Polar 3-alkylidene-5-pivaloyloxymethyl-5′-hydroxymethyl-γ-lactones as protein kinase C ligands and antitumor agents

Kang, Jae-Hoon; Kim, Yerim; Won, Shin-Hye; Park, Song‐Kyu; Lee, Chang Woo; Kim, Hwan‐Mook; Lewin, Nancy E.; Perry, Nicholas A.; Pearce, Larry V.; Lundberg, Daniel J.; Surawski, Robert J.; Blumberg, Peter M.; Lee, Jeeyeon

doi:10.1016/j.bmcl.2009.12.058

Cited by 6 publications

(4 citation statements)

References 15 publications

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“…In addition, the Eheteroarylidenes showed better binding affinities to PKCα and RasGRP3 compared with the respective Z-isomers. DAG-lactones with polar groups in the 3-alkylidene chains were synthesized to improve water solubility [179]. In most cases, the modifications had little effect on binding affinity, and ligands with good PKCα-binding affinity (Ki = 3.2-5 nM) also showed significant antitumor activity against colon cancer and leukemia cell lines.…”

Section: Selectivity Of Dag-lactones Among C1 Domain Containing Proteinsmentioning

confidence: 99%

Current Status and Future Prospects of C1 Domain Ligands as Drug Candidates

Gennäs

Talman²,

Yli‐Kauhaluoma³

et al. 2011

CTMC

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Protein kinase C (PKC) comprises a family of ten isoforms that play roles in diverse cellular processes such as proliferation, apoptosis and differentiation. PKC isoforms respond to Gprotein coupled receptor-and receptor tyrosine kinase-signaling via binding the second messenger diacylglycerol with C1 domains. Aberrant signaling through PKC isoforms and other C1 domain-containing proteins has been implicated in several pathological disorders.Drug discovery concerning C1 domains has exploited natural products and rationally designed compounds. Currently, molecules from several classes of C1 domain-binding compounds are in clinical trials; however, still more have the potential to enter the drug development pipeline. This review gives a summary of the recent developments in C1 domain-binding compounds.

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Section: Selectivity Of Dag-lactones Among C1 Domain Containing Proteinsmentioning

confidence: 99%

Current Status and Future Prospects of C1 Domain Ligands as Drug Candidates

Gennäs

Talman²,

Yli‐Kauhaluoma³

et al. 2011

CTMC

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“…Kang et al synthesized and investigated a series of DAG-lactones with polar 3-alkylidene substituents as PKC α and antitumor agents ( Figure 17 ). The structure-activity relationships revealed that compounds 312 , 313 , and 314 with an ether side chain have high binding affinities (K i = 3–5 nM) and excellent antitumor effects on colon cancer (Colo205, GI 50 = 0.120–0.260 μg/mL) and leukemia cancer (K562, GI 50 = 0.140–0.200 μg/mL) cell lines [ 195 ].…”

Section: Biological Activities and Chemistry Of Natural And Synthementioning

confidence: 99%

“…Due to high lipophilicity of synthesized DAGLs, it was attempted to reduce the lipophilicity by incorporating more polar side substituents in the 3-alkylidene chain. DAG-lactones with polar 3-alkylidene chains were synthesized by alkylation of the protected 5,5-disubstituted γ -lactone with various polar side chains ( Scheme 69 ) [ 195 ].…”

Section: Biological Activities and Chemistry Of Natural And Synthementioning

confidence: 99%

“… Synthesis of hydroxyl and ether DAG-lactone analogs [ 195 ]. Reagents and conditions: (a) CAN, CH 3 CN–H 2 O, 0 °C; (b) (CH 3 ) 3 CCOCl, Et 3 N, DMAP, CH 2 Cl 2 ; (c) LiHMDS, CH 3 (CH 2 ) 12 CHO for 350 – 351 , RO(CH 2 )nCHO for 352 – 362 , TrO(CH 2 )nCHO for 363 – 366 , THF, −78 °C; (d) (i) MsCl, NEt 3 , CH 2 Cl 2 , (ii) DBU; (e) BCl 3 , CH 2 Cl 2 , −78 °C; (f) CF 3 CO 2 H, CH 2 Cl 2 , 0 °C.…”

Section: Figures Schemes and Tablementioning

confidence: 99%

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Natural and Synthetic Lactones Possessing Antitumor Activities

Kim

Sengupta

Sim

2021

IJMS

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Cancer is one of the leading causes of death globally, accounting for an estimated 8 million deaths each year. As a result, there have been urgent unmet medical needs to discover novel oncology drugs. Natural and synthetic lactones have a broad spectrum of biological uses including anti-tumor, anti-helminthic, anti-microbial, and anti-inflammatory activities. Particularly, several natural and synthetic lactones have emerged as anti-cancer agents over the past decades. In this review, we address natural and synthetic lactones focusing on their anti-tumor activities and synthetic routes. Moreover, we aim to highlight our journey towards chemical modification and biological evaluation of a resorcylic acid lactone, L-783277 (4). We anticipate that utilization of the natural and synthetic lactones as novel scaffolds would benefit the process of oncology drug discovery campaigns based on natural products.

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Organocatalytic Synthesis of Lactones by the Oxidation of Alkenoic Acids

et al. 2017

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Along the lines of modern sustainable oxidation, a green and mild organocatalytic synthetic procedure for the synthesis of hydroxylactones from alkenoic acids is described. The reaction includes the activation of H2O2 by an organocatalyst (2,2,2‐trifluoromethylacetophenone), the oxidation of an olefinic group to the corresponding epoxide, and intramolecular lactonization to afford a variety of substituted γ‐ or δ‐lactones with multiple substitution patterns in good to high yields. The product can be obtained with high purity after simple extraction if the conversion is quantitative. Attempts to render the process asymmetric met with limited success.

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Polar 3-alkylidene-5-pivaloyloxymethyl-5′-hydroxymethyl-γ-lactones as protein kinase C ligands and antitumor agents

Cited by 6 publications

References 15 publications

Current Status and Future Prospects of C1 Domain Ligands as Drug Candidates

Current Status and Future Prospects of C1 Domain Ligands as Drug Candidates

Natural and Synthetic Lactones Possessing Antitumor Activities

Organocatalytic Synthesis of Lactones by the Oxidation of Alkenoic Acids

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