227

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(2 E )‐3‐(Tributylstannyl)‐2‐propenoic acid

Anderl¹

2022

Encyclopedia of Reagents for Organic Synthesis

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Hydrozirconation of Alkynes

Milligan,

Hammill,

Crocker

et al. 2023

Organic Reactions

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Since the first preparation of organozirconocenes from alkenes and alkynes in 1972, hydrozirconation has become one of the most commonly used stoichiometric methods to convert readily available starting materials into reactive but stable organometallic intermediates. A broad range of subsequent transformations may be employed to convert organozirconocenes in situ into high‐value functionalized products, often with the strategic formation of one (or several) new carbon–carbon bonds. This chapter focuses on the hydrozirconation of terminal and internal alkynes, and the subsequent synthetic transformations of the resulting alkenylzirconocenes. Zirconocene hydrochloride, Cp 2 Zr(H)Cl, is most frequently employed for the hydrozirconation step and can be used as a reagent or prepared in situ. Subsequent reactions of alkenylzirconocenes include additions to inorganic electrophiles such as halogens, as well as in situ ligand transfers to other metals, such as palladium and zinc, that further expand the range of accessible bond formations. The initial discussion focuses on the mechanism and stereochemical considerations, and on the steric and electronic factors that determine the regiochemistry of the either kinetically or thermodynamically controlled hydrozirconation. The “Scope and Limitations” section presents information on functional group compatibilities and is organized by the type of synthetic transformation of alkenylzirconocenes. Representative applications of the hydrozirconation of alkynes are showcased in syntheses of natural products, comparisons to alternative methods for the hydrometallation of alkynes. The goal of this chapter is to demonstrate the significance of hydrozirconation in organic synthesis, including the utility of the stoichiometric zirconium organometallics obtained from alkyne substrates, and to provide inspiration for the future development of new synthetic methods and strategies.

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Isolation and First Total Synthesis of PM050489 and PM060184, Two New Marine Anticancer Compounds

Cited by 101 publications

References 32 publications

A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs

A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs

(2 E )‐3‐(Tributylstannyl)‐2‐propenoic acid

Hydrozirconation of Alkynes

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