Synthesis and biological evaluation of cis-restrained carbocyclic combretastatin A-4 analogs: Influence of the ring size and saturation on cytotoxic properties

Nowikow, Christina; Fuerst, Rita; Kauderer, Maria; Dank, Christian; Schmid, Walther; Hajdúch, Marián; Řehulka, Jiří; Gurská, Soňa; Mokshyna, Olena; Polishchuk, Pavel; Zupkó, István; Džubák, Petr; Rinner, Uwe

doi:10.1016/j.bmc.2019.07.048

Cited by 19 publications

(13 citation statements)

References 51 publications

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“…Currently, she is a PhD candidate working on an NWO TTW project; her goal is to generate novel 3D fragments by using unique synthetic chemistry methodologies such as high-pressure chemistry and flow chemistry. phobic pocket in the target enzyme, [17,[22][23][24][25][26][27][28][29][30] prevent cis/transisomerization, [31][32][33] improve metabolic stability, [34][35][36] replace aromatic groups as an aryl isostere, [37] conformationally restrict (part of) the molecule [38][39][40][41] or reduce planarity. [42] The use of cyclobutanes in current drugs is limited compared to the use of other recurring structural moieties.…”

Section: Influence On Pharmacological Activitymentioning

confidence: 99%

“…The substitution pattern on the aromatic rings was crucial for its activity, as well as the cis-configuration of the alkene in order to efficiently direct the aromatic substituents to the tubulin target. To enhance the in vivo potency, Nowikow et al [32] wanted to overcome alkene isomerization under physiological conditions by chemically locking the scaffold into the cis-orientation. This was achieved by synthesizing saturated and unsaturated cisconstrained carbocycles from cyclobutyl up to cyclohexyl analogues.…”

Section: Cyclobutanes In Anticancer Compoundsmentioning

confidence: 99%

“…Locks scaffold in biologically active cis-conformation Inducing increased potency Tubulin polymerization inhibitor [32] Cancer Locked into cis-conformation but lower potency Tubulin polymerization inhibitor [33] Cancer…”

Section: Chemical Stabilitymentioning

confidence: 99%

“…This saturation increase also correlates to higher water solubility and lower melting points, both of which are key to successfully develop a lead compound [16] . Moreover, the cyclobutyl ring can be used to direct key pharmacophore groups, [17–22] fill a hydrophobic pocket in the target enzyme, [17,22–30] prevent cis / trans ‐isomerization, [31–33] improve metabolic stability, [34–36] replace aromatic groups as an aryl isostere, [37] conformationally restrict (part of) the molecule [38–41] or reduce planarity [42]…”

Section: Influence On Pharmacological Activitymentioning

confidence: 99%

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Cyclobutanes in Small‐Molecule Drug Candidates

Kolk¹,

Jansen²,

Rutjes³

et al. 2022

ChemMedChem

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Cyclobutanes are increasingly used in medicinal chemistry in the search for relevant biological properties. Important characteristics of the cyclobutane ring include its unique puckered structure, longer CÀ C bond lengths, increased CÀ C π-character and relative chemical inertness for a highly strained carbocycle. This review will focus on contributions of cyclobutane rings in drug candidates to arrive at favorable properties. Cyclobutanes have been employed for improving multiple factors such as preventing cis/trans-isomerization by replacing alkenes, replacing larger cyclic systems, increasing metabolic stability, directing key pharmacophore groups, inducing conformational restriction, reducing planarity, as aryl isostere and filling hydrophobic pockets.[a] M. R. van der Kolk, M.

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Section: Influence On Pharmacological Activitymentioning

confidence: 99%

Section: Cyclobutanes In Anticancer Compoundsmentioning

confidence: 99%

Section: Chemical Stabilitymentioning

confidence: 99%

Section: Influence On Pharmacological Activitymentioning

confidence: 99%

See 2 more Smart Citations

Cyclobutanes in Small‐Molecule Drug Candidates

Kolk¹,

Jansen²,

Rutjes³

et al. 2022

ChemMedChem

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“…As presented in Scheme , the cobalt precatalyst proved tolerant of ester and boron functional groups, expanding the scope of the cycloaddition reaction, as the in situ protocol relied on excess alkyl aluminum reagents that were incompatible with Lewis basic functional groups . The compatibility with alkyl boronate esters is attractive for access to cyclobutenes that can be used in subsequent cross-coupling reactions . Attempts to expand the scope of the reaction to terminal alkynes were unsuccessful, as the addition of excess ethylene to solutions containing phenylacetylene or 1-octyne in the presence of [(dppf)Co(η 6 -C 7 H 8 )][BAr F 4 ] resulted in an intractable mixture of products.…”

Section: Resultsmentioning

confidence: 94%

Well-Defined Cationic Cobalt(I) Precatalyst for Olefin-Alkyne [2 + 2] Cycloaddition and Olefin-Diene Hydrovinylation Reactions: Experimental Evidence for Metallacycle Intermediates

et al. 2021

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The synthesis and characterization of the cationic cobalt(I) arene complex, [(dppf)Co(η 6 -C 7 H 8 )][BAr F 4 ] (dppf = 1,1′-bis(diphenylphosphino)ferrocene; BAr F 4 = B[(3,5-(CF 3 ) 2 )-C 6 H 3 ] 4 ) from an air-stable cobalt precursor is described. Dissolution in benzene-d 6 or tetrahydrofuran (THF) resulted in rapid arene substitution and generated [(dppf)Co(η 6 -C 6 H 6 )]-[BAr F 4 ] or [(dppf)Co(THF) 2 ][BAr F 4]. The latter compound was characterized by a combination of X-ray diffraction and magnetometry and established an S = 1 cobalt(I) derivative. The isolated bis(phosphine)cobalt complexes were evaluated as precatalysts for carbon−carbon bond-forming reactions. The [2 + 2] cycloaddition of internal alkynes and olefins was observed with cobalt precatalyst loadings of 0.25 mol % with high chemoselectivity. The catalytic method was compatible with Lewis basic functional groups, an advantage over in situ-generated catalysts that rely on excess trialkyl aluminum activators. The cationic bis(phosphine) cobalt arene complex was also an effective catalyst precursor for the hydrovinylation of isoprene with ethylene. In both C−C bondforming reactions, the corresponding cobalt(0) complex, [(dppf)Co(COD)] (COD = 1,5-cyclooctadiene), was inactive, providing strong evidence of the role of cobalt(I) during catalysis. In both catalytic reactions, deuterium crossover experiments provide experimental evidence of the role of metallacyclic intermediates during turnover.

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Ethene‐1,1‐disulfonyl Difluoride (EDSF) for SuFEx Click Chemistry: Synthesis of SuFExable 1,1‐Bissulfonylfluoride Substituted Cyclobutene Hubs

et al. 2023

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We present the synthesis of 1,1-bis(fluorosulfonyl)-2-(pyridin-1-ium-1-yl)ethan-1-ide, a bench-stable precursor to ethene-1,1-disulfonyl difluoride (EDSF). The novel SuFEx reagent, EDSF, is demonstrated in the preparation of 26 unique 1,1-bissulfonylfluoride substituted cyclobutenes via a cycloaddition reaction. The regioselective click cycloaddition reaction is rapid, straightforward, and highly efficient, enabling the generation of highly functionalized 4membered ring (4MR) carbocycles. These carbocycles are valuable structural motifs found in numerous bioactive natural products and pharmaceutically relevant small molecules. Additionally, we showcase diversification of the novel cyclobutene cores through selective Cs 2 CO 3 -activated SuFEx click chemistry between a single SÀ F group and an aryl alcohol, yielding the corresponding sulfonate ester products with high efficiency. Finally, density functional theory calculations offer mechanistic insights about the reaction pathway.

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Synthesis and biological evaluation of cis-restrained carbocyclic combretastatin A-4 analogs: Influence of the ring size and saturation on cytotoxic properties

Cited by 19 publications

References 51 publications

Cyclobutanes in Small‐Molecule Drug Candidates

Cyclobutanes in Small‐Molecule Drug Candidates

Well-Defined Cationic Cobalt(I) Precatalyst for Olefin-Alkyne [2 + 2] Cycloaddition and Olefin-Diene Hydrovinylation Reactions: Experimental Evidence for Metallacycle Intermediates

Ethene‐1,1‐disulfonyl Difluoride (EDSF) for SuFEx Click Chemistry: Synthesis of SuFExable 1,1‐Bissulfonylfluoride Substituted Cyclobutene Hubs

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